Oxford Handbook of Rheumatology (Oxford Medical Handbooks)

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OxfordHandbookofRheumatology

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Rheumatology

FourthEdition

GavinClunie

ConsultantRheumatologistandMetabolicBonePhysician,

Addenbrooke’sHospital,Cambridge,UK

NickWilkinson

ConsultantPaediatricandAdolescentRheumatologist,

EvelinaLondonChildren’sHospital,London,UK

ElenaNikiphorou

ConsultantRheumatologist,WhittingtonHospital;

ClinicalResearcher,AcademicRheumatologyDepartment,

King’sCollegeLondon,UK

DeepakJadon

ConsultantRheumatologistandDirectorofthe

RheumatologyResearchUnit,

Addenbrooke’sHospital,Cambridge,UK

GreatClarendonStreet,Oxford,OX26DP,UnitedKingdom

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Foreword

I am pleased to introduce you to the 4th edition of the Oxford Handbook of

Rheumatology. This edition has increased in size, but continues to be just as

accessible. It presents the reader with a pragmatic approach to making a

differentialdiagnosis.Theapproachtothinkingabouthowtomakesenseofthe

history and clinical findings is clear. The common rheumatological conditions

are covered well, and the new edition incorporates relevant sections on

paediatricandadolescentrheumatology.

FromthedaysofSirWilliamOsler,theartoflisteningtoandobservingthe

patient has been a key focus of what defines a good doctor. Medicine has

advancedconsiderablysincehisday,butthecorevaluesofaphysicianhavenot

changed.

The focus on good clinical history taking and examination technique is a

reminderofthecoreskillsetthatweuseasphysicians.Whenallelsefails,go

backto thebasicprinciples,andback tothepatient.Thisbook showsushow

importantthatskillsetis.

ProfessorJaneDacreMD,PRCP

President

RoyalCollegeofPhysicians

London,UK

Preface

Rheumaticmusculoskeletalconditionsarecommonbothingeneralandhospital

practice.Musculoskeletalsymptomsareaprimaryfeatureofmanymultisystem

illnesses,not onlyintheautoimmunejointandconnective tissuediseases, but

alsometabolic,endocrine,neoplastic,andinfectiousconditions.Symptomsare

also common in the context of injury, age-related change, and psychological

distress.Manyconditionsinrheumatologyareamajorsourceofmorbidityand

mortality.

We have kept the format of the previous edition for this version but

importantly have updated the text to include paediatric and adolescent

rheumatology.

Part I remains as a guide to evaluation of rheumatic and musculoskeletal

disease from the point of referral and reflects the way clinical

problems/symptomspresenttotheclinicianinreallife.Wehaveconsideredhow

this happens for adults, and new in this version, for children and adolescents,

affected by rheumatological and musculoskeletal disease. The reader will find

detail on musculoskeletal anatomy and functional anatomy in this part of the

book.

PartIIremainsasthesectionofthebookwherethereadercanfinddisease-

specificinformation(e.g.spondyloarthritis,vasculitis,backpain,andsoon).We

have included paediatric sections in each chapter where there is relevance for

disease occurring in children and adolescents, noting the difference in disease

anditsmanagementinchildrenandadolescentscomparedwithadults.

PartIIIremainsasmedicinemanagementandcontainschaptersondrugsused

inrheumatologypractice,glucocorticoidinjectiontherapy,andrheumatological

emergencies.

Wehavetriedtoavoidduplicationbutcrossreferencebetweenchapters.We

hopethisbookishelpfulandinformativeforalldoctors,physiotherapists,and

specialistnursingpractitionerswhoarefacedwithmanagingpeopleandpatients

with undiagnosed musculoskeletal symptoms or established rheumatic

musculoskeletaldiseases.

Acknowledgements

Theauthorswouldliketoacknowledgetheworkoftheco-founderauthor-editor

of the textbook Dr Alan Hakim for his contribution, whom together with Dr

Clunie,devisedandwrotethebookfromthefirsteditionandco-author-editorDr

InamHaq(whojoinedforthe2ndand3rdeditions),inhelpingtoestablishthe

Oxford Handbook of Rheumatology as the market leader small textbook for

rheumatology.

Contents
Contributors
Symbolsandabbreviations
PartIThepresentationofrheumaticdisease
1 Evaluatingrheumatologicalandmusculoskeletalsymptoms
2 Musculoskeletalassessmentandpatternsofdisease:makingaworking
diagnosis
3 Regionalmusculoskeletalsymptoms:makingaworkingdiagnosis
4 Thespectrumofdisordersassociatedwithadultrheumaticand
musculoskeletaldiseases
PartIITheclinicalfeaturesandmanagementofrheumaticdiseases
5 Rheumatoidarthritis
6 Osteoarthritis
7 Crystal-inducedmusculoskeletaldisease
8 Thespondyloarthritidesincludingpsoriaticarthritis
9 Juvenileidiopathicarthritis
10 Systemiclupuserythematosus
11 Antiphospholipidsyndrome
12 Sjögren’ssyndrome
13 Systemicsclerosisandrelateddisorders
14 Idiopathicinflammatorymyopathiesincludingpolymyositisand
dermatomyositis
15 Primaryvasculitides
16 Metabolicbonediseases

Infectionandrheumaticdisease
Rareautoinflammatoryandmiscellaneousdiseases
Hereditarydisordersofconnectivetissue
Commonupperlimbmusculoskeletallesions
Spinaldisordersandbackpain
Chronicpainsyndromes
PartIIIMedicinemanagementandemergencies
Drugsusedinrheumatologypractice
Glucocorticoidinjectiontherapy
Rheumatologicalemergencies
Index

Contributors

DrEmmaDavies

SpecialistRegistrarinRheumatology,RoyalNationalHospitalforRheumatic

Diseases,Bath,UK

DrCatherineFairris

SpecialistRegistrarinRheumatology,RoyalNationalHospitalforRheumatic

Diseases,Bath,UK

DrShabinaHabibi

SeniorClinicalResearchFellow,RoyalNationalHospitalforRheumatic

Diseases,Bath,UK

DrPhilipHamann

PhDResearchFellow&SpecialistRegistrarinRheumatology,RoyalNational

HospitalforRheumaticDiseases,Bath,UK

DrDobrinaHull

SpecialistRegistrarinRheumatology,GuysandStThomas’HospitalNHS

FoundationTrust,London,UK

DrEiphyuHtut

SpecialistRegistrarinRheumatology,Addenbrooke’sHospital,Cambridge

UniversityHospitalsNHSFoundationTrust,Cambridge,UK

DrAnthonyIsaacs

SpecialistRegistrarinRheumatology,TheWhittingtonHospitalNHSTrust,

London,UK

DrRituMalayia

SpecialistRegistrarinRheumatology,GuysandStThomas’HospitalNHS

FoundationTrust,London,UK

DrSerainaPalmer

FellowinPaediatricRheumatology,Kinderspital,Zürich,Switzerland

DrElizabethReilly

SpecialistRegistrarinRheumatology,RoyalNationalHospitalforRheumatic

Diseases,Bath,UK

DrMalihaSheikh

SpecialistRegistrarinRheumatology,Addenbrooke’sHospital,Cambridge

UniversityHospitalsNHSFoundationTrust,Cambridge,UK

DrGiuliaVarnier

FellowinPaediatricRheumatology,EvelinaLondonChildren’sHospital,Guys

andStThomas’HospitalNHSFoundationTrust,London,UK

DrNatashaWeisz

SpecialistRegistrarinRheumatology,TheWhittingtonHospitalNHSTrust,

London,UK

DrCeeYiYong

SpecialistRegistrarinRheumatology,NorfolkandNorwichUniversityHospitals

NHSFoundationTrust,Norwich,UK

Symbolsandabbreviations

cross-reference

α alpha

β beta

↑ increased

↓ decreased

↔ normal

> greaterthan

< lessthan

~ approximately

∴ therefore

AAV ANCA-associatedvasculitis

ABA abatacept

AC adhesivecapsulitis

ACA anticentromereantibody

ACE angiotensin-convertingenzyme

AChA acrodermatitischronicumatrophicans

AC(J) acromioclavicular(joint)

ACL anticardiolipin

ACPA anticitrullinatedpeptideantibody(-ies)

ACR AmericanCollegeofRheumatology

AD autosomaldominant

ADM abductordigitiminimi

AFF atypicalfemoralfracture

AICTD autoimmuneconnectivetissuedisease

AIS autoinflammatorysyndrome

AKI acutekidneyinjury

ALNT anterolateralneospinothalamictract

ALP alkalinephosphatase

ALT alaninetransaminase

AMA amyloidA

AML amyloidL

ANA antinuclearantibody

ANCA antineutrophilcytoplasmicantibody

Anti-β2GP1 anti-β2glycoprotein-1

AOSD adult-onsetStill’sdisease

AP anteroposterior

APB abductorpollicisbrevis

APL abductorpollicislongus

APL antiphospholipid

APRIL aproliferationinducing-ligand

APS antiphospholipid(antibody)syndrome

APTT activatedpartialthromboplastintime

AR autosomalrecessive

ARA AmericanRheumatismAssociation

ARB angiotensinIIreceptorblocker

ARDS adultrespiratorydistresssyndrome

ARTEMIS AbataceptTreatmentinPolymyositisandDermatomyositistrial

AS ankylosingspondylitis

ASAS AssessmentofSpondyloarthritisInternationalSociety

AST aspartatetransaminase

ASOT antistreptolysinOtitre

ASU avocado/soybeanunsaponifiable

ATN acutetubularnecrosis

axSpA axialspondyloarthritis

AZA azathioprine

β2GP1 β2glycoprotein-1

BAFF B-cellactivatingfactor(seealsoBLyS)

BAL bronchoalveolarlavage

BCP basiccalciumphosphate(crystals)

BD Behçet’sdisease

bDMARD biologicdisease-modifyingantirheumaticdrug

BILAG BritishIslesLupusAssessmentGroup

BLyS B-lymphocytestimulator(seealsoBAFF)

BMC bonemineralcontent

BMD bonemineraldensity

BMI bodymassindex

BSR BritishSocietyofRheumatology

BVAS BirminghamVasculitisActivityScore

C cervical(e.g.C6isthesixthcervicalvertebra)

CA coracoacromial

CADM clinicallyamyopathicdermatomyositis

CAMPS CARD14-mediatedpsoriasis

CANDLE chronicatypicalneutrophilicdermatosiswithlipodystrophyand

elevatedtemperature

cAPS catastrophicantiphospholipidsyndrome

CAPS cryopyrin-associatedperiodicfeversyndromes

CARD caspaseactivationandrecruitmentdomain

CBT cognitiveandbehaviouraltherapy

CCP cycliccitrullinatedpeptide

CDAI ClinicalDiseaseActivityIndex

CHB congenitalheartblock

CHCC ChapelHillConsensusConference

CINCA chronic,infantile,neurological,cutaneous,andarticular

syndrome

CK creatinekinase

CKD chronickidneydisease

CMC(J) carpometacarpal(joint)

CMP comprehensivemetabolicpanel

CMV cytomegalovirus

CNO chronicnon-bacterialosteomyelitis

CNS centralnervoussystem

COMP cartilageoligomericmatrixprotein

COX cyclooxygenase

CPP calciumpyrophosphate

CPPD calciumpyrophosphatedeposition

CREST calcinosis,Raynaud’s,(o)esophagealdysmotility,sclerodactyly,

telangiectasia(syndrome)

CRMO chronicrecurrentmultifocalosteomyelitis

CRP C-reactiveprotein

CRPS complexregionalpainsyndrome

CS congenitalscoliosis

CSF cerebrospinalfluid

CT computedtomography

CTX collagenX-link

cTnC cardiactroponinC

cTnT cardiactroponinT

CTS carpaltunnelsyndrome

CWP chronicwidespreadpain

CXR chestradiograph

CYC cyclophosphamide

DAS DiseaseActivityScore

dcSScl diffusecutaneoussystemicsclerosis

DIC diffuseintravascularcoagulation

DILE drug-inducedlupuserythematosus

DIP(J) distalinterphalangeal(joint)

DIRA deficiencyofIL-1receptoragonist

DISH diffuseidiopathicskeletalhyperostosis

DITRA deficiencyofinterleukin36receptorantagonist

DLCO diffusioncapacityforcarbonmonoxide

DOMS delayed-onsetmuscularstrain

DM dermatomyositis

DMARD disease-modifyingantirheumaticdrug

DVT deepveinthrombosis

DXA dual-energyX-rayabsorptiometry

EA enteropathicarthritis

EANM EuropeanAssociationofNuclearMedicine

EBV Epstein–Barrvirus

ECG electrocardiogram

ECM erythemachronicummigrans

ECRB extensorcarpiradialisbrevis

ECRL extensorcarpiradialislongus

ECU extensorcarpiulnaris

ED extensordigitorum

EDL extensordigitorumlongus

EDM extensordigitiminimi

EDS Ehlers–Danlossyndrome

EED erythemaelevatumdictinum

EHL extensorhallucislongus

EI extensorindicis

EGPA eosinophilicgranulomatosisandpolyangiitis

ELISA enzyme-linkedimmunosorbentassay

ELMS Eaton–Lambertmyasthenicsyndrome

EM erythemamigrans

EMG electromyography

EN erythemanodosum

ENA extractablenuclearantigen

ENT ear,nose,andthroat

EPB extensorpollicisbrevis

EPL extensorpollicislongus

ERA enthesitis-relatedarthritis

ESR erythrocytesedimentationrate

ESSG EuropeanSpondyloarthropathyStudyGroup

EULAR EuropeanLeagueAgainstRheumatism

F female

FBC fullbloodcount

FCAS familialcoldautoinflammatorysyndrome

FCR flexorcarpiradialis

FCU flexorcarpiulnaris

FD fibrousdysplasia

FDA FoodandDrugAdministration

F-FDG

fluorine-18fluorodeoxyglucose

FDL flexordigitorumlongus

FDP flexordigitorumprofundus

FDS flexordigitorumsuperficialis

FENa fractionalexcretionofsodium

FFS Five-FactorScore

FGF fibroblastgrowthfactor

FHB flexorhallucisbrevis

FHH familialhypocalciurichypercalcaemia

FJ facetjoint

FLS FractureLiaisonService

FM fibromyalgia

FMF familialMediterraneanfever

FPL flexorpollicislongus

FR flexorretinaculum

FVSG FrenchVasculitisStudyGroup

GALS gait,arms,legs,spine(examination)

GARA gut-associatedreactivearthritis

GBS Guillain–Barrésyndrome

GC glucocorticoid

GCA giantcellarteritis

GFR glomerularfiltrationrate

GH(J) glenohumeral(joint)

GI gastrointestinal

GIO glucocorticoid-inducedosteoporosis

GLA gammalinoleicacid

GOA generalizedosteoarthritis

GORD gastro-oesophagealrefluxdisease

HA hydroxyapatite

HAQ HealthAssessmentQuestionnaire

HCQ hydroxychloroquine

HDCT hereditarydisorderofconnectivetissue

h-EDS hypermobility(type)Ehlers–Danlossyndrome

HELLP haemolysis,elevatedliverenzymes,andlowplatelets

HIDS hyperIgDsyndrome

HIV humanimmunodeficiencyvirus

HLA humanleucocyteantigen

HMG-COA 3-hydroxy-3-methyl-glutaryl-coenzymeA

HPOA hypertrophicpulmonaryosteoarthropathy

HPT hyperparathyroidism

HRT hormonereplacementtherapy

HSCT haematopoieticstemcelltransplantation

HSP Henoch–Schönleinpurpura

HUS haemolyticuraemicsyndrome

HTLV humanT-cellleukaemiavirus

IA intra-articular

IBD inflammatoryboweldisease

IBM inclusion-bodymyositis

ICD implantablecardioverterdefibrillator

IFN interferon

IgG4-RD immunoglobulinG4-relateddisease

IGRA interferongammareleaseassay

IIM idiopathicinflammatorymyopathy

IL interleukin

ILAR InternationalLeagueofAssociationsforRheumatology

ILD interstitiallungdisease

IM intramuscular(ly)

IMM idiopathicinflammatorymyopathy

INR internationalnormalizedratio

IP interphalangeal

ISCD InternationalSocietyofClinicalDensitometry

ISG InternationalStudyGroup

ISN InternationalSocietyforNephrology

ITB iliotibialband

IV intravenous(ly)

IVDU intravenousdruguser

IVIg intravenousimmunoglobulin

JAK Januskinase

JAS juvenileankylosingspondylitis

JCA juvenilechronicarthritis

JDM juveniledermatomyositis

JIA juvenileidiopathicarthritis

JIIM juvenileidiopathicinflammatoryarthritis

JIO juvenileidiopathicosteoporosis

JPM juvenilepolymyositis

JPsA juvenilepsoriaticarthritis

JRA juvenilerheumatoidarthritis

JSLE juvenilesystemiclupuserythematosus

JSpA juvenilespondyloarthritis

KD Kawasakidisease

KUB kidneyureterbladder

L lumbar(e.g.L5isthefifthlumbarvertebra)

LA lupusanticoagulant

LCL lateralcollateralligament

lcSScl limitedcutaneoussystemicsclerosis

LDA low-doseaspirin(75–150mg/day)

LDH lactatedehydrogenase

LE lupuserythematosus

LEF leflunomide

LFTs liverfunctiontests

LGL largegranularlymphocyte

LH luteinizinghormone

LHE lateralhumeralepicondylitis

LIP lymphocyticinterstitialpneumonitis

LLLT low-levellasertherapy

LMWH low-molecular-weightheparin

M male

MAA myositis-associatedautoantibodies

MAGIC mouthandgenitalulcerswithinflamedcartilage

MAS macrophageactivationsyndrome

MCL medialcollateralligament

MCP(J) metacarpophalangeal(joint)

MCTD mixedconnectivetissuedisease

MDI MyositisDiseaseIndex

MDP methylenediphosphonate

MDT multidisciplinaryteam

MEN mycophenolatemofetil

MEVK mevalonatekinase

MFS Marfansyndrome

MG myastheniagravis

MHC majorhistocompatibilitycomplex

MKD mevalonatekinasedeficiency

MMF mycophenolatemofetil

MMPI MinnesotaMultiphasicPersonalityInventory

MMT manualmuscletest

mNY modifiedNewYork

MPA microscopicpolyangiitis

MPO myeloperoxidase

MR magneticresonance

MRA magneticresonanceangiography

MRI magneticresonanceimaging

MSA myositis-specificautoantibodies

MSK musculoskeletal

MSU monosodiumurate

MTP(J) metatarsophalangeal(joint)

MTX methotrexate

MUA manipulationunderanaesthesia

MVA mevalonicaciduria

MVK mevalonatekinase

MWS Muckle–Wellssyndrome

MYOACT myositisdiseaseactivityindex

MYODAM myositisdamageindex

NAI non-accidentalinjury

NCS nerveconductionstudy

NICE NationalInstituteforHealthandCareExcellence(UK)

NLE neonatallupuserythematosus

NLRs NOD-likereceptors

NMS neuromuscularscoliosis

NO nitrousoxide

NOAC noveloralanticoagulant

NOD nucleotide-bindingoligomerizationdomain

NOMID neonatal-onsetmultisysteminflammatorydisease

NSAID non-steroidalanti-inflammatorydrug

NSF nephrogenicsystemicfibrosis

OA osteoarthritis

OI osteogenesisimperfecta

OMIN OnlineMendelianInheritanceinMan

ONFH osteonecrosisofthefemoralhead

OO osteoidosteoma

OT occupationaltherapist

PAH pulmonaryarteryhypertension

PAMPS pathogen-associatedmolecularpatterns

PAN polyarteritisnodosum

PAPA pyogenicarthritis,pyodermagangrenosum,andacne

PBC primarybiliarycirrhosis

PCR polymerasechainreaction

PDB Paget’sdiseaseofbone

PDE5 phosphodiesterasetype5

PE pulmonaryembolism

PET positronemissiontomography

PFAPA periodicfever,aphthousstomatitis,pharyngitis,adenitis

syndrome

PHP pseudohypoparathyroidism

PIN posteriorinterosseousnerve

PIP(J) proximalinterphalangeal(joint)

PL palmarislongus

PM polymyositis

PML progressivemultifocalleucoencephalopathy

PMN polymorphonuclearneutrophil

PMR polymyalgiarheumatica

PoTS posturalorthostatictachycardiasyndrome

PRR pattern-recognitionreceptor

Ps psoriasis

PsA psoriaticarthritis

PSA prostatic-specificantigen

PTH parathyroidhormone

PUO pyrexiaofunknownorigin

PV plasmaviscosity

PVNS pigmentedvillonodularsynovitis

RA rheumatoidarthritis

RAID rareautoinflammatorydisease

RAPS rivaroxabanforantiphospholipidantibodysyndrome

RCT randomizedcontrolledtrial

RD Raynaud’sdisease

ReA reactivearthritis

RF rheumatoidfactor

RhF rheumaticfever

RNA ribonucleicacid

RNP ribonuclearprotein

ROD renalosteodystrophy

RP relapsingpolychondritis

RPS RenalPathologySociety

RSD reflexsympatheticdystrophy(algo/osteodystrophy)

RSI repetitivestraininjury

PE remittingseronegativesymmetricalsynovitiswithpittingoedema

RTA renaltubularacidosis

RTX rituximab

sACE serumangiotensinconvertingenzyme

SAI subacromialimpingement

SAA serumamyloidA

SADAI SimplifiedDiseaseActivityIndex

SAPHO synovitis,acne,palmoplantarpustulosis,hyperostosis,aseptic

osteomyelitis(syndrome)

SARA sexuallyacquiredreactivearthritis

SC subcutaneous

SC(J) sternoclavicular(joint)

Scl systemicscleroderma

SCS spinalcordstimulation

SD standarddeviation

sDMARD syntheticdisease-modifyingantirheumaticdrug

SERM selectiveoestrogenreceptormodulator

SHPT secondaryhyperparathyroidism

SI(J) sacroiliac(joint)

SIP SicknessImpactProfile

SLE systemiclupuserythematosus

SLEDAI SystemicLupusErythematosusDiseaseActivityIndex

SLICC SystemicLupusInternationalCollaboratingcriteria

SNRI serotonin-norepinephrinere-uptakeinhibitors

SoJIA systemic-onsetjuvenileidiopathicarthritis

SpA spondyloarthritis

SRC sclerodermarenalcrisis

SRP signalrecognitionpeptide

SS Sjögren’ssyndrome

SScl systemicsclerosis

SSRI selectiveserotoninreuptakeinhibitor

SSZ sulfasalazine

STIR shorttauinversionrecovery

SUA serumuricacid

SUFE slippedupperfemoralepiphysis

T thoracic(e.g.T5isthefifththoracicvertebra)

TA Takayasuarteritis

TB tuberculosis

TCZ tocilizumab

TENS transcutaneouselectricalnervestimulation

TFT thyroidfunctiontest

TGF transferringgrowthfactor

TIA transientischaemicattack

TLRs Toll-likereceptors

TM(J) temporomandibular(joint)

TNFα tumournecrosisfactor(alpha)

tPA tissueplasminogenactivator

TPMT thiopurineS-methyltransferase

TRAPS tumournecrosisfactor-associatedperiodicsyndrome

TSH thyroid-stimulatinghormone

TTP thromboticthrombocytopenicpurpura

U&E ureaandelectrolytes(inUKtestincludescreatinine)

UC ulcerativecolitis

uPCR urineprotein:creatinineratio

US ultrasound

UV ultraviolet

VAS visualanaloguescale

VDI VasculitisDamageIndex

vs versus

WBC whitebloodcell

WHO WorldHealthOrganization

WRD work-relateddisorder

XLHR X-linkedhypophosphataemicrickets

PartI

Thepresentationofrheumatic

disease

Chapter1
Evaluatingrheumatologicalandmusculoskeletal
symptoms
Introduction
Musculoskeletalpaininadults
Elicitedpainonexaminationinadults
Otherpresentingsymptomsinadults
Theadultgait,arms,legs,spine(GALS)screeningexamination
Painassessmentinchildrenandadolescents
Limpandgaitconcernsinchildrenandadolescents
Pyrexia, fatigue and unexplained acute-phase response in children and
adolescents
ThepaediatricGALSscreen
Introduction
Adultsandchildrencanpresentwithmusculoskeletal(MSK),inflammatory,and
autoimmunediseasesinvariedways.Symptomscanbesimpleandfocal,suchas
regionalpain,orgeneralandnon-specific,ofteninthecontextofageneralized
processsuchasfeverorfatigue.Thefollowingareimportantpointsinassessing
thetime,type,andnatureofpresentation:
• Whysomeonehaspresentedataparticulartime.
• Whatistheimpactofsymptoms,emotionallyandfunctionally.
• The individual’s perceptions, fears, or cultural references that might modify
(amplifyorsuppress)expressionofthesymptoms.
• What fears, beliefs, and factors might present a barrier to effective medical
engagement.
• The same pathological processes might present variably at different ages:
broadlyspeaking,theyoung,adults,andtheelderly.
Inthischapter,theassessmentofsymptomshasbeenseparatedintotwoparts.

First,theassessmentofsymptomsinadultsandsecond,thepatternsofdisease

presentationinchildrenandadolescents.

Musculoskeletalpaininadults

Introduction

Themostcommonpresentingsymptomtotherheumatologistisunexplainedor

ineffectivelytreatedMSKpain.

• Painisdefinedbyitssubjectivedescription,whichmayvarydependingonits

physical(orbiological)cause,thepatient’sunderstandingofit,itsimpacton

function,andtheemotionalandbehaviouralresponseitinvokes.

• Painisparticularlypronetobe‘coloured’bycultural,linguistic,andreligious

differences.Therefore,painisnotmerelyanunpleasantsensationtomany;it

is,ineffect,an‘emotionalchange’.

• Painexperienceisdifferentforeveryindividual.

Localizationofpain

Adultsusuallylocalizepainaccurately,althoughtherearesomesituationsworth

notinginrheumaticdiseasewherepaincanbepoorlylocalized(Table1.1):

• Adults maynotclearly differentiate between periarticularand articularpain,

referringtobursitis,tendonitis,andotherformsofsofttissueinjuryas‘joint

pain’.Therefore,itisimportanttoconfirmthepreciselocationofthepainon

physicalexamination.

• Pain maybewell localizedbut causedbya distantlesion, e.g.interscapular

pain caused by mechanical problemsinthecervicalspine,or right shoulder

paincausedbyacutecholecystitis.

• Paincausedbyneurologicalabnormalities,ischaemicpain,andpainreferred

fromvisceraisharderforthepatienttovisualizeorexpress,andthehistory

maybegivenwithvariedinterpretations.

• Bone pain is generally constant despite movement or change in posture—

unlikemuscular,synovial,ligament,ortendonpain—andoftendisturbssleep.

Fracture, tumour, and metabolic bone disease are all possible causes. Such

constant,local,sleep-disturbingpainshouldalwaysbeinvestigated.

• PatternsofpaindistributionareassociatedwithcertainMSKconditions.For

example,polymyalgiarheumatica(PMR)typicallyaffectstheshouldergirdle

andhips, whereasrheumatoidarthritis (RA)affectsthe jointssymmetrically,

withapredilectionforthehandsandfeet.

• Patternsofpaindistributionmayoverlap,especiallyintheelderly,whomay

have several conditions simultaneously, e.g. hip and/or knee osteoarthritis

(OA), peripheral vascular disease, and degenerative lumbar spine all may

causelowerextremitydiscomfort.

Table1.1Clinicalpointersinconditionsinadultswherepainispoorlylocalized

Diagnosis Clinicalpointer

Periarticular

shoulderpain

Referredtodeltoidinsertion—notspecificforlesion

buttypicalinrotatorcufflesions

Carpaltunnel

syndrome

Nocturnalparaesthesiasand/orpain,oftendiffuse—

patientsoftenreportsymptomsinallfingersbut

detailedassessmentthenisneededtodisclose5th

fingersparing

Insertionalgluteus

medius

tendonitis/enthesitis

Nocturnalpainlyingonaffectedside

Hipsynovitis Groin/outerthighpainradiatingtotheknee

Thequalityofpain

Someindividualsfindithardtodescribepainorusedescriptorsofseverity.A

description of the quality of pain can often help to discriminate the cause.

Certain pain descriptors in adults are associated with non-organic pain

syndromes(Table1.2):

• Burning pain, hyperpathia (i.e. an exaggerated response to painful stimuli),

andallodynia(i.e.painfromstimulithatarenormallynotpainful)suggesta

neurologicalorcentral‘painsensitization’cause.

• Achangeinthedescriptionofpaininapatientwithalong-standingcondition

isworthnoting,sinceitmaydenotethepresenceofasecondcondition,e.g.a

fractureorsepticarthritisinapatientwithestablishedRA.

• Repeated, embellished, or elaborate descriptions (‘catastrophizing’) may

suggest non-organic pain, but be aware that such a presentation may be

cultural. Such descriptions may associate with illness behaviour in the

consultationorduringtheexamination.

Painfromtrauma/damagetotissues(‘mechanical’)inadults

Ingeneral,mechanicaldisordersareworsenedbyactivityandrelievedbyrest.

Thisdoesnotmeanpainisnotpresentatrest;inseveremechanical/degenerative

disorders,paindisturbssleep.

• A good knowledge of anatomy and functional anatomy should allow

localization of affected structures though localization of pains in young

childrencanbedifficult.

• An appreciation of secondary muscle spasm is important as such pain can

mask,toadegree,localizationofamechanicalpain,particularlyintheback.

Inflammatorymusculoskeletalpaininadults

Inflammatorylesionscausingpaintypicallydosowithorafterimmobility,such

aswhengettingoutofbedorafteralongcarjourney.

• InflammatoryMSKpainisoftendescribedwith‘stiffness’.

• Inflammatory joint pains from RA, inflammatory OA and peripheral joint

diseaseinpsoriaticarthropathy(PsA)oraxialspondyloarthritis(axSpA)can

bepresentonwakingandeasewithjointmovement.

• Anassessmentofinflammatorybackpainisakeyassessmentinayoungadult

withbackpain(painatnight,pain/stiffnessintheearlymorningeasingwith

movement; resolution or significant improvement with non-steroidal anti-

inflammatory drugs (NSAIDs); associated posterior pelvic/buttock pains of

similarqualityanddescription);axSpAneedstoberuledout.

Table1.2TermsfromtheMcGillpainscalethathelpdistinguishbetweenorganicandnon-organicpain

syndromes(adults)

Organic Non-organic

Pounding Flickering

Jumping Shooting

Pricking Lancinating(‘shooting’)

Sharp Lacerating

Pinching Crushing

Hot Searing

Tender Splitting

Nagging Torturing

Spreading Piercing

Annoying Unbearable

Tiring Exhausting

Fearful Terrifying

Tight Tearing

Elicitedpainonexaminationinadults

In adults, eliciting pain or discomfort by the use of different examination

techniquesmaybeusedtoprovidecluestothediagnosis:

• Palpationandcomparisonofactiveandpassiverangeofmotioncanbeusedto

reproduce pain and localize pathology. This requires practice and a good

knowledgeofanatomy.

• Manyoftheclassicphysicalexamsignsandmanoeuvreshaveahighdegree

ofinter-observervariability.Interpretationshouldtakeintoaccountthecontext

inwhichtheexaminationisdoneandtheeffectsofsuggestibility.

• Palpation and passive range of motion exercises are performed while the

patientisrelaxed.

• Theconceptof‘passive’movementistheassumptionthatwhenthepatientis

completelyrelaxed,themusclesandtendonsaroundthejointareremovedas

potentialsourcesofpain;intheory,passiverangeofmotionislimitedonlyby

pain at the true joint. This assumption has its own limitations, however,

especially since passive movements of the joint will still cause some

movement of the soft tissues. In some cases (e.g. shoulder rotator cuff

disease),thejointmaybepainfultomovepassivelybecauseofsubluxationor

impingementduetoamusculotendinouslesion.

• The clinician should be aware of myofascial pain when palpating

musculotendinousstructures,especiallyaroundtheneckandshoulderregions.

Myofascialpainissaidtooccurwhenthereisactivationofatriggerpointthat

elicitspaininazonestereotypicalfortheindividualmuscle.Itisoftenaching

innature.

• Trigger points are associated with palpable tender bands. It is not clear

whether trigger points are the same as the tender points characteristic of

fibromyalgia.

• Some lesions may cause pain primarily on movement and may not be

amenabletodisclosurefromstaticpalpation(e.g.enthesitis).Donotdismiss

thereportoffocalpain(orthinkofitasreferredonly)ifthereisnotenderness

at the site on static examination. Pain may only occur with tissue

function/movement.

• Local anaesthetic infiltration at the site of a painful structure is sometimes

usedtohelplocalizepathology,e.g.injectionundertheacromionmayprovide

substantial relief from a ‘shoulder impingement syndrome’. However, the

technique is reliable only if localization of the injected anaesthetic can be

guaranteed. Few, if any, rigorously controlled trials have shown it to give

specificresultsforanycondition.

• Always complete a regional MSK examination by examining the adjacent

more proximal structures/joint. Typically, patterns of pain referral extend

distally so problems at one joint can cause symptoms in the area of the

adjacentdistaljoint.

Otherpresentingsymptomsinadults

Stiffness

StiffnessisacommonpresentingsymptomofMSKrheumatologicaldisease.It

may be a manifestation of inflammation or reduced movement due to

mechanicalpathologyincludingswelling,orbeusedbyanindividualtodescribe

reducedmovementduetopain

• Stiffness is often worse after a period of rest. Short periods (<30 min) of

stiffnessthatpersistaftermobilizingisnotameaningfulobservation.Stiffness

lasting>30minandoftenseveralhoursaftermobilizingisatypicalsymptom

ofinflammatoryarthritis.

• Stiffnesscanoccurinnormaljoints.Individualstypicallyclickorcracktheir

jointstostretchthetissuesandgainrelief.

• Stiffnessmaybeamanifestation of tissue fibrosis; in tendons, for example,

fibrosismaycausenodulestoformthatintheirmostextremeleadtolocking

ortriggering.

• Swelling may arise as a result of synovitis in a joint or tendon, oedema,

cellulitis,haematomaorvaricosities,ganglia(commonaroundthewrist),tophi

(fingers,toes),cysts,ornodules(e.g.RAnodulesoverelbows,ornodulesin

fasciaasinDupuytren’sinthehand).

Swelling

• Thereportofswellinghasshowntobeunreliableinmanyinstances.Regard

‘swelling’asasignonexaminationunlessthedescriptionofitasasymptomis

convincingandthestoryhasbeenelicitedverycarefully.

• Nerve compressionor irritationcan oftenbe perceivedasswelling(thinkof

howyourlipfeels—butisn’t—afteradentalanaesthetici.e.swollen!)andcan

colourthereportingofcarpaltunnelsyndromesymptom.

Clunks,snaps,andclicks

• ‘Clicks’areoftenthefocusofsymptomreportsandcancausesomeanxiety.

However, ‘clicks’ from many different structures are not specific for

‘pathology’.

• Inducedsnapslikecrackingknucklesareusuallynoisescreatedfromthequick

expansionofgas/airwithinaconfinedspace.

• ‘Clunks’, however, may denote structural loss of integrity (e.g.

femoroacetabular impingement, multidirectional instability of shoulder in

hypermobile Ehlers–Danlos syndrome (EDS)) and are arguably then more

likelytobeassociatedwith‘pathology’comparedwith‘clicks’.

Constitutionalsymptoms

Fatigue, fevers, sweats, and excessive sweating sometimes occur with many

differentrheumatologicaldiseases.

• Itiskeytoascertainwhatismeantbyfatigue,differentiatingitfromlackof

sleep,deconditioning,orspecificmuscleweakness.

• Fatigueisexperiencedbymanypatientsinassociationwithsystemicillness,

anaemia,endocrinopathy,ormetabolicpathologybutalsofrommoreinsidious

(psychosocialinfluenced)processessuchasfrustration,stress,andanxietyor

asaconsequenceofdisturbedsleep.

• Fatigue often has to be interrogated as sometimes patients won’t report it,

thinkingitispartofageing,orbecauseoftheirstageinlife(e.g.menopause),

orbecauseoftheirworkpattern.

• Feversandsweatscan,onthefaceofit,suggestsystemicinfection,butthese

symptoms can be associated with autoimmune connective tissue diseases

particularly systemic lupus erythematosus (SLE), and in systemic vasculitis

andseverecasesofcrystal-inducedinflammatorydisease(e.g.gout).

• Flushes are often drug induced but are often used to describe generalized

vascularreactivityoraresponsetotachycardiaorothersymptoms(secondary

effects).

• Excessive sweating is associated with glucocorticoid (GC) use, generalized

inflammatory diseases such as giant cell arteritis (GCA) and autoimmune

conditions such as SLE. True hyperhidrosis is associated with acne and

SAPHO (synovitis, acne, palmoplantar pustulosis, hyperostosis, aseptic

osteomyelitis)syndrome.

Rashes

Therearemanyrheumatologicalconditionsthataremanifestinpartbyrashes.

Theassociationmaybetemporallyrelatedorseparateintimesoabroadviewof

thehistoryoftherashneedstobetaken.Thelatterisexceptionallyimportantfor

thediagnosisofpsoriasisdisease.

• Erythematous rashes occur with viral arthritis, with SLE (as urticarias) and

adult-onsetStill’sdisease(AOSD)typically.

• Acne oracneiformrashescanoccurinSAPHOsyndrome,Behçet’s disease,

andpsoriasisdisease.

• Pustulesoccurinaformofpsoriasisdisease,candenotegonococcaldiseasein

the right clinical context, and are a hallmark lesion of vasculitides (with

palpablepurpura).

• LivedoreticularisisakeyfeatureofSLEbutmostnotablyantiphospholipid

syndrome(APS).Itcanbesevereenoughtocausealocalizedvasculitis.

• A brawny, violaceous, slightly raised, confluent, skin eruption is typical of

dermatomyositis(uppertrunk,periorbital,andbacksofhandstypically).

• Psoriasisisnotoriouslyvariedanddiffersparticularlyinrelationtowhereitis.

An atlas of typical psoriasis appearances is a very useful tool in the

rheumatologyclinic.

Theadultgait,arms,legs,spine(GALS)

screeningexamination

AsanintroductiontoageneralMSKexaminationitishelpfultobefamiliarwith

the GALS screen,

 designed to quickly identify the regions of the body

functionally affected. Table 1.3 and Fig. 1.1, and Table 1.4 and Fig. 1.2

demonstratethisprocessintextandvisualformat.

Table1.4Physicalexaminationscreeningtool—gait,arms,legs,andspine(GALS)inadults

Position Observation/action Cuetopatientforactive

movements

Gait and

spine

Patient

standing

Active

(patient-

initiated)

movements

Gait:smoothmovement,arm

swing,pelvictilt,normalstride

length,abilitytoturnquickly

‘Walktotheendofthe

room,turn,andwalkback

tome’

Lumbarspine:

Lumbarforwardflexion ‘Bendforwardandtouch

yourknees/ankles/toes’

Lumbarlateralflexion ‘Placeyourhandsbyyour

side;bendtotheside

runningyourhanddown

theoutsideofyourleg

towardyourknee’

Trendelenburgtest.Ifopposite

sideofthepelvisdropsbelow

thehorizontal,suggests

weaknessofthehipabductorson

theweight-bearingleg

‘Standononeleg...now

theother’

Neck and

thoracic

spine

Patient sitting

facingyou

Active

(patient-

initiated)

movements

Neck:smoothmovement,nopain/stiffness

Forwardflexion ‘Putyourchintoyour

chest’

Sideflexion ‘Tipyourearontoyour

shoulder’

Extension ‘Tiltyourheadback’

Rotation ‘Turnyourheadontoyour

shoulder’

Thoracicspine:smoothmovement,nopain/stiffness

1)Lateralchestexpansion

2)Rotation ‘Foldyourarms,turn

bodytothe...’

Hands,

wrists,

elbows,

and

shoulders

Patient sitting

facingyou

Active

(patient-

initiated)

movements

and

palpation

Hand,wrist,finger:swelling

deformity

‘Placebothhandsoutin

front,palmsdownand

fingersstraight’

Handpronation:observepalms

andgripfunction

‘Turnthehandsover,

palmsup’—‘makeafist’

GentlysqueezetheMCPjoints

bycompressingtherowofjoints

together.Assessforpain.Feel

forwarmth.Lookforoperation

scars

‘Placepalmsofhands

togetherasiftopray,with

elbowsouttotheside’

Wristextensionandflexion ‘Withtheelbowsinthe

samepositionplacethe

handsbacktobackwith

thefingerspointingdown’

Elbows:lookfornodules,rash ‘Bendyourelbows

bringingyourhandsupto

yourshoulders’

Shoulders:

Abductionto180°

‘Raisearmssideways,up

topointattheceiling’

Rotation ‘Touchthesmallofyour

back’

Hips, knees,

andankles

Patient supine

oncouch

Passive

examination

of hips and

knees

Some active

movements

Hips:liftleg(bendedknee)andpositionupperlegvertical.

Rotatelowerleg

Knees:

Flexandextendkneefeelingthe

patellawithpalmofhandfor

‘crepitus’andwithbackofhand

forwarmth

Feelbackoftheknee,calf,and

Achillestendonforpainand

swelling

Anklesandfeet:gentlysqueeze

theMTPjointsbycompressing

theforefoot.Assessforpain.

‘Turn your ankles in a

circular motion’ ‘Now

upanddown’

‘Wiggleyourtoes’

• ThenumberinginTable1.3correspondswiththatinFig.1.1.

• Table1.4documentstheverbalcommandsrequiredinFig1.2.

The adult GALS and paediatric GALS (pGALS) examination screens are

valuable, quick assessment tools for identifying sites of major MSK

abnormalities and function before entering into a more detailed physical

examination.

The adult GALS screen is summarized in Table 1.4. The pGALS screen

(video format) is detailed at:  http://www.arthritisresearchuk.org/health-

professionals-and-students/video-resources/pgals.aspx

Table1.3Examinationinadults—generalinspection

Position Observation

Observefromthefront:

1 Neck Abnormalflexion(torticollis,effectofkyphosis)

Shoulder

Musclebulkacrossthechest,shoulderswelling,

acromioclavicularjointOA,chestdeformities

3 Elbow Full(orhyper)extension,jointswelling,nodules

4 Pelvis Level—tiltedlowerononesidemaybeleglengthdifferenceor

spinalcurvature(scoliosis)

Quadriceps

Musclebulk

6 Knee Alignment—bow-legged(varusdeformity)orknock-kneed

(valgusdeformity);swellingabovepatella(synovitis)

7 Midfoot Swelling,operationscars

Lossofmidfootarch—flatfeet

Observefromtheback:

Shoulder

Musclebulkacrossdeltoid,trapezius,andscapularmuscles

9 Spine

alignment

Scoliosis/kyphosis

10 Gluteal Musclebulk/pelvicasymmetry

11 Knee Swelling

12 Calf Musclebulk,swelling

Hindfoot

Out-turning(eversion)oftheheelassociatedwithflat-foot

Achillestendonswelling

Observefromtheside:

14 Spine

alignment

Cervical—normallordosis;dorsal/thoracic—normalkyphosis;

lumbar—normallordosis

15 Knee Excessiveextension—hypermobility

Fig.1.1Physicalexamination—generalinspection.MeasurelumbarflexionusingtheSchöbertest.With

thepatientstandingupright,makeahorizontalmarkacrossthesacraldimplesandasecondmarkoverthe

spine10cmabove.Thepatientthenbendsforwardasfaraspossible.Re-measurethedistancebetweenthe

marks.Itshouldincreasefrom10to>15cm;lesssuggestsrestriction.AdaptedfromHoughtonAR,Gray

D.(2010)Chamberlain’sSymptomsandSignsinClinicalMedicine:AnIntroductiontoMedicalDiagnosis,

13thedition.HodderArnold,London.

Fig.1.2Physicalexaminationscreeningmanoeuvres.AdaptedfromHoughtonAR,GrayD.(2010)

Chamberlain’sSymptomsandSignsinClinicalMedicine:AnIntroductiontoMedicalDiagnosis,13th

edition.HodderArnold,London.

References

1. Doherty M, Dacre P, Dieppe P, Snaith M. The ‘GALS’ locomotor screen. Ann Rheum Dis

1992;51:1165–9.

2. HakimAJ.Themusculoskeletalsystem.In:HoughtonAR,GrayD(eds),Chamberlain’sSymptomsand

SignsinClinicalMedicine,13ed.London:HodderArnold,2010.

Painassessmentinchildrenandadolescents

Introduction

Moreapparentinchildren,thanatotherages,isthatthelevelofdistressfrom

pain does not correlate well with the severity of the underlying or causative

pathology.

• Somechildrenwillcomplainlittleofpain,but‘silently’losethefunctionofa

limbduetoinflammationofajoint,muscle,orbone.

• Somechildren,perhapsfuelledbyconcernorlackofconcernofaparent,may

becomedistressedwithanessentiallynormalexamination.

• Allreportsofpainandwhatrelievespainshouldbebelieved.

• Thus, all childrenrequirethorough assessment, which here isguidedby the

ageanddevelopmentofthepatient.

Painassessmentinspecificscenarios

Thenon-orminimallyverbalchild

Intheveryyoung,orthosewithcognitiveoremotionalimpairment,thehistory

ofpainanditsimpactissoughtfromtheparentorcarerandcorrelatedwithan

astuteclinicalexaminationthatlooksfordistress.

• Parents mayvolunteer that,attimes ofdistress,sleep isdisturbed orcertain

activitiesormovementsareimpaired.

• Attentionshouldbepaidtospecificactivitiessuchasmovementofalegwhen

nappychangingorchangeinaffectwhenapartofthebodyistouched.Both

canbecarefullycorroboratedduringexaminationfeelingfor,butnottryingto

overcome, any resistance to joint movement and monitoring facial

expressions.Preciselocalizationofthe painortenderness, however, maybe

difficult.

• Babiesandtoddlersmaybebetterexaminedonaparent’slap,especiallyatthe

startoftheexamination.

Thetoddlerandschool-agedchild

• Childrenfrom<3yearsoldcanvolunteerhelpfulinformationandattemptsto

engage them in friendly discussion will provide reassurance before

examination.

• Engagement of the young child is also optimized with an appropriate

environmentthatincludesfreelyaccessibletoys,aplayspecialist,andrelaxed

parentswhofeeltheyhavebeenheard.

• Youngchildrenmightnotunderstandthewordpainandparentsmayhelpin

thechoiceoflanguage.Useofapictureorcuddlytoymayhelptolocalizethe

siteofpainandtheuseoftheFacesPainScaleisastandardtooltoindicate

pain intensity, see:  http://www.iasp-pain.org/Education/Content.aspx?

ItemNumber=1519.

• Alotofinformationcanbegainedfromwatchingachildatplaywhilehistory

taking and thereafter all children and toddlers are best approached with

confidenceandease.

• BeginningwiththepGALSas aplayfulexerciseofcopying oftenfacilitates

cooperationwiththemoreformalregionalexam(see ‘ThepaediatricGALS

screen’andalsoat http://www.arthritisresearchuk.org/health-professionals-

and-students/video-resources/pgals.aspx).

• Look, feel, and move limbs and joints with careful facial observation and

appropriate reassurance. Swelling may arise from subcutaneous tissues,

tendons, or joints, and may include oedema, lymphoedema, cellulitis, and

haematoma.

• Clicking is common and normal unless associated with a jarring or locking

movement.

• Pain at end of range of joint movement typically indicates intra-articular

pathology.

Teenagers

• Byspeakingdirectlytotheyoungperson,amoreaccurateclinicalpicturewill

beacquiredthanfromspeakingtoparentsalone.

• Direct, friendly questioning willalsohelp engage and optimize examination

andanyfutureappointment.

• Supplemental information from parents may be helpful as may any

discordancebetweenhistories.

• Where possible, teenagers should be offered to be seen on their own, with

parents included fully in the consultation thereafter. This is now considered

bestpractice.

• Explainconfidentiality,andrespectforprivacyandmodestywillalsopromote

trustandoptimizeclinicalassessment.

• Avoidnon-verbalsignalsthatappeartojudgetheindividual.

• Identify problems with sleep. Early morning wakening with pain may be

associatedwithinflammatoryormalignantconditions,whereasdifficultywith

sleepinitiationormaintenancemaybeassociatedwithchronicpain.

• In particular, insufficient sleep is associated with pain amplification and

reducedresilience.

• In a study of chest pain, only 1 in 300 patients had associated cardiac

pathologywhichwasclearlyapparentonexamination.

• Over90%ofbackpainisbenignorbiomechanicalinnature.

• Frequent associations with chronic pain include bowel, bladder, and

psychologicaldisturbances.

Limpandgaitconcernsinchildrenand

adolescents

Most cases of limp (an asymmetric gait pattern) present acutely and so are

commonlyseeninA&E/emergencyroombyanorthopaedicsurgeontoruleout

infectionandmalignancyiftherearesystemicfeatures,orPerthesdiseaseand

slippedupperfemoralepiphysis(SUFE)iftherearenosystemicfeatures.Most

cases of acute limp, however, have a preceding illness and are diagnosed as

irritable hip or transient tenosynovitis. Subacute or long-standing limp or

concernsaboutgaitmaypresenttorheumatologists.

Age-specificassessment

Toddlersandpre-schoolchildren

• Review the child with reference to normal development and spend time

observingthegait,firstnotingnormalvariants(see pp.37–39).

• Enquireaboutageofonset(whenonsetisatthetimeoffirstwalking,consider

developmentalhipdysplasia).

• Noteanyprecedingillnessortrauma.

• Takecarenottosimplyascribelimptotraumainthepresenceofotherfeatures

andifthehistoryisincongruent,considernon-accidentalinjury(NAI)history.

• Immunosuppressionmaymasksepsis.

• Morningstiffnessistypicalofjuvenileidiopathicarthritis(JIA).

• Carefullyobservefootpositionwhenthechildiswalkingforfootandankle

involvementinJIA.

• Consider that referred pain from the abdomen or groin may be present and

avoidasimplefocusonthehip.

• Weaknesspredominatesinneuromuscularconditionsandtheremayhavebeen

sloworevenlossofgrossmotormilestones.

• Localizing pain or tenderness may be difficult for young children and the

youngchildshouldbeassessedaspreviouslydescribedforpain.

• Thesolesofthefeetshouldbeexamined.

School-agedchildrenandadolescents

• An insidious onset of limp is typical of Perthes disease and JIA, the latter

havingassociatedstiffnessafterprolongedrest.

• Otherosteochondrosesshouldalsobeconsidered(see Table16.11).

• Association with exercise and evening predominance is typical of

biomechanicalconditions.

• New-onset limp in adolescents raises concerns for chronic SUFE or bone

tumour.

• Hip restriction or pain at the limits of internal or external rotation requires

furtherinvestigation.

Pyrexia,fatigue,andunexplainedacute-phase

responseinchildrenandadolescents

Feverandpyrexiaofunknownorigin(PUO)

• Persistent or intermittent low-grade fever especially when associated with

failure to gain or loss of weight will raise suspicion of malignancy and

multisystemdisease,suchasSLE.

• Documentingtheperiodicityoffevermaybehelpful.

• AsubacutefeverorPUO(intermittentorpersistentfever>38°Cfor>3weeks)

may indicate contact with infectious diseases, travel, tick bite exposure,

medication use (‘drug fever’), and sexually acquired infection (in an

adolescent).

• A full systems enquiry should be backed up by a detailed examination

includingnailfoldcapillaries,lymphnodeassessment,fundoscopy,andcardiac

auscultation.

• ‘Phonephotos(takenbythechild,adolescent,orparent)ofrashescanhelpin

the assessment of relapsing–remitting rashes and ultimately as a record to

sharewithotherprofessionals,suchasadermatologist.

Unexplainedacute-phaseresponse

• An unexplained erythrocyte sedimentation rate (ESR) >15 mm/min has a

differentialdiagnosissimilartothatoffever/PUOandacompletehistoryand

examinationisrequired.

• Persistentincrease(over6–12weeks)inplateletcountandC-reactiveprotein

(CRP)increasesthelikelihoodofaninflammatorydiseasebeingfound.

• Biopsy of any suspected lesion can be helpful and whole-body magnetic

resonanceimaging(MRI)canbeahelpfulscreenformalignancyortolocate

sourcesoflocalizedinflammation.

• Other causes include renal disease especially when there is azotaemia,

multiple myeloma, and anaemia of chronic disease associated with iron

deficiency.

Fatigue

• Itisunclearfromwhatagechildrenreportnegativeexperiencesofgeneralized

exhaustion, which as in adults may accompany any illness, but it may be

reportedbyparentsasapresentingsymptom.

• Itiskeytoascertainwhatismeantbyfatigue,differentiatingitfromlackof

sleep,deconditioning,orspecificmuscleweakness.

• Itisimportanttounderstandspecificconcernsoftheparent(e.g.asenseofnot

beinglistenedto).

• Otherenquiriesshouldincludedetailsabouttheonsetoffatigue,medication,

andappetite.

• A full systems enquiry may raise suspicion of active inflammation;

malignancy; endocrine disorder; distress from pain, bowel, or bladder

dysfunction;skinsensitivities;andotherfunctionaldisorders.

• Investigations are usually directed by suspicion of any underlying disorder,

but, as in pain assessment, care should be taken to avoid unnecessary or

endless investigations that prevent effective engagement in a management

plan.

• Simplescreeningtestsincludeinflammatorymarkers,fullbloodcount(FBC),

thyroidfunction,andantinuclearantibody(ANA).

ThepaediatricGALSscreen

The adult GALS MSK disease screening examination has been modified to a

paediatricform(pGALS)tofacilitateengagementofpatientsasyoungas2years

and to account for subtleties in joint restriction of joints typically involved in

JIA.

• Limbs should be adequately exposed to permit full examination and the

pGALSisdemonstratedbythedoctorfacingthepatientandencouragingthem

tocopy.Inthisway,afullscreeningjointexaminationcanbeplayedoutasa

game without touching the patient initially, thereby building rapport and

patientconfidence.

• Gaitexaminationisdiscussedindetailin pp.37–39.

• Supplementaltoneckexaminationisrangeofmotionandasymmetryofjaw

opening.Temporomandibularjointmovementshouldallowthreefingersofthe

patient’shandtobeheldverticallyintheiropenmouth.

• JointmovementrestrictionisasignofdiseaseactivityinJIAconditions.Asa

result,whereJIAissuspected,increasedattentionshouldbepaidtoflexionat

allfingerjoints,extensionoftheelbow,andinversionandeversionofthefoot,

checkingsubtalarandmidfootjoints.

• A full demonstration of pGALS can be found at

http://www.arthritisresearchuk.org/health-professionals-and-students/video-

resources/pgals.aspx

Chapter2

Musculoskeletalassessmentandpatternsof

disease:makingaworkingdiagnosis

Introduction

Musculoskeletal(MSK)featuresnottobemissed

Assessmentofchildrenandadolescents

AssessmentofpatternsofMSKfeaturesinadults

Introduction

• Whenevaluatingaperson—childoradult—withfocalorwidespreadpain,itis

importanttoconsiderthatthepainmaybederivedfromjoints.Sometimesit

won’t be obvious. MSK pain may arise from joints (disease of synovium,

cartilage, or bone) but also entheses, tendons, muscles, or a combination of

structures,orcanbereferredfromsitetosite(usuallyfromproximaltodistal),

or can be associated with/secondary to neurogenic lesions. Patterns of

presentationofpaincanbeusefulpointerstodiagnosis.

• Morethanoneinfivegeneralpractitioner(GP)consultationsareforpatients

with MSK problems, with osteoarthritis (OA) the most common cause of

chronicpainandrestrictedactivityintheover50s.

• MSKpainisthepresentingsymptomin6–13%ofconsultationsinpaediatric

primarycarewith additionalconsultationsfor concernsaboutgait, swelling,

andweakness.

• MSKpaininthepaediatricpopulationiscommonanditsprevalenceincreases

withage.Chronicseverepain,lasting>3monthsandaffectingqualityoflife,

iscommontoo,withaprevalenceofupto16%insecondaryschool-agedgirls.

• The majority of causes (>80%) of MSK pains are self-limiting and have

minimalimpactonqualityoflife.Inthisrespect,painisnotasensitivemarker

of disease yet it is still important to provide reassurance to avoid symptom

amplificationandprolongeddisability.

• Butalso,MSKpaincanbeapresentingfeatureofconditionsnottobemissed

and other long-term conditions that may result in tissue damage or

significantlyaffectparticipationandqualityoflife.

• The challenge is to understand pain in the context of other symptoms and

signs.Manydiagnosescanbemadewithoutinvestigations.

• Tocategorizetheapproachtoassessment,wehavesubclassifiedthepatterns

ofpain/diseaseinto:

• features/conditionsnottobemissed.

• normalvariants.

• inflammatoryarthritis.

• non-inflammatoryMSKpain.

• To helpinthe assessmentofinflammatory arthritis,wehave categorizedby

age, numberofjoints,and by joint number. Although not the convention in

paediatrics, we have taken a threshold of 3 joints to define multi-articular

involvement:

• mono/oligoarticulararthritisinchildren(1–2joints).

• monoarthritisinadults.

• oligoarthritisinadults.

• poly-articulararthritisinchildren(≥3joints).

• poly-articulararthritisinadults.

• arthritisandsystemicfeatures(childrenandadolescents).

• Widespreadpainsarealsothepresentingfeatureofchronicpainsyndromes.

Musculoskeletal(MSK)featuresnottobemissed

(thatmaybeindicativeofseriousdisease)

Generalconsiderations

AmongthemanyMSK,inflammatory,andautoimmunediseasesthatpresentto

rheumatologists, some require prompt intervention including life-threatening

conditions: cancer, infection, and non-accidental injury (NAI) in children and

vulnerable adults (Box 2.1). Complex regional pain syndrome (CRPS) is

includedhereduetothelevelofassociatedincapacitationandearlyintervention

beingessential.

Box2.1Conditions‘nottobemissed’inchildrenandadolescents

Keyfeaturesthatmayindicatetheseconditionsincludesystemicsymptoms,a

historyoftraumathatdoesnotadequatelyexplainexaminationfindings,focal

unexplainedbonepainandtendernesslastingmorethanafewweeks,andin

childrenmarkeddisabilityorlossofdevelopmentalmilestones.

• Septicarthritis,osteomyelitis

• Acutelymphoblasticleukaemia,lymphoma

• Bonetumours(e.g.sarcoma)

• Neuroblastomainchildren

• NAI

• CRPS.

• Unexplainedandpersistentfocalpainandbonytendernessinchildrenisa‘red

flag’. Such pain lasting more than 2 weeks raises the suspicion of bone

cancers.

• ‘Focal’meansabletoclearlypointtothesiteofbonepainortendernessandis

often associated with a limp or disability, and where the pain cannot be

explainedbyosteochondroses,trauma,orinfection.

• Inchildren,bonecancersaretypicallyassociatedwithweightlossandfatigue.

Earlymetastasizationisassociatedwithincreasedmortalitynecessitatingearly

recognition.

Keyfeatureswhichshouldtriggerreferralforfurtherassessmentin

childrenandadolescents

• Limp(seealso ‘Assessmentofthelimpingchild’pp.37–39).

• Persistentlocalized(unilateral)painthroughthenight.

• Jointrestrictionorpersistentjointswelling.

• Impairedfunctionalability.

• Schoolabsenceorteacherconcern.

• Morning symptomsunexplainedby the previousday activities andtiredness

afterdisturbedsleep.

• Widespreadpain.

• Worryingthoughtsoranxietyofthepatientorparent.

• Systemic features such as fever, malaise, anorexia, weight loss, rash, raised

acute-phase response and abnormal growth or development. For example,

thesefeaturesmightleadtodisclosureof:

• septic arthritis or osteomyelitis (high fever, hot and tender joint, or limb

pain).

• leukaemia, lymphoma neuroblastoma, lupus, or vasculitis (persistent >2

weeksoflow-gradefevertypicallyassociatedwitharash).

• Kawasakidisease(highspikingfeverinunder6swithlimbpains).

• multisysteminflammatorydisorders.

• reactivearthritis.

• chronic infections including tuberculosis (TB) (travel history and contact

tracingisimportant).

• other reactive illnesseswith or without clearinfection (e.g. Lyme disease,

Streptococcus, Henoch–Schönlein purpura (HSP)); in all of these, the

presenceofrashmaybeindicativeofdiagnosis.

• Ahistoryoftraumaincongruentwithexamfindingscouldbeconsistentwith

NAIorCRPS.InNAI,themechanismofinjurymaynotexplainitsextentor

severity, and should be discussed with a paediatrician or lead clinician. In

CRPS,thereisfrequentlyahistoryofminortrauma.

• Reportedlossofmilestones.

• Loss of peer or social contact or significant reduction in physical activity.

These changes should not be dismissed as behavioural or anxiety induced

(whether parent or child) without plans for a timely review of resolution or

progression.

• Suspicion of neuromuscular disease. The onset of muscular dystrophies,

congenitalandmetabolicmyopathies,andneuropathiesareofteninsidiousin

onset.Muscleweakness,musclefatigue,numbness,anddelayeddevelopment

predominatebutmaybeassociatedwithwidespreadorfocalpainthatisthe

presentingfeature.

• Suspected problems with pain processing. Notably CRPS, juvenile

fibromyalgia,andsensoryintegration-autisticspectrumandanxietydisorders

can be associated with very high levels of disability due to altered pain

processing.Therecanbecompleteschoolabsenceandgrosslyabnormalsleep

routinesattributedtopain.

• Hypermobility with widespread pain. Hypermobility does not indicate the

causeofthepain.Caremustbetakenwhenusingtheterm‘hypermobility’as

it can be perceived as disabling with a poor outcome. The cause of pain is

often complex, but with effective communication and a range of integrated

strategies that includes a focus on self-management and resilience, the

outcomewillbeexcellentwithfullparticipationinanormalqualityoflife.

• Inconsideringtheabove-listedfeatures,whichshouldpromptfurtherreferral,

thereareotherkeypointswhichmaybehelpfulintheassessment:

• Attributingpaintonon-specifictraumaorsprainorinternaldisruptionofthe

jointcanbereassessedafter2–3weekstoseeifithasresolved.

• Arthritis is commonly associated with persistent and prolonged morning

stiffnessandjointrestriction.Painisnotamajorfeatureandanyreportof

jointswellingunreliable.

• Bonelesionsareindicatedbypainandfocaltendernessoftenwithconsistent

symptomsatnight.Painisoftenintense(e.g.osteoidosteomaorleukaemia

withmarrowinvolvement).

• Pain from muscle lesions localize well to the affected muscle. Functional

weakness,notattributabletofearofmovementfrompain,maybeindicated

bywalkingontiptoesanddifficultiesclimbingstairs,andputtingonT-shirts

orjumpers.

• Lesionsfromligaments,tendons,andenthesesmaybedifficulttoestablish

duetothesymptomstheycausecoexistingwithsymptomsfromassociated

muscleandbonelesions.

• Focal tenderness may be revealing, particularly at entheses including the

heel,patella,anteriorsuperioriliacspine,andplantarfascia.

• Entheseal and ligamentous pain can be intense and often seemingly

disproportionatetoexaminationfindings.

• Weight falling across centiles or unexplained weight loss >5% in an

adolescentneedsdetailedassessment.

Keyfeaturestoidentifypromptingfurtherurgentrheumatological

assessment—adults

For non-rheumatologists, generally the more systemic features present

associatedwithMSKsymptoms,themoretheneedtoobtainurgentassessment:

• Fevers and sweats canindicatesinister disease but candenoteinfection and

bothautoinflammatoryandautoimmunedisease.

• Feverandsweatscanaccompanyseveregoutorvasculitis,includingGCAin

theelderly.

• Arthralgiasandmyalgiascanbepartofaparaneoplasticsyndrome—however,

featuresarenotspecificandtheconditionisrare.

• Most rheumatologists would consider obtaining an extensive panel of lab

investigationsandchestX-ray(CXR)inpatientswithsevereMSKsymptoms

andsystemicfeatures.

• Systemic features in the context of a positive ANA require that a thorough

examination is done and urinalysis obtained to rule out renal disease

associatedwithSLE.

• Severepainandswellinginajointwithorwithoutsystemicfeaturesrequires

prompt assessment, and aspiration of fluid from the joint for Gram stain,

culture,andpolarizedlightmicroscopy(?crystals).

• Incipient cord compression can present with progressive stiffness and limb

weaknesswithoutpain.Such‘neurological’stiffnessreportedasasymptom,is

amimicofstiffnessfromsymptomsassociatedwithperipheralMSKlesions.

Keyfeaturesnecessitatingtimelyrheumatologicalreferral—adults

ManyhealthcaresystemsdooperateabasicMSKserviceinprimarycaresetting

tosupportprimarycaredoctorsinmanagingtheextensiveamountbenign/self-

limiting of MSK disease seen. However, all systems sensibly require triage

processestopromptlyidentifypatientsthatrequirepromptonwardreferraltoa

rheumatologist:

• Keysymptomstoidentifyandwhy:

• Multiple small joint pain/stiffness—might be RA which requires early

treatmenttoreducepermanentjointdamageanddisability.

• Inflammatorybackpain(see Chapter8)—whichcanpredictthepresence

ofaxSpA/AS.

• SystemicsymptomspluspositiveANAmightbeanautoimmuneconnective

tissue disease (e.g. SLE) which can in some patients cause serious organ

disease.

• Severe unexplained temporal head pain and/or scalp sensitivity and/or

amaurosisfugaxwithhighCRPorESR—mightbeGCAandrequireprompt

steroidtreatment.

• Apragmaticwayofscreeningforinflammatorysmalljointarthritishasbeen

adopted as an educational initiative by The UK Royal College of General

Practitioners.The3‘Ss’:Stiffness,Swelling,andapositiveSqueezetest(pain

elicitedbysqueezingtheknuckles).

• Insidious cord compression can present with progressive stiffness and limb

weakness without pain. Such ‘neurological’ stiffness is a mimic of ‘MSK’

stiffness.

• Goutandsepticarthritiscanlookexactlythesame—soaspirate!

• Polymyalgiarheumatica(PMR)-typesymptomscanbethepredominanttype

of MSK symptomology in a number of conditions including pyrophosphate

arthritis,psoriasis-relatedMSK disease,axSpA,and autoimmune connective

tissuediseases.AwiseGPconsiderstheconditionasymptom-complexwhich

mayhaveanunderlyingdiseaseexplanation.

Assessmentofchildrenandadolescents

Normalvariants

Effective reassurance that a child has a normal variant avoids unnecessary

referral,investigation,andintervention.SeeTable2.1.

Table2.1NormalMSKvariationinchildrenandadolescents

Normal Prevalence Notes

variant

Genuvarum

(bowlegs)

Verycommon<2yrsold IfprogressiveconsiderBlount’s

disease,rickets,skeletaldysplasia

Genu

valgum

(knock

knees)

Physiological4–7yrs;

andasamildconditionis

commonthereafter

Referifintermalleolardistance>8

cm,unilateral,gaitismodified,

deteriorating,ornewonsetin

adulthood

In-

toeing/out-

toeing

Commoninunder5s Usuallyresolvesby9yrs.Causes

includemetatarsusadductus,

femoralanteversion,andtibial

torsion.Refer>9yrsifgait

affected

Toewalking 7–24%ofchildren

(especiallyinautistic

spectrumdisorder)

Usuallyresolvesby3yrs.If

obligate,newonset,progressive,or

unilateralconsiderneuromuscular

andorthopaedicdisorders

Femoral

anteversion

Common4–7yrs Presentsasin-toeingand

occasionallylimbpain.Rarely

requiressurgicalintervention

Hypermobile

hands

Verycommon<5yrs.At

13yrsispresentin30%

boys,46%girls

Noclearassociationwithpain.

Maybeassociatedwith

developmentandcoordination

delayneedingwritingsupport

Hypermobile

knees

Common<5yrs.Affects

8–11%atage13yrs

Maybeassociatedwith

patellofemoralpainandassociated

biomechanicalimbalance

Flatfeet(pes

planus)

Universalinitially.

Affects>40%atages3–

6yrsand1in7adults.

Longitudinalarch

developsat3–5yrs

Shoeinsertsstabilizebutdonot

correctthefoot.Exerciseswill

addressbiomechanicalpain.Rigid

flatfootindicatesboneorneural

problem

Higharch

(pescavus)

Affects10%ofthe

population

Assessbiomechanicsandfor

neuromusculardisorderif

progressiveorconcern.Consider

spinaltumourifunilateral

Benign

nocturnal

limbpainof

childhood

Commoninchildren3–12

yrs.Peaksatage6yrs.

Occursinupto40%

under5s

Furtherassessmentifassociated

withdisability,focaltenderness,

systemicfeatures,significant

morningstiffness,swelling,

erythema,weakness

Inflammatoryarthritisinchildrenandadolescents

Thekeyfeaturesofrecognizinginflammatoryarthritisare:

• Consistentmorningstiffnesslasting>30min.

• Swellingwithjointrestriction.

• Associatedmuscleatrophy

• Involvementof>1–2joints(seeTable2.2).

Table2.2Typicalpatternsofjointinvolvementinthevariousinflammatoryjuvenileconditions

1–2

joints

≥3

joints

SepticarthritisincludingTB xx

JIA xx xx

Reactive/viralarthritis xx x

Post-streptococcalarthritis xx x

Rheumaticfever x

Inflammatoryboweldisease(IBD)-relatedarthritis x x

Henoch–Schönleinpurpura(HSP) x x

Haemophilia x

Lymedisease x

Foreignbodysynovitis x

Malignancy x x

Autoinflammatorydisease(e.g.familialMediterranean

fever(FMF))

x x

Multisystemautoimmunedisease x

Pigmentedvillonodularsynovitis(PVNS) x

Chronicrecurrentmultifocalosteomyelitis(CRMO) x x

Sarcoid x x

Non-inflammatoryconditions x

Infectiousfeatures

• Thefeaturesofareactivearthritismayincludeprecedingsymptomsofaviral

infectionsuchascoryzaornon-specificrash.

• Otherviralfeatures include‘slappedcheek’of parvovirus,awidespread and

facialmacularrashofrubella, andsorethroatof mumps,althoughtheseare

rarely seen due to vaccination. In this respect, a vaccination history is

required.

• Vaccinations may be associated with arthralgia and myalgia but are not

associatedwiththedevelopmentofJIA.

• A non-SpA reactive arthritis is usually short lived, typically 3–6 weeks in

duration although may be up to 8 weeks. However, a uniphasic reactive

arthritisinachildwhoishumanleucocyteantigen(HLA)-B27positive(with

related features such as conjunctivitis, urethritis, psoriasiform rash) may be

considerablylonger.Inthissituation,thereistypicallyahistoryofdiarrhoeain

children.

• Associateddiarrhoea,especiallybloodydiarrhoeaandafever,shouldalertto

entericorganismssuchasShigella,Yersinia,Campylobacter,andSalmonella,

whichmaybeculturedfromthestool.

• EscherichiacoliandClostridiumdifficilearealsoknowntotriggerareactive

arthritis.

• Post-streptococcal arthritis is typically associated with a sore throat without

cough and a very painful, marginally swollen, often flitting polyarthritis.

Mucocutaneous features may include rash of scarlet fever and strawberry

tongue.

• Acuterheumaticfever(RhF)shouldalsobeconsideredwiththeabove-listed

features (see  Chapter 17) and additional clinical features may include

erythema marginatum, skin nodules, a pericardial rub or new-onset murmur

(andprolongedECGPRinterval),andchorea.

• In moderate- to high-risk incidence populations there are newly revised

internationalguidelinesforthediagnosisofRhF(2015StatementofAmerican

HeartAssociation).LowriskisanincidenceofRhF<2per100,000school-

aged children or all-age prevalence of rheumatic heart disease <1 per 1000.

New criteria include echocardiographic and Doppler findings and

monoarthritisandpolyarthralgiaasmajorcriteria.

Historyoftrauma

• Trauma is common and often the event that draws attention to an already

swollenjoint.

• Haemarthrosis from internal joint disruption or periarticular swelling from

quadricepscontusionortearoccurswithin2hoursoftrauma.

• Traumamayincludeapenetratinginjurywithapunctumfromablackthornor

similarforeignbody.

• A mechanism of injury incongruous with examination findings may raise

suspicionofNAIorCRPS(see Chapter22).

Systemsenquiryandpastmedicalhistory

• May indicate features of coeliac or IBD or raise suspicion of multisystem

inflammatorydisorderssuchasSLEorvasculitis.

• Other conditions associated with an increasedriskofarthritis include cystic

fibrosis,coeliacdisease,Down’ssyndrome,andothergeneticconditions.

Familyhistory

• EnquireaboutarthritidesincludingaxSpA/ASandrelatedconditionssuchas

IBD,psoriasis,andpreviousiritis.

• Patients may volunteer haemophilia, FMF, SLE, and other autoimmune

diseases.

• The familyhistoryis also veryhelpfulin raising parentalorpatient worries

about cancer or perceptions about arthritis or joint pains as witnessed in an

older family member who may have RA, osteoarthritis, or fibromyalgia or

otherconditions.

Travelhistoryandinfectiouscontacts

• Previous travel history may raise suspicion of TB, Salmonella, and other

entericorganisms.

• Travel history should incorporate enquiry about unusual infections such as

brucellosisandleishmaniosisfromendemicareas.Enquiryaboutconsumption

ofunpasteurizedmilkproductsmaybehelpful.

• Insectbitesandcontactwithticsincludingtraveltoendemicruralareasmay

leadtoconsiderationofLymedisease(see Chapter17)andotherconditions.

• Scratches from a cat and associated lymphadenitis or lymphangina is

suggestiveofBartonellainfection.

Responsetomedication

• Theoutcomeofmedicationusecanbeviewedasa‘test’initself.Resultsof

the‘test’willhelpguidefuturemanagement.

• Failure to respond to intra-articular steroids can raise the suspicion of

undiagnosedTBandPVNS.

Examination

• Routine examination should include height and weight and a well-practised

paediatricpGALS(see Chapter1).

• Observethechildatplayfirstandrespecttheprivacyofadolescents.

• Beattentiveofandreassuringaboutpainfulmovements.

• pGALSisaquick,excellentscreeningtoolforjointrestriction,oftenkeyto

finding multiple joint involvement when just 1 or 2 joints were initially

suspected.Itisalsoavaluableandplayfulwayofengagingayoungerchildin

examinationwithouttouchingthechildandavoidingdistress.

• Evensubtledifferencesinrangeofmotionmaysignifysynovialthickening.

• Anydoubtaboutthepresenceofsynovitiscanbeaddressedwithultrasound

(orMRI,asdirectedlaterinthissection).

RegionalMSKexamination

• Subsequent assessmentshould includecomparisonof bothsides,assessment

formusclewasting,scars,deformity,tenosynovitis,enthesitis,andspinaland

hipdisease.

• Muscle wasting, a clear sign of chronicity, typically affects vastus medialis

withkneeinvolvementand calfwithankleinvolvement.Upperlimbmuscle

wastingisusuallylessprominentthaninadults.

• Tenosynovitis is more commonly seen around the ankle, but may be

mechanical in origin rather than inflammatory. It is not associated with any

specificsubtypeofJIA.

• Involvementofthetendonsofthehandmayresultintriggerfinger.

• Enthesitis discriminates enthesitis-related arthritis from other forms of JIA;

areasoftendernessincludeAchilles’insertion,patellartendon,attachmentof

quadsandhamstringstopelvis,andplantarfascia.

• Examination of the spine should include the Schöber test of spinal drift in

enthesitis-related arthritis (ERA; see  Chapter 9) and distraction of the

sacroiliac joints (with four quadrant test) to illicit any discomfort of these

joints.

Characteristicrashes

• Psoriasisandassociatednailpits(see Chapter8).

• PalmarpustulosisandacneofSAPHO(see Chapter8).

• Henoch–Schönleinpurpura(HSP;see Chapter18).

• ErythemachronicummigransofLymedisease(see Chapter17).

• Erythemamarginatum.

• Erythema nodosum of vasculitis and sarcoid (see  Chapters 15 and 18,

respectively).

• Lipodystrophyand/orskinthickeningwithpinkhaloinscleroderma.

• Othervasculiticrashesespeciallyinvolvingthepalmorfingertips.

• Nailbedcapillarychangesofsystemicsclerosis(SScl),SLE,andautoimmune

overlapconditions.

Investigations:imaging

Itisrecommendedthatimagingshouldbediscussedwitharadiologistwhenever

possible:

• Ultrasound(US)canbehelpfulwhenexamfindingsareequivocal.

• But US is associated with a high false-negative rate in routine clinical

situationsespeciallyforfeet,ankles,andsmalljointsofthehand.

• UScanpickupearlyerosionsthatmayguidechangesinmedication.

• MRI may be less available or immediate but is better for demonstrating

chondral changes and bone and entheseal oedema. It has a very low false-

negativerateforsynovitisandlowfalse-positiveratewhenusinggadolinium

enhancement.

• MRI is the investigationofchoicefor pelvic and spinal assessmentandhas

characteristicfindingsforPVNS.

• Radiographscanbehelpfulwhensuspiciousofskeletaldysplasiaormetabolic

bone disease (including rickets and scurvy) and for assessing bone

mineralization.

• Radiographs may also demonstrate periarticular osteopenia, erosions, and

loosebodies ofosteochondritis althoughUS isthepreferredinvestigationin

thiscircumstance.

• DXA scanning grades bone mass (BMD) against average expected but data

needs adjustment for bone growth and pubertal changes (bone mineral

apparentdensity(BMAD)).Anumberofapproachestodatacorrectionexist,

butshouldbeinterpretedwithcaution.

• When malignancy or infection is suspected, a whole-body MRI (+fat

suppression sequences) may be helpful, and has replaced bone scintigraphy

andfluorine-18fluorodeoxyglucose(

FDG)positronemissiontomography–

computedtomography(PET-CT)scans,whichimparthighradiation.

• Whole-body MRI is also used when non-bacterial osteomyelitis (including

CRMO and SAPHO (see  Chapter 18 and Chapter 8, respectively) is

suspected.

Laboratorytests

• Autoimmune serology is helpful in multisystem inflammatory disorders but

nottypicallyinJIA,forwhichtherearenodiagnostictests.

• ANAisnotdiagnostic.Itisnowconsideredariskfactorforuveitisalthough

eyeinflammationstilloccursinthosewhoareANAnegative.Furtherresearch

intothevalueoftestingANAisongoing.

• ESRandFBCmaybenormalinactiveJIA.

• Thrombocytosisiscommoninmostinflammatoryconditionsandcanbevery

highinsystemic-onsetJIA,alongwithneutrophilia.

• Platelet and lymphocyte counts are commonly low in juvenile SLE and

antiphospholipidsyndrome.

• A low platelet and neutrophil count in the presence of raised inflammatory

markersandarthritismayindicatemalignancy.

• A high neutrophil count—especially with ‘bands’ on film inspection—may

indicateinfection.

• Interpretation of antistreptolysin O titre (ASOT) can be difficult. The most

reliableclinicalfeatureforstreptococcalinfectionissorethroatwithoutcough.

Serial ASOT are required and combined measurement of anti-streptococcal

DNAseBandstreptozymemaybehelpful.

• Rheumatoidfactor(RF)-positivepolyarticularJIAoccursin<5%ofJIAand

has a characteristic symmetrical appearance. RF should not be considered a

routinetestandismorelikelytobemisinterpretedwhenfalselypositive.

• Lyme serology should only be requested in keeping with Lyme disease

diagnosticguidelines(see Chapter17).

• ForsuspectedTB,interferon-γassays(IGRA),CXR,andMantouxtestsare

importantifsynovialaspirationforcultureisnotdone.

Jointaspirationandsynovialbiopsy

Care should be taken to avoid psychological trauma when undertaking this

procedureasitmayleadtolossoftrustandfutureproblemswithvenesection,

routineexamination,aswellasrepeatsteroidinjection.

• Joint injections may be done under general anaesthesia or with the aid of

inhaledagentssuchasEntonox

• Joint aspirationforGram stain andcultureis the investigationofchoice for

septicarthritisandwhenconsideringTBsynovitis.

• Insomecentres,synovialfluidcelldifferentialscanbedeterminedwhichmay

behelpfulindifferentiatingbetweenlow-gradesepsisandautoimmunity.

• Bloody taps are common but if the blood runs through the whole of the

sample,haemarthrosisshouldbeconsideredandmaybeattributabletotrauma,

bleedingdiathesis,PVNS,orhaemangioma.

• Crystal arthropathy is very rare in children and adolescents and is not a

commonpresentationofhyperuricaemia.

• Synovial biopsy is helpful when considering PVNS, sarcoid, chronic

infections,andmalignancy.Arthroscopicbiopsyhasahigheryieldthanneedle

biopsy.

Assessmentofgaitandthelimpingchild

The normal gait is a complex automatic process that in a child requires

developmentofmuscles,bones,joints,andligamentseffectivelycontrolledand

coordinatedbytheneurologicalsystem.Imbalancesinanyofthisprocesswill

leadtoproblemsbutingeneral,adelayedgaitisusuallyattributabletoslower

cephalocaudal myelinization of normal development. It is inappropriate to

ascribe hypermobility or hypotonia to this delay or related problems with

balanceandcoordination.Slowerdevelopmentmaybeperceivedasaproblem,

but is not a medical disorder. Catch up with peers takes time and the finer

adjustmentstothegaitpatternmaynotoccuruntilthechildis8–10yearsofage.

Asimpleviewofnormalgaitincludesa:

• Stancephasestartingwiththeheelstrike,progressingthroughplantar-flexion

totoe-off.Assessmentalsolooksatbasewidthandsingle-limbsupporttime.

• Swingphasefromtoe-offtoheelstrikewithforwardrotationandtiltingofthe

pelvis and a stable lumbar spine and abdomen. Assessment also includes

cadenceandstridelength.

Assessmentofalimp

Alimpisanasymmetricgait,butmanypeopleinterpretotherabnormalitiesof

gait as a limp. Some abnormalities of gait are listed as follows. Examples of

causesoflimpinchildrenattendingA&EareshowninTable2.3.

• Antalgicgaitresultsfrompainorstiffnessleadingtoashorterstancephase.

• Trendelenburg limp or gait is attributable to weak hip abduction causing a

bodyswayinstancephaseandadroopofthehipintheswingphase.

• Waddlinggaitisattributabletoneuromuscularorarticularstiffnessaroundthe

pelvis.

• Stiff-legged(peg-leg)gaitresultsfromlossofkneeflexionandcircumduction

withpelvicelevationontheaffectedside.

• Toewalkingmaybehabitual,typicallyresolvingat3yearsormaybedueto

muscle contractures or spasticity. Check whether the child can heel strike

when concentrating. Unilateral toe walking may indicate a lower-extremity

lengthinequalityorbefromawoundtotheheel.

• Highsteppinggaitmayresultfromdifficultieswithdorsiflexionofthefoot,

usually associated with peroneal neuropathies lower motor neuron

neurologicaldisease(e.g.spinabifida,polio)andperipheralneuropathies(e.g.

hereditarymotorsensoryneuropathyI/II).

• Stoopedgaitmightindicateabdominalpathology.

• Clumsygait is often describedbutrarely seen in formal assessment.Itisin

part the result of inattention and may also be from subtle physiological

developmental delay (often associated with handwriting difficulties and

learningdelayordisability).Mayincludemorefrankneurodevelopmentalor

metabolicdisorders.

• Ataxicgait.

Table2.3CausesofalimpinchildrenseeninA&E;medianage4.4years(interquartilerange2.9–7.5

years)

Finaldiagnosis No.(%) Mediandaysto

presentation

‘Irritablehip’ 96(40%) 1

Nofinaldiagnosis 72(30%) 1

Musclestrain/overuse 42(17%) 3

Perthesdisease 5(2%) 30

Osteomyelitis 4(2%) 0.5

Localinfection 5(2%) N/A

JIA 2(1%) N/A

Trauma/fracture/toddlerfracture 4(1%) 2

Osteochondrosis 2(1%) N/A

Neoplasia 2(1%) N/A

Back/abdominal 3(1%) N/A

SlippedUpperFemoralEpiphysis

(SUFE)

1(0.5%) 30

Other 5(1.5%)

Total 243

(100%)

Furthergaitassessment

ShouldfollowgeneralMSKassessmentplus:

• Localizesiteofpathology(andincludebackandabdomen;see Chapter3)—

20%oflimpsarenotassociatedwithpain.

• Lookforbiomechanicalimbalances.

• Trivialinjuryortraumamaybeunwitnessedandtoddlerfracturesmissedon

conventionalradiographs.

• IncongruenceorinconsistencyinhistoryraisessuspicionofNAI.

• Considersports-relatedinjuriesandoverusesyndromes.

• Neurovascularstatus,includingstrength,sensation,andreflexes,canalsobe

assessedwhilethechildissittingorsupine.

• Measureandcomparelower-extremitylengths.

• Walk,run,andhopallowassessmentofcoordination,strength,andbringout

subtleabnormalityandprovidedevelopmentalassessment.

• Alsoassessskin,soleoffeet,nails,andshoes.

Assessmentofmusclepainandweaknessinchildrenandadolescents

Changesingait,anddifficultyclimbingstairsandputtingonjumpersorT-shirts

maybeattributabletomusclepainorweakness.

• In the history of acute muscle pain there should be enquiry about trauma,

previousbiomechanicalmusclepains,precedingviralinfection,andfeverand

site.

• Benignmyositisofchildhoodisatransientillnessthattypicallypresentswith

calf pain in the 4–10-year-old age range 3 days after onset of fever and is

associated with a high creatine kinase (CK). Guillain–Barré syndrome also

affectsdistalmusclesandfollowscertainviralorbacterialinfectionsbutwill

beassociatedwithgradualprogression,markedweakness,sensorysymptoms,

andnormalCK.

• Chronic myositis may also be associated with a low-grade fever, muscle

tendernessandhighCK.

• Juvenile dermatomyositis, SLE, pyomyositis, and some periodic fevers with

myalgiawillhavecharacteristicrashes.

• Non-inflammatory causes of muscle weakness include neuromuscular

conditions, such as muscular dystrophies, that are progressive with loss of

motor milestones; upper motor neuron lesions including spinal compression

with increased reflexes; or anterior horn cell conditions, neuropathies, and

metabolicmusclediseasewithabsentreflexes.Theseconditionsrarelycause

muscletenderness.

• MuscleweaknessandTrendelenburggaitarealsoseeningrossdeconditioning

fromsedentarybehaviourandchronicpainconditions.Tendernessiscommon

alongwithsymptomaticdeteriorationtowardstheendoftheday.

• Widespreadmyalgiasofjuvenilefibromyalgiaandenthesitismaybeconfused

witheachother.

Jointpainswithsystemicfeaturesinchildrenandadolescents

Wherethereisfever,rash,andarthritis,diagnosesotherthansystemic-onsetJIA

(SoJIA; previously known as Still’s disease) ought to be considered first and

beforeatrialofsteroidswhichwillmaskinfections,malignancy,andKawasaki

disease.

• Travel, infection contact, social, and family histories are vital in terms of

disclosingahistorysuggestiveofinfection.

• Thereshouldbeafullenquiryaboutsymptomsreferabletoeachorgansystem,

whichmaypointtoadiagnosisofmultisysteminflammatorydisease.

• Characterizingthefever,includingfluctuationthroughouttheday,periodicity,

and duration may be diagnostic of SoJIA, Kawasaki disease, and specific

periodicfevers(see Chapter18).

• A ‘quotidian’ fever occurring once or twice a day with return to baseline is

characteristicofSoJIA,Kawasakidiseasehasahighspikingfeverforatleast

5days.Forperiodicfeverssee Chapter18.

• Lookforandcharacterizeanyrash.ThismayfacilitatediagnosesofSoJIAfor

which there are multiple typical rashes, lupus, dermatomyositis, periodic

fevers and vasculitis. Other important rashes are those of pyoderma and

neutrophilic dermatoses, scleroderma, and Behçet’s disease; all may need

distinguishingfromviralexanthemsandfungalinfection.

• Ocular features may include red eye, pain, double vision, photophobia, and

blurring.

• Ear, nose, and throat (ENT) features may include sinusitis, crusting, bloody

discharge,tinnitus,hearingloss,facialweakness,oralulceration,sorethroat,

parotitis,anddrymouth.

Non-inflammatoryMSKconditionsinchildrenandadolescents

(SeealsoBox2.2.)

Principlesofdiagnosis

• Biomechanicalandnon-inflammatorypainisverycommoninhealthychildren

andadolescentsandisbyfarthecommonestcauseofMSKpain.

• Hypermobilityinthenormalpopulationiscommonandcareshouldbetaken

before ascribing focal or widespread MSK pain to the hypermobility

syndrome/Ehlers–Danlossyndrome(EDS)type3.Inappropriate/over-zealous

useofthediagnosticlabelcanreflectamisunderstandingofthemultifactorial

nature of MSK pain and project a ‘disabling’ rather than ‘enabling’

formulationontopatients.Inturn,thiscanleadtoparentalconfusion,alackof

flexibilityovertreatmentstrategies,andexcessdisability.

• Biomechanicalpaintypicallyincreaseswithactivityandoccursintheevening

or following morning or two after increased physical activity. It may be

associatedwithstiffnessatthesetimes.

• Biomechanicalpainmaybeassociatedwithminorswellingandtendernessand

may occur with inflammatory or other conditions. It commonly occurs with

chronicarthritisduetomuscleandjointinhibitionfromactiveinflammation

andsubsequentMSKimbalance.

• Focal bone pain occurs with osteochondroses and osteoid osteoma and

although very rare, osteosarcomas should be considered in the absence of

typicalfeaturesofanosteochondrosis.

• Neuromuscular conditions manifest by weakness may present with (often

initiallyfocal)pain.

Contributoryfactorstochronicnon-inflammatoryMSKpainsandtheir

impact

• MSK imbalance—from tight and/or weak musculature or ligaments

(patellofemoralsyndromeisanexample).

• General deconditioning—whether through overall lack of background

effectivephysicalactivity,excesssedentarybehaviour,oravoidanceofactivity

duetopain.

• Repetitivephysicalactivityinthepresenceofsuboptimalmuscularcontrol.

• Subchondralorotherbonystress.

• Features of gross motor development (including proprioception) which are

slower than global development or development of peers and siblings—

development requires nerve myelination and neuromuscular imprinting, so

practicewillnotimproverateofchange(asoccurswithnocturnalenuresis).

• The pace of proprioceptive movement programming, which continues to

developuntilpuberty.

• Suboptimalstrengthforrangeofjointmovement(aswithsomehypermobile

joints).

• Adversegaitorotherpatternsofmovementincludingtrackingofpatella.For

example, gaitmaturationand improvements in gait efficiency continue until

afterskeletalmaturity.

• A‘boomandbust’approachtophysicalactivity.

• Lossofconfidenceinspecificmovements.

• Difficultiesinpainself-appraisal.

• Centralandperipheralpainpathway(orneuromatrix)sensitization.

• Difficulties with background sensory processing as occurs in patients with

autisticspectrumdisorders.

• Ruminatingorattentivebehaviours.

• Reinforcingparentalorotherfamilymemberresponses.

• Socialandenvironmentalfactorsincludingthoseatschool.

Box2.2Typicalnon-inflammatoryMSKdisordersinchildrenand

adolescents

Painfulconditionsfromfocallesions

• Patellofemoralsyndrome

• Otherbiomechanicalimbalances

• Tendinopathyandenthesitis(includingERA)

• Perthesdisease(groin,thigh)

• SlippedUpperFemoralEpiphysis(SUFE)(groin,thigh)

• Osteochondroses

• Neuroblastoma

• Osteoidosteoma

• CRPS

• Osteosarcoma

• Stressfracture

• PVNS(usuallylargejoint).

ConditionsthatmaybeassociatedwithwidespreadMSKpain

• Haemophilia

• Juvenilefibromyalgia

• NAI

• Skeletaldysplasias

• Marfansyndrome

• Ehlers–Danlossyndrome

• Osteogenesisimperfecta(focalormultiplefractures)

• Musculardystrophiesandotherneuromuscularconditions

• Rickets

• VitaminCdeficiency-scurvy

• Hyperparathyroidism

• X-linkedhypophosphataemicrickets(fractures/bonepain).

Notablefeaturesinthehistory(‘pearls’)

• Osteochondroses develop gradually and are associated with pain and

tendernessattypicaltendoninsertionorjointsites.

• Lockingorgellingofajointmayindicateanosteochondritisdissecanslesion

(typicallyelbow,knee,ankle).

• Weakness may beindicated by difficulty climbingstairs, or gettingup from

thefloor(e.g.atschoolassembly).

• Non-participation in physical education lessons, extracurricular sport, and

otherphysicalactivitymayindicateeitherasignificantimpactofacondition

orgeneraldeconditioningandreflectcyclesofbehaviourinresponsetopain.

• Disruptionatthehipmaypresentasinsidiousonsetofkneepainorlimp.This

includes Perthes disease in childrenaged4–10yearsandsubacuteSUFE in

peripubertaladolescentswithanincreasedincidenceinthoseoverweight.

• Withrespecttokneejointpain/lesions:

• Meniscaltearsareassociatedwithanacuteevent.

• Cruciateligamenttearsarealsoassociatedwithacutetraumaandtheremay

beahistoryofpoppingwithinthekneeandimmediateswelling.

• Skeletal dysplasias may present with limb pain and deformity but usually

presentwithafamilyhistoryanddisproportionateshortstatureorinthecase

of osteogenesis imperfecta, fractures. Occasionally, suspicion arises when

polyarthropathy fails to respond to conventional treatments for arthritis and

bilateralhipdysplasiaorPerthesdisease.

Otheraspectsofthehistory

• Typical features which might suggest a functional disorder include irritable

bowelsyndrome,dizziness,paraesthesiae,headaches,andbladderdysfunction.

• Family history may indicate other painful conditions but these are very

unlikelytobegeneticallyrelatedotherthanthroughbodytypeandpatternsof

movementandbehaviour.

• Responsetomedicationwillhelptoguidefuturemanagement.

• Engagementwith,andresponseto,othertreatmentsincludingphysiotherapy,

osteopathy, and complementary therapies will also help guide future

management.

• Assessment of ‘engagement’ includes an understanding of the patient’s

cooperationwithhomeexercise programmesandthiscanbecorrelatedwith

exam findings (e.g. persistence of tight musculature or specific areas of

deconditioning).

Examination:general

• Routine examination should include measuring height and weight and a

pGALS(see Chapter1).

• There should be a general assessment of conditioning and posture, which

includes the presence of spinal contour noting any hyperlordosis or loss of

lordosis.

• Gaithaspredictivepatterns(seealso ‘Gaitassessment’,pp.37–39):

• Noteanyantalgicgaitfromtraumaorinflammation.

• A Trendelenburg or waddling gait can occur from hip abductor weakness

fromneuromusculardisordersorhipjointdisorders.

• Circumductiongaitfromhemiplegia orleglengthdiscrepancyattributable

tochronickneesynovitis(see Plate1).

• Ataxiaduetoneurologicalinvolvement.

• Toe walking—if unilateral or not correctable with advice, upper motor

neuronorlysosomaldisordersshouldbeconsidered.

• WeaknesscanbeassessedthoughtheGowersigninayoungerchild,risingout

of a chair without use of upper limbs, sustained neck flexor strength, and

wingingofscapulaewhenpushingagainstawall.

• RegionalMSKassessmentisdescribedin Chapter3andisusuallykeyto

diagnosisandmanagementofnon-inflammatoryconditions.

• Regionalexaminationshouldincludeassessmentofadjacentregionsgiventhe

functionalconnectionbetweenregions.

Investigations:imaging

Theprinciplesofimaginginyoungchildrenaretominimizeproceduretimeand

radiation exposure wherever possible and to request imaging judiciously

followingdiscussionwithapaediatricradiologist.

• Radiographs are often normal in early joint inflammation, but they are the

investigation of choice if considering periosteal lesions, traumatic or stress

fractures, mineralization defects (e.g. rickets), or major structural conditions

suchasskeletaldysplasia.

• ConsiderUSifthereislikelihoodofjoint/tendonsynovitis,anosteochondral

lesion,oraligament,enthesis,ortendonlesion.

• MRI and further radiological investigation may include assessment of any

organ,especiallyforfeetandankles,hips,andspine.

• Where there is a pyrexia of unknown origin or similar broad differential

diagnosis,whole-bodyMRI(withfatsuppressedsequences)maybehelpful.

Investigations:laboratorytests

• Allinvestigationsshouldbeperformedwithaclearunderstandingofhowto

interpret the results and specific tests (such as serology for multisystem

disorders,Streptococcus,Borrelia,etc.)shouldbeinterpretedaccordingtothe

pre-testprobability.

• Weakpositiveresultsforlupusanticoagulant,RF,ANA,ENA,andASOTmay

needrepeating.

• Serologicaltestsshouldalsobeinterpretedwithcautionafterimmunoglobulin

infusionsorseriousinfectionsandHIV.

ChronicpainwithoutidentifiableMSKabnormalitiesinchildrenand

adolescents

Keyconsiderations

Chronic pain is defined (for research purposes) as the presence of pain or

discomfort for >3 months. This may be continuous in the same location or

intermittent. This may be a useful definition for clinical purposes and to help

raisechronicpainsyndromesordisordersinthedifferentialdiagnosis.

• In most circumstances, there is a characteristic history and examination

findings and a positive diagnosis should be made. This does not require

investigation.

• Treating these conditions as diagnoses of exclusion tends to undermine the

diagnosis and raise suspicion in the patient or parent that sufficient

investigationhasnotbeendonetoruleoutalternativecausesofpain.

• Ifinvestigationsareordered,theexactpurposeofthisinvestigationshouldbe

explainedandshouldbeframedinthecontextofapositivediagnosis.

• In children and adolescents, both local, or regional, and widespread chronic

painoccurs.This includesthe currentterminologyof complexregional pain

syndrome (CRPS) and juvenile fibromyalgia (FM), both pain processing or

neuromatrixproblems.Thereshouldbeguardeduseoftheseterminologiesas

thereisafarbetterprognosisinchildrenandadolescentsthaninadultsanduse

ofsuchtermsmayleadtounintendedinterpretations.

• The commonest cause of regional and widespread pain, however, remains

biomechanical problems typically associated with growth and development.

Thisincludesbenignnocturnallimbpainsofchildhood.

• Itislikelythatpatientswillhaveseenotherprofessionalsandatthebeginning

thepatientorparentshouldbeaskedwhattheyhopefromtheconsultation.

• LocalizedpainsuchasCRPSistypicallyassociatedwithanepisodeofminor

trauma(majortraumaisusuallyassociatedwithhighlevelsofappraisaland

adjustment) in circumstances that may be challenging or alarming (e.g.

unanticipated summersault on a trampoline, unexpected fall, excessively

boisterousplay,roadtrafficaccident,orthepresenceofexhaustionfromlack

ofsleeporheatstroke).

• The pain often builds up over time and the source of pain is considered

mysterious and unexplained to patient and/or parent. This is frequently

compounded by inconsistent assessment and explanation by health

professionalsandbyagitatingfamilymembersorfriends.

• WidespreadidiopathicpainincludingjuvenileFMisusuallyinsidiousinonset

withgradualimpositiononqualityoflifeovertime.

• Thelevelsofdisabilityanddistressforbothlocalizedandwidespreadchronic

pain are usually well in excess of the clinical findings from history and

examination,butshouldnotbedismissed.

• The needs of patients with chronic pain should be clearly identified to help

direct an effective treatment strategy that often requires a multidisciplinary

approach (input from experienced physiotherapist, occupational therapist

(OT),andpsychologist).

• Theroleofmedicationisunclearandifused,medicineuseshouldbeclosely

monitoredforbenefitandsideeffects.Medicationtendstobemosteffective

when used to support engagement with other physical and psychological

therapeuticstrategies.

AssessmentofpatternsofMSKfeaturesinadults

Whenevaluating anadult withjoint, tendon,and muscleproblems, ithelps to

initiallyconsiderwhatisnormalvariationandwhatisabnormaland,inthecase

of jointpains,the likely number ofjointsinvolved. Whether monoarticular (1

joint),oligoarticular(2–3 joints),orpolyarticular(>3joints)willinfluencethe

initialdifferentialdiagnosisandworkingdiagnosis.

• Forexample,RAcanpresentwithmonoarthritisbutitwouldbeaveryunusual

presentation whereas gout in men typically presents as a single site of

inflammation.

• The differential diagnosis generates a working diagnosis which in turns

dictatestoadegreewhattestsaredoneandinwhatorder.

Normalvariants

NormalvariantfeaturesofMSKorigininchildrenareusuallydevelopmentalin

origin (see  Table 2.1, p. 32). In adults, varied skeletal morphological

appearances are not usually associated with disease directly, though their

mechanical effects may lead to secondary MSK problems, notably early

degeneration.

• Inadults,asymmetricMSKappearances,however,aremorelikelytorepresent

relevantpathology.

• Adults can come to clinical attention, reporting noticeable change in MSK

appearance though invariably, such changes, if indeed present at all, but

without pain and other features, are not sinister and rarely indicate serious

disease.

• Adult MSK appearancesdovarynotably. Typical sites ofhighvariation are

neck length, kyphotic/hyperlordotic lumbar thoracolumbar spine contour,

degree of shoulder protraction, sloping shoulders, degree of elbow valgus,

pelviswidthandtilt,degreeoffemoralanteversionangle,Q-angleattheknee,

degreeoftibialtorsion,in-toeing/out-turn,and reducibleplano-valgusinthe

feet.

• Subtle appearances of some MSK structures, however, can indicate an

underlying condition and occasionally are not identified through childhood

and adolescenceand lead to(alate) diagnosis ofthecondition in adulthood

(e.g. trichorhinophalangeal syndrome, hypermobility syndrome/EDS3, and

Scheuermann’sdisease).

Monoarticularpaininadults

• Acute pain and swelling of a joint follows intra-articular trauma such as

cruciate or meniscus tears in the knee. History will be key indiscriminating

traumaorspontaneousinflammation;MRIisessentialtoidentifythecauseof

trauma.

• Acuteinflammatorymonoarthritisiscommonlyduetocrystalarthropathiesin

theolderpatient(see Chapter7), infection (particularly gonococcal in the

youngeradult; Chapter17) or haemarthrosis, the causes of which include

trauma,bleedingdisorder,vitaminCdeficiency,synovialhaemangioma,and

PVNS.

• AspirationoffluidforGramstain,culture,andpolarizedlightmicroscopyis

anearlypriorityofmanagement.

• Afractureacrossthejointlinemayalsocauseanacutemonoarthritis.Stress

fracturesoccuras theresultof repetitiveloadingof bone,andcan be found

withoccupational, recreational,or athleticactivities. Stressfractures maybe

small and therefore can be missed on plain radiographs; MRI may be more

sensitiveandshouldbeconsideredifthepatientisatrisk.

• Non-gonococcal septic arthritis is particularly important to consider in the

elderly, who may not present with the signs and symptoms expected with

infection.Non-gonococcalsepticarthritisisarheumatologicalemergency(see

 Chapters 17 and 25), and should be treated with intravenous antibiotics

immediatelyonsuspicion.

• In the UK, although Staphylococcus aureus is the most common organism

causing septic arthritis in the elderly, it is prudent to consider atypical

infections(e.g.Gramnegative).

• SepticarthritispreferentiallyoccursinpatientswithRA,inpatientswithrenal

disease,andimmunocompromisedpatients.

• Thepresenceofcrystalsinmonoarticularjointfluidaspiratesdoesnotexclude

infection.

• Distinguishing a swollen digital joint from a swollen digit is important in

discriminating dactylitis—usually associated with PsA and other

spondyloarthritides.

• Not all great toe pain/swelling is gout. The great toe is very commonly

affectedinPsA—checkif digitisdactylitic andthereisnail disease—see

Chapter8.

• Boxing glove-type swellingofa hand is a typicalmanifestationof calcium-

containing crystal-induced inflammation, particularly calcium pyrophosphate

deposition(CPPD)-pseudogout—onhandradiographslookforthejointspace

lossandmarkedsclerosisofarticularsurfacesofbonesinCPPDofthecarpal

jointsandchondrocalcinosisinthewristtriangularfibrocartilagecomplex.

Oligoarticularpaininadults

(SeealsoTable2.4.)

Theassessmentofaninflamedjoint

• Theclinicalfeaturesofinflammationandpainatanygivensynovialjointand

the differential diagnosis in the context of other possible regional MSK

diagnosesarediscussedin Chapter3.

• Synovitis is the term given to inflammation of the synovial lining. This

inflammationmaybeaconsequenceofarangeofcellularprocesses,andisnot

specificforanyonediagnosis.Jointeffusionsoftenaccompanysynovitis.

• Inflammation of periarticular tissues may accompany synovitis. Enthesitis

(inflammation at a tendon or ligament insertion into bone) or tenosynovitis

(inflammationofthetendonitself)maybethemostprominentfeature.

History:generalpoints

• Pain and stiffness are typical features of synovitis and enthesitis. Both are

often worseinthemorning, or after periods of immobility. The presence or

absence of stiffness does not discriminate between different causes of

synovitis.

• Pain is often severe in acute joint inflammation. In chronic situations, pain

may be less severe (due to mechanisms that increase physical and

psychological tolerance). There are no specific descriptors that discriminate

painfromsynovitisorenthesitis.

• Swelling, either due to synovial thickening or effusion, often accompanies

synovitis.

• Apatient’sreportofswellingisnotalwaysreliable.Patientswithcarpaltunnel

syndrome, for example, will frequently report that their hands are swollen,

evenwhennoswellingisvisible.

• Reducedmobilityinajointaffectedbyenthesitis/synovitisisalmostuniversal

regardlessofitscause.

Examination:generalpoints

• Swellingmaybeobservedordetectedbypalpation.Itsabsencedoesnotrule

outsynovitisorenthesitis.Synovialswellingneedstobediscriminatedfrom

bonyswelling,fat,andotherconnectivetissueswellings(e.g.ganglia,nodules,

etc.).Withoutimagingorattemptingtoaspiratejointfluid,itmaybedifficult

todiscriminatesynovialthickeningfromeffusion.

• Skin erythema (implying periarticular inflammation) and warmth do not

alwaysaccompanyjointinflammation,buttheyarecommonwithcrystalline

and septic arthritis. Erythema can also occur in reactive arthritis, rheumatic

fever,andwithnascentHeberden’sorBouchard’snodesinosteoarthritis(OA;

see Chapter6).

Table 2.4 Common causes of monoarticular/oligoarticular joint inflammation and typical patterns of

presentation(adults)

Disease Typicalpattern

Gout

(see  Chapter

Age>40yrs.Initiallypresentsasanacutemonoarthritis.

Strongassociationwithhyperuricaemia,renal

impairment,anddiuretics.Possiblegeneralsymptoms

mimickingsepsis.Possiblefamilyhistory.Acute-phase

reactantsandserumwhitebloodcellsoftenhigh.Joint

fluiduratecrystalsseenbypolarizedlightmicroscopy.

Jointerosionsandtophioccurinchronicdisease

Spondyloarthritis

(see Chapter

Age<40yrs,menmorethanwomen.Mostly

oligoarticularlowerlimbjointenthesitis/synovitis.May

occurwithsacroiliitis,urethritisorcervicitis,uveitis,gut

inflammation,psoriasis(scalyorpustular).Possible

familyhistory.ESR/CRPmaybenormal.Moresevere

courseifHLA-B27positive

CPPDarthritis

(see Chapter

Meanage72yrs.Oligoarticular,acutemonoarticular

(25%),andoccasionallypolyarticularpatternsofsynovitis

Haemarthrosis Obvioustraumadoesnotalwaysoccur.Swellingusually

considerable.Causesincludetrauma(e.g.cruciaterupture

orintra-articularfracture),PVNS,bleedingdiatheses,and

chondrocalcinosis

Osteoarthritis

(see Chapter

Softtissueswellingisusuallynotasobviousasbony

hypertrophy(osteophytes).Typicaldistribution(e.g.first

carpometacarpalandkneejoints)

Rheumatoid

arthritis(see

Chapter5)

Caninitiallypresentwithanoligoarthritisthatevolves

intoasymmetricalpolyarthritis.Canrarelypresentasan

acutemonoarthritis

Septic arthritis

(excluding

Neisseria

gonorrhoeae)

(see  Chapter

17)

MostcommoncauseStaphylococcusaureus.Associated

withchronicarthritis,jointprostheses,andreducedhost

immunity.Peakincidenceinelderly.Systemicsymptoms

commonandsometimesovert.SynovialfluidisGram+ve

in50%ofcasesandculture+vein90%ofcases

Gonococcal

arthritis(see

Chapter17)

Age15–30yrsinurbanpopulationsandwithinherited

deficiencyofcomplementsC5toC9.Oneformpresentsas

anacutesepticmonoarthritis.OrganismdetectedbyGram

stainofjointfluidin25%andbyculturein50%inthe

secondgroup

• Tenderness of thickened synovium is common, but is not always present.

Severely tender swelling suggests joint infection, haemarthrosis, or an acute

inflammatoryreactiontocrystals.

• Inflammation of entheses results in ‘bony’ tenderness at joint margins, and

sitesoftendonorligamentinsertion.

• Decreasedrangeofmotionisalmostalwaysdemonstrableinajointaffected

by synovitis or enthesitis. The degree to which passive and active range of

motionisreduceddependsonanumberofofteninterdependentfactors(e.g.

pain,sizeofeffusion,periarticularmuscleweakness,orpain).

• Movementofajoint affectedby synovitisorenthesitiswillinducepainand

stiffness,althoughneitherisspecific.Affectedjointswilldemonstratereduced

rangeonactiveorpassiverangeofmotionexercises;movingthejointbeyond

thatpointwillelicitpain.

• The age,sex,and occupationofthe patient givenon-specific, but important

clues:

• Oligoarthritis is uncommon in young adults. SpA, especially reactive

arthritis, is likely to be the main cause; 75% of patients who develop

reactivearthritisare<40yearsold.

• Gouttypicallyoccursinthose>40yearsold,andisthemostcommoncause

ofinflammatoryarthritisinmen(self-reportedin1in74menand1in156

women).

• ThemeanageofpatientswithCPPDarthritisisabout72years(range63–93

years).

• Areas endemic for tick infection (forestation) with Borrelia are at risk of

Lymearthritis.

History:whichjointsareaffected?

Someprocessesaremorecommonincertainjointsthanothers:

• Shoulder synovitis is typical in hydroxyapatite arthritis (Milwaukee

shoulder/kneesyndrome)andALamyloidosis(see Chapter18).

• Involvementofashoulderorhipisextremelyunusualingout.

• CPPDarthritis(aspseudogout)occursrarelyinthesmallfingerjoints(see

Chapter7).

• Thekneeisthecommonlyinvolvedinacutecrystallinearthropathyandseptic

arthritis(bothgonococcalandnon-gonococcal).

• Large knee effusions are common with Lyme arthritis, but this is a non-

specific finding. Large effusions can also be seen with septic and psoriatic

arthritis(see Chapter8).

• In theory, there are many causes of synovitis in a single first

metatarsophalangeal(MTP)joint,butthemajorityofcaseswillbeduetogout;

50–70% of first attacks occur in this joint. Care is needed in not mistaking

dactylitisduetoPsAforgout.

History:precedingfactors

Factors preceding swelling of a single joint or oligoarthritis may be highly

relevant.Theseincludetraumaandinfection:

• Acutenon-traumaticmonoarticularsynovitisismostcommonlyduetocrystal-

inducedsynovitisorsynovitisassociatedwithSpA.

• A preceding history of trauma typically suggests intra-articular fracture

(with/without haemarthrosis), a meniscus tear (knee), or an intra-articular

loosebody,suchasanosteochondralfragment(whichmaycausethepatientto

complainabouta‘locking’knee).

• Twinges of joint pain often precede an acute attack of gout. Acute arthritis

(‘pseudogout’)occursin25%ofpatientswithCPPDarthritis.

• In hydroxyapatite arthritis, synovitis is usually mild to moderate, gradual in

onset,andtypicallyworseatnight.

• AnacutemonoarthritiswithfeverinFMF(see Chapter18)isamimicof

septicarthritis.Suchjointmanifestationsarepresentinupto75%ofcases.

• Septic arthritis should always be considered (and promptly ruled out) as a

causeofacutejointswelling(see Chapter25).

History:familyandsocialhistory

Theremaybeimportantcluesfromthefamilyandsocialhistory:

• Both gout and SpA have a familial component. Between 6% and 18% of

patientswithgoutalsohaveafamilyhistoryofgout.Theremaybeafamily

history of SpA or uveitis in patients who have reactive, psoriatic, or

enteropathicarthritisorankylosingspondylitis(AS).

• Gout in young adults suggests an inherited abnormality (usually increased

urate production from 5-phosphoribosyl-1-pyrophosphate synthetase ‘super’-

activity,sincetheotherenzymedeficienciespresentinchildhood).

• Excessive alcohol consumption is associated with gout. Alcohol can also

contributetolacticacidosisthatinhibitsuratebreakdown.

• ConsiderLymediseaseifpatientslive,work,orvisitendemicareas;outsideof

the United States, this includes Europe, Russia, China, and Japan. Peak

incidenceoccursduringthesummer.

• Brucella arthritis is generally monoarticular and occurs primarily in areas

where domesticated animals are infected and poor methods of animal

husbandry,feedinghabits,andhygienestandardscoexist.

History:askaboutotherassociatedfeatures

Associatedextra-articularfeaturesincludepreviouseye,gastrointestinal,cardiac,

andgenitourinarysymptoms:

• Low-grade fever, malaise, and anorexia occur commonly in both septic

arthritisandgout.Markedfevercanoccuringoutandonlyoccursinabouta

thirdofpatientswithsepticarthritis.

• AskaboutanycurrentorpreviousfeatureswhichmightsuggestSpA:

• backorbuttockpain(enthesitisorsacroiliitis).

• swellingofadigit(dactylitis).

• plantarheelpain(plantarfasciitis).

• redeyewithirritation(anterioruveitis).

• urethritis,balanitis,cervicitis,recurrentoracutediarrhoea(reactivearthritis)

—besuspiciousofpreviousdiagnosisofIBD—askaboutgettingupatnight

to open bowels and passing slime/mucus—both suggestive symptoms for

IBD.

• psoriasis.

• symptomsofinflammatoryboweldisease.

• Behçet’sdisease(see Chapter18)cancauseanoligoarthritis.Otherfeatures

includepainfuloralandgenitalulcers,anduveitis.

• Theinvolvementofmorethanonejointdoesnotruleoutsepticarthritis.Inup

to20%ofcases,multiplejointscanbecomeinfected.

Examination:general

• Always compare sides, to establish if the changes are symmetric or

asymmetric.

• Itisimportanttoestablishfromtheexaminationwhetherthereistruesynovial

swelling.Ahistoryofswellingisnotalwaysreliableandother,non-synovial,

pathologycanpresentwithsingleoroligoarticularjointpain.

Examinationofaffectedjoints

Examinethe affected jointsfor tenderness.Checkpassiverangeof motionfor

evidenceoflockingorinstability:

• Acuteprocessessuchascrystalarthritis,infection,andpost-traumaticeffusion

oftenleadtopainfulswelling,markedtendernessofswollensofttissues,and

painfullyrestrictedactiveandpassivemovementofthejoint.Thesefeatures

areusuallylessovertwithchronicarthritis.

• Instabilityofanacutelyinflamedjointortestsforcartilagedamageintheknee

maybedifficultto demonstrate.Further examinationwillbe necessaryafter

drainageofjointfluid.

• Detectionofenthesistendernessaroundtheaffectedjointsoratothersitesisa

usefulcluetothediagnosisofSpA.

Examinationofothermusculoskeletalstructures

• Examine the low back and typicalsitesofbonytenderness—sacroiliitis and

enthesitisarecommonfeaturesofSpA.

• Tendonitis is not specific and can occur in gout, CPPD arthritis, SpA, and

gonococcalinfection.

Examination:lookforskinrashesandanyinflammation

Oligoarthritismaybepartofasystemicinflammatoryorinfectiouscondition:

• Temperature and tachycardia can occur with some non-infectious causes of

acutearthritis(e.g.crystalarthritis),althoughtheirpresenceinthecontextof

oligoarticularjointswellingrequiresexclusionofjointinfection.

• Goutytophimaybeseeninthepinnaeandinotherperipherallocations.They

canbedifficulttodiscriminateclinicallyfromrheumatoidnodules.Polarized

lightmicroscopyofmaterialobtainedbyneedleaspirationwillbediagnostic

fortophi.

• Thehallmarkofrelapsingpolychondritis(see Chapter18) islobe-sparing,

full-thicknessinflammationofthepinna.

• Mouthulcersarecommon;however,cropsorlargepainfultongueandbuccal

lesionsassociatedwitholigoarticulararthritissuggestBehçet’sdisease.

• Atypicalsitefortheosteitis(tenderswellingofbone)ofSAPHOsyndrome

(see Chapter16)isaroundthesternumandclavicles.

• Skinerythemaoverajointsuggestscrystalarthritisorinfection.

• Associated skin rashes may include erythema nodosum (associated with

ankle/knee synovitis in acute sarcoid), purpuric pustular rashes (Behçet’s,

gonococcal infection, and SAPHO syndrome), erythema marginatum

(rheumaticfever),orkeratodermablennorrhagica(aggressive-lookingrashof

thesoleofthefootinsexuallyacquiredreactivearthritis).

• Psoriasismaybeassociatedwithbothsynovitisandenthesitis.

Investigations

ThepresenceofsynovitiscanbeconfirmedbyobtainingUSorMRIofthejoints

inquestion.Atlargerjoints,botharesensitiveforthedetectionofeffusionand

synovialthickening.Inflammationatperiarticularorcapsularenthesescanalso

beseen.

Laboratorytests:jointfluid

The most important investigation of a patient with monoarticular synovitis is

jointaspirationandpromptexaminationoffluid.Fluidshouldbesentinsterile

bottlesformicroscopyandculture:

• The appearance of synovial fluid is not specific; however, blood or

bloodstaining suggests haemarthrosis from trauma (including the aspiration

attempt),ahaemorrhagicdiathesis,haemangioma,PVNS,andsynovioma.

• Turbidity (decreased clarity) of fluid relates to cellular, crystal, lipid, and

fibrinouscontent.Synovialfluidinsepticarthritisandacutecrystalarthritisis

frequentlyturbidduetotheeffectsofahighnumberofneutrophils.

• Cell counts give some diagnostic guidance but are non-specific (Table 2.5).

Thereisahighprobabilityofinfectionorgoutiftheneutrophildifferentialis

>90%.

• Jointfluideosinophiliaisnotspecific.

• Polarizedlightmicroscopyoffluidcandiscriminateurate(3–20µminlength,

needle-shaped,andnegatively birefringent—blueandthen yellowasthe red

platecompensatorisrotatedthrough90°)andcalcium-containingcrystalssuch

ascalciumpyrophosphate(positivelybirefringentcrystals,typicallysmalland

rectangularorrhomboidinshape).

• Lipid and cholesterol crystals are not uncommon in joint fluid samples, but

theirsignificanceisunknown.

• Crystalsappearinginsynoviumlesscommonly,butintypicalsettingsinclude

hydroxyapatite associated with Milwaukee shoulder (and knee) syndrome

(alizarin red-S stain positive), calcium oxalate in end-stage renal failure on

dialysis (may need scanning electron microscopy to confirm), cystine in

cystinosis,andxanthineinxanthinosis.

• Thepresenceofcrystalsinjointfluiddoesnotexcludeinfection.

• The most common causes of non-gonococcal septic arthritis in Europe and

North America are Staphylococcus aureus (40–50%), Staphylococcus

epidermidis (10–15%), Streptococcal species (20%), and Gram-negative

bacteria(15%).

Table2.5Characteristicsofjointfluid

Characteristic Normal GroupI(non-

inflammatory)

GroupII

(inflammatory)

GroupIII

(septic)

Viscosity Very

high

High Low Variable

Colour None Straw Strawor

opalescent

Variable

with

organisms

Clarity Clear Clear Translucentor

opaque

Opaque

Leucocytes

(cells/mm

)

200 200–2000 2000–50,000 >50,000

Polymorphonuclear

neutrophils(%)

<25 25 Often>50 >75

Investigations:radiographs

Radiographs can confirm an effusion,showcharacteristicpatternsofchondral

and bone destruction (e.g. in infection or erosive gout), and can reveal intra-

articularcalcificationassociatedwithCPPDorhydroxyapatitearthritis.

• Septicarthritiscausespatchyosteopeniaandlossofbonecortex.

• ‘Punched-out’erosions(withinjointsoraroundmetaphyses;‘LulworthCove

erosions’),softtissueswellings(tophi),andpatchycalcificationarehallmarks

ofchronicgout.

• Intra-articular calcification may commonly be either chondrocalcinosis (fine

linear or punctate fibrocartilage calcification) or larger loose bodies (often

withprolificosteophytes)—bothareassociatedwithCPPDarthritis.

• Numerousregularlyshapedcalcificmassesinajointmaybeduetosynovial

chondromatosis(mostcommoninmiddle-agedmen;50%ofcasesaffectthe

knee).

• ThepresenceoferosionsdoesnotimplicateRA.Thearthritismaybedueto

an enthesitis associated with SpA or erosive OA. Discrimination of erosive

enthesitis,RAerosions,OA-associatedsubchondralcysts,andgouterosionsis

often poorly done by non-MSK radiologists and the unwary/unlearned

rheumatologist!

Investigations:furtherimaging

Furtherimagingshouldbediscussedwithyourradiologists:

• MRIconfirmationof traumatizedstructuressuchasmeniscusdamageinthe

kneeandlabraldamageintheshouldershouldbesoughtifsuspected.

• US of knee or shoulder might be first-line imaging depending on the

experience of the radiologist when considering periarticular lesions (e.g.

anteriorkneestructurelesionsaroundthepatellarligamentortherotatorcuff

oftheshoulder).

• MRI can confirm synovitis, although appearances are usually non-specific.

CharacteristicMRIappearancesofenthesitisandassociatedosteitisandPVNS

arerecognized.

Otherlaboratoryinvestigationstoconsider

• FBC, acute-phase response (ESR, CRP). Neutrophilia is not specific for

infectionandcanoccurincrystalarthritis.

• Bloodurea,electrolytes,creatinine,andurate(e.g. hyperuricaemiaandrenal

impairmentassociatedwithgout).

• Blood calcium, phosphate, albumin, alkaline phosphatase (±PTH), thyroid

functiontests,andferritintoscreenforhyperparathyroidism,thyroiddisease,

andhaemochromatosis,allofwhichcanbeassociatedwithCPPDarthritis.

• Autoantibodies: RF and anticitrullinated peptide antibody (ACPA) may help

identifyearlyRA.RFisnotspecificforRAandislessspecificthanACPA.Be

awareoftheassociationofRFwithprimarySjögren’ssyndrome.

• Immunoglobulin M (IgM) Borrelia burgdorferi serology may help diagnose

Lymediseaseinpatientsatrisk(e.g.acutearthropathyormigratoryarthritis).

• Antibodies to the streptococcal antigens streptolysin O (ASOT) DNAase B,

hyaluronidase,andstreptozymemaybeusefulinpatientswhohavehadsore

throat,migratoryarthritis,orfeaturesofrheumaticfever(see Chapter18).

Investigations:synovialbiopsy

• If there is a haemarthrosis or suspicion of PVNS, MRI of the joint is wise

beforebiopsytocharacterizethevascularityofalesion.

• Considerabiopsytoevaluateamonoarthritisofunclearaetiology.Biopsymay

be helpful to diagnose sarcoid arthropathy (see  Chapter 18), infectious

arthritis,orcrystalarthropathywhentheusualdiagnostictestsarenegative.

• Formalinfixationofsamplesissufficientinmostcases.Samplesforpolarized

light microscopy are best fixed in alcohol (urate is dissolved by formalin).

Snapfreezinginnitrogenisessentialifimmuno-histochemistryisrequired.

• Arthroscopicbiopsywillyieldmoretissuethanneedlebiopsyandwillallow

jointirrigation.

• Congo red staining of synovium, ideally with polarized light microscopy,

shouldberequestedifAA,AL,orβ

-microglobulinamyloidisapossibility

(see Chapter18).Thisshouldbeconsideredinpatientswithmyeloma(AL)

and long-term dialysis patients (β

-microglobulin). AA amyloid is an

uncommon, but recognized complication of RA, AS, FMF, and Crohn’s

disease.

WidespreadMSKpainsinadults

Widespread MSK pain is a common reason for adults to seek medical advice

(Table 2.6). Although some patients will have a polyarticular arthritis, many

conditions are characterized by MSK symptoms which may be diffuse or

multicentric. In addition, the interpretation and reporting of symptoms varies

considerablyandcanbeasourceofconfusion.Thissectionreviewsimportant

aspectsofthehistory,examination,andinvestigationsintheinitialevaluationof

patientswhopresentwithnon-localized,multicentricpains.

Initialimpressions

• Thinkbroadlyaboutthepossiblediagnoses.

• Usewhatyouknowabouttheepidemiologyoflikelyconditions.Forexample,

a35-year-oldmanwithperipheraljointpainsismorelikelytohavepsoriatic

arthritis(see Chapter8)thanRAorgeneralizedOA(see Chapter6),SLE

(see Chapter10),orPMR.

Age,gender,andracialbackground

• Whatcluescanbedrawnfromtheage,sex,andracialbackground?

• The degree to which these factors influence the likelihood of disease varies

according to the prevalence of the disease in the local population. Review

whatyouknowaboutepidemiologyofdiseases.

Previousdiagnoses

PresentingfeaturesmaybeputincontextearlyifyouhaveknowledgeofMSK

associationsofdiagnosesthathavealreadybeenmade.Forexample:

• Synovitis in patients with (radiological) chondrocalcinosis (CPPD

disease/arthritis).

• Arthropathyinpatientswithhyperparathyroidismandhypercalcaemia(see

Chapter16,CPPDarthritis/pseudogout).

• Enthesitis/synovitisinpatientswithCrohn’sdiseaseorulcerativecolitis(see

Chapter8,Spondyloarthritis).

• Polyarticularsynovitisandmyalgiainpatientswithlymphoma.

• Crystal-induced orβ

-microglobulin deposition arthritis and osteodystrophy

inchronicrenaldisease(see Chapter16).

Takingahistory

First, establish whether pains arise from joints or tendons/entheses, muscles,

bone,orareneurologic.

• Althoughthepatientmayreport ‘jointpains’,taketimetoestablishwhether

thepainsaretrulyfromthejointorperiarticulartissues.

• Listencarefullytothedescriptionofthepains;trytodetermineifthepatient

hasasingleconditionoranumberofoverlappingcausesofpain.
Table2.6BroadcategoriesofconditionsthatmaypresentwithwidespreadMSKpain
Common Inflammatorypolyarthritis(e.g.RAorpsoriaticarthritis)
Generalized(nodal)OA(see Chapter6)
Fibromyalgia/chronicpainsyndromes(see Chapter22)
Non-specificmyalgiasandarthralgias*associatedwithinfection
(e.g.viruses)(see Chapter17)
Less
common
Myoarthralgias*inautoimmuneconnectivetissuediseases
Myalgias/muscleinflammation(e.g.polymyositis)(see Chapter
14)
Myoarthralgias*withneoplasiaand/orskeletalmetastases
PolyostoticPaget’sdisease(see Chapter16)
Rare Metabolicbonediseases(e.g.osteomalacia,see Chapter8)
Metabolicmyopathies(e.g.hypokalaemia;see Chapter14)
Neurologicaldisease(Parkinson’sdisease)
*Incertainsituations/conditionspatientsmaycomplainofbothmuscleandjointpains.Thisiseasily
appreciatedifyou’veeverhadinfluenza!
Obtainadetailedhistoryofthepainatdifferentsites
• Agoodhistoryshouldhelpnarrowthedifferentialdiagnosisconsiderably.For
example,a70-year-oldmanreferredwith‘widespreadjointpainsmostlyinhis
legs’couldhavemultipleweight-bearingjointOAorlumbosacralnerveroot
claudication symptoms (see  Chapters 3 and 6 and  Chapter 21,
respectively).Amiddle-agedwomanwith‘handandneckpain’couldhavean
arthropathyorradicularpainassociatedwithcervicalspondylosis.
• Widespread paindueto bone pathology could bedueto skeletal metastasis.
Bonypainisoftenunremitting,andchangeslittlewithchangesinpostureand
movement.
• Onepitfallistoassumethatallpainsarisefromasinglepathologicalprocess.
Forexample,inanolderpatient,multiplepathologiesfrequentlyexistandcan
becomplicatedtounravel.Thefollowingareallcommonintheelderly:
• osteoarthritis(any/multiplejoints).

• CPPDarthritis.

• rotatorcuffarthropathy.

• sarcopenia/fallsrisk.

• PMR.

• spinalstenosisoflumbarcanalwithlegsymptoms.

• primaryhyperparathyroidism.

• CKD-relatedMSKsymptoms.

• hypovitaminosisD/osteomalacia.

Jointpainatrest,afterrest,orwithjointuse?

Establishwhetherpainarisesfromjointsortendons/entheses.

• Pain occurring with inflammation is conventionally regarded as being

associatedwithmorningstiffnessorstiffnessafterperiodsofrest.Ittendsto

be prominent in conditions such as RA, SpA, PMR, and myositis.

Inflammatoryjointpainoftenimprovesintheday.

• Milddegreesofimmobility-associatedpainandstiffnessoccurinsomeother

conditions, such as OA and fibromyalgia, although such forms of stiffness

generallylastfor<1h.Stiffnessmayalsobeafeatureofmusclespasmand

soft-tissueoedema.

• Mechanical joint damage such as OA is also painful. Unlike inflammatory

jointpain,mechanicaljointpainisworsenedbyuse,andimproveswithrest.

Ask,anddocumentindetail,whichjointsareaffected

• AsymmetricpolyarthritisaffectingthesmalljointsistypicalforRA.RAcan

also present withcarpaltunnelsyndrome,tenosynovitis, tennis elbow, or an

asymmetric pattern of joint involvement, and can be preceded by a

palindromic pattern of joint pain (see  ‘Ask about the pattern of joint

symptomsovertime’,pp.57–58).

• Arthritis from parvovirus B19 infection may also be polyarticular and

symmetricbutalsomaycausemyopathyandgeneralsymptoms.

• Small joint pain in the hands occurs in nodal generalized OA. Distal

interphalangeal joints (DIPJs), proximal interphalangeal joints (PIPJs), and

thumbjointsareusuallyaffected.OAisalsoassociatedwithpaininthespine,

hips,andknees.

• Thecombinationofsacroiliac(lowbackandbuttock),pelvic,andlowerlimb

joint/enthesis pain, typically in an asymmetric oligoarticular pattern, is

suggestive of SpA. Typical sites of involvement include anterior knee,

posteriorandinferiorheel(plantarfascia).

• Enthesitis can affect the wrists and small joints of the hand and feet (e.g.

plantarfasciaoriginandinsertionatmetatarsalheads)andmaybedifficultto

distinguishfromRAonclinicalgroundsalone.

• CPPD typically favours the large and medium-sized joints, but a picture of

multiple joint involvement similar to that in RA is possible (including

tenosynovitis).

• Widespreadarthralgias/arthritisoccursinpatientswithleukaemia,lymphoma,

myeloma,andcertaininfections.

Askaboutthepatternofjointsymptomsovertime

• Ashort,strikinghistoryofmarked,acutepolyarticularsymptomsoftenoccurs

withsystemicinfection(Table2.7).Prominentmalaiseandfevershouldraise

suspicionofinfection.

• There may be a longer history than is first volunteered. Autoimmune

rheumaticandconnectivetissuediseasesmayevolveoveraperiodoftimeand

often naturally relapse and remit; the first symptoms of disease may be

dismissedbythepatientasirrelevant.

• Conventionally,persistentinflammatoryjointsymptomsshouldbepresentfor

atleast6weeksbeforeRAisdiagnosed.

• Migratory arthralgias occur in 10% of RA patients initially: a single joint

becomesinflamedforafewdaysthenimprovesandadifferentjointbecomes

affected for a few days and so on. A similar pattern can occur in post-

streptococcalarthritis,granulomatosiswithpolyangiitis(previouslyknownas

Wegener’sgranulomatosis),sarcoidosis,Lymedisease,andWhipple’sdisease.

• RecurrentpainsfromvariousMSKlesions,whichhaveoccurredfrominjury

or have developed insidiously, are typical in patients with underlying

hypermobility(e.g.EDSincludinghypermobility-EDS,OI,MarfanSyndrome

etc)(see Chapter19).

• Theonsetofenthesopathymaybeinsidiousoracute.

Table2.7Commoninfectionsthatcanpresentwithacutepolyarthritisandaraisedacute-phaseresponse

Infection Commonextra-articular

clinicalfeatures

Keylaboratory

diagnostictestsin

acuteinfection

Rheumaticfever

(groupAhaemolytic

streptococci)

Acuteinfection1–2weeks

earlier,fever,rash,carditis

Positivethroatswab

culture.HighASOT(in

80%)

Post-streptococcal Acuteinfection3–4weeks Asabove

earlier,tenosynovitis

ParvovirusB19

(adults*)

Severeflu-likeillnessat

onset,variousrashes

Anti-B19IgM

Rubella(alsopost-

vaccine)

Fever,coryza,malaise,

briefrash

Culture.Anti-rubella

IgM

HepatitisB Fever,myalgia,malaise,

urticaria,abnormalliver

function

Bilirubin+,ALT+,

AST+,anti-HBsAg,

anti-HBcAg

Lymedisease(Borrelia

burgdorferi)

Tickbites,fever,

headache,myalgias,

fatigue,nervepalsies

Anti-BbIgM(ELISA+

immunofluorescence)

Toxoplasmagondii Myositis,paraesthesias Anti-ToxoIgM

*ThepresentationofparvovirusB19illnessmaybequitedifferentinchildren.

Evenifserologicaltestshavehighsensitivityandspecificity,thepositivepredictivevalueofthetestis

lowiftheclinicallikelihoodoftheinfectionislow.Therefore,donotuseserologicaltests

indiscriminately.

Istherewidespreadmusclepain?

Ifyouthinkthereiswidespreadmusclepain,considerthat:

• Themyalgiasmaybefibromyalgiaorenthesitis.

• Painlocatingtomusclegroupareasmaybeischaemicorneurologicinorigin,

andnotnecessarilyduetointrinsicmuscledisease.

• Thedifferentialdiagnosisofpolymyositis(PM)anddermatomyositis(DM)is

broad,butmanyoftheseconditionsarerare(Table2.8andsee Chapter14).

Askaboutthedistributionanddescriptionofmyalgiasandweakness

• True weakness may denote either myopathy or a neurological condition.

However, patients may report a feeling of weakness if muscles are painful,

therefore,relymoreonyourexaminationbeforedecidingmusclesareweak.

• PMR (rare in patients <55 years old), myositis, and endocrine or metabolic

myopathiestypicallypresentwithproximalweakness.

• PMR does not lead to objective weakness; instead, patients experience

proximal muscle pain and stiffness that is worse in the morning, and is

frequentlydescribedbythepatientas‘weakness’.

• Althoughrare,truncalmusclepain,andstiffnesscanbeapresentingfeatureof

Parkinson’sdisease.

• Cramp-like pains may be a presenting feature of any myopathy (e.g.

hypokalaemic) or even motor neuron disease. However, some patients may

interpretradicular(nerveroot)painsas‘cramp-like’.

• Inflammatory,endocrine,andmetabolicmyopathiesareoftennotpainful.

• Occasionally, some genetic muscle diseases (e.g. myophosphorylase, acid

maltase deficiency), can present atypically late (in adults) with progressive

weaknessthatmaybemistakenforPM.

Askaboutthepatternofmusclepainsovertime

• Severe,acutemusclepainoccursinavarietyofconditions.Themostcommon

causes are viral, neoplastic, and drugs. Some toxic causes may result in

rhabdomyolysis,myoglobinuria,andacutekidneyinjury(AKI).

• UsuallyPM/DMischaracterizedbyslowlyevolving butprogressivemuscle

painandweakness(e.g.weekstomonths).

• Low-grade episodic muscle pains may denote a previously undisclosed

hereditarymetabolicmyopathy.

• Fibromyalgia (see Chapter22) is a chronic pain syndrome and symptoms

mayhavebeenpresentforaconsiderabletimeatpresentation.

Arethepainsischaemic?

• Ischaemic muscle pain often occurs predictably in association with repeated

activityandeasesorresolvesonrest(‘claudication’).Considerthisespecially

ifpainsareconfinedtoasinglelimborbothlegs.

Table2.8Themajorcausesofmyopathiesandconditionsassociatedwithdiffusemyalgia

Infectiousmyositis Viruses(e.g.influenza,hepatitisBorC,Coxsackie,

HIV,HTLV-I)

Bacteria(e.g.Borreliaburgdorferi(Lymedisease))

Other(e.g.malariatoxoplasmosis)

Endocrineand

metabolic

Hypo/hyperthyroidism

Hypercortisolism

Hyperparathyroidism

Hypocalcaemic,hypokalaemic

Autoimmune

diseases

Polymyositis

Dermatomyositis

SLE

Systemicsclerosis(SScl)

Sjögren’ssyndrome

RA,Vasculitis(e.g.PAN,AAV,rheumatoidvasculitis)

Myastheniagravis

Eosinophilicfasciitis

Carcinomatousmyopathy

Idiopathic Fibromyalgia(musclesshouldnotbeweak)

Inclusionbodymyositis

Sarcoidmyositis

Drugs Lipid-loweringdrugs(e.g.fibrates,gemfibrozil,

niacin)

Anti-immune(e.g.colchicine,ciclosporin,

penicillamine*)

Rhabdomyolysis(e.g.alcohol,opiates)

TNFαinhibitors

Others(e.g.azathioprine,chloroquine*)

Muscular

dystrophies

Limbgirdle

Facioscapulohumeral

Congenital

myopathies†

Mitochondrialmyopathy

Myophosphorylasedeficiency

Lipidstoragediseases

*Drugsmostlikelytocausepainfulmyopathy.

†Becauseofvariableseverity,someconditionsmaynotpresentuntiladulthood.

Note:Guillain–Barrésyndromeandmotorneurondiseasemaybeconsideredinthedifferential

diagnosisofnon-painfulmuscleweakness

• Thedistributionofpainsmaygivecluesastositesofunderlyingpathology,

e.g.upperextremitiesareaffectedbysubclavianarterystenosisandthoracic

outlet syndrome; lower extremities are affected by atherosclerotic vascular

diseaseorlumbarnerverootstenosis.

• Ischaemic pains in the context of a highly inflammatory state may suggest

systemicvasculitis,suchaspolyarteritisnodosa.

Widespreadpainmaybeduetobonepathology

• Bone pains are unremitting and disturb sleep. They could denote serious

pathology—radiographicandlaboratoryinvestigationsareimportant.

• The major diagnoses to consider include disseminated malignancy, multiple

myeloma, metabolic bone disease (e.g. renal osteodystrophy,

hyperparathyroidism,osteomalacia),andpolyostoticPaget’sdisease.

Specificquestionsareoftenrequiredbecausepreviousproblemsmaynotbe

regardedasrelevantbythepatient.Forexample:

• Forthosewithjointpainsahistoryofthefollowingmaybeofhelp:

• otherautoimmunediseases(increasedriskofRA,SLE,etc.).

• Raynaud’sphenomenon(associationwithSScl,RA,andSLE).

• dryeyes(possibleSjögren’ssyndrome).

• uveitisoracute‘redeye’(associationwithSpA).

• recurrent injuries/joint dislocations (association with joint hypermobility

syndrome.

• genital,urine,orseveregutinfection(linkwithSpA).

• psoriasis(associationwithSpA).

• diabetes(cheiroarthropathy).

• Forthoseinwhommyalgias/myositisseemslikely:

• precedingviralillness(possibleviralmyositis).

• foreigntravel(tropicalmyositis).

• otherautoimmunedisease(associatedwithPM/DM).

• previouserythemanodosum(sarcoid).

• drugsandsubstanceabuse.

• Forallpatients:

• weightlossoranorexia(associationwithmalignancy).

• feversornightsweats(associationwithinfection).

• sorethroat(possiblepost-streptococcalcondition).

• persistentspinalpain(associationwithfibromyalgia).

• rashes(associationwithLymedisease,SLE,DM,vasculitis).

• Forthosewithwidespreadbonypain:

• historyofrickets(associationwithosteomalacia).

• chronicrenaldisease(willprecederenalosteodystrophyandmaypredispose

tocrystallinearthritisandosteoarticulardepositionofβ

-microglobulin).

Psychosocialandsexualhistory

• Precedingsexualactivityandgenitalinfectionisimportantprimarilybecause

of an association of Chlamydia trachomatis infection with reactive arthritis

andenthesitis/SpA(see Chapter8).

• ReactivearthritishasanassociationwithHIV.HIVisalsoassociatedwithPM,

andisariskfactorforpyomyositis.

• ThereisanassociationofanxietyanddepressionwithFM(see Chapter22).

Askabouttravel

• Residencein,ortravelto,ruralareaspopulatedbydeermightbeimportantin

indicating a risk of exposure to Borrelia burgdorferi and contracting Lyme

disease(the spirocheteis carriedby ticksthat colonizedeer,boar, andother

animalsandbiteothermammals).

• Plasmodium falciparum (intertropical areas), Trypanosoma (mainly South

America), Trichinella, and cysticerci (tapeworm larval cysts) infections are

associatedwithmyalgias/myositis.

Familyhistory

Askaboutfamilywitharthritisorautoimmunediseases:

• There is a hereditary component to psoriatic arthritis, SpA, large joint and

generalizednodalOA,andhyperuricaemia/gout.

• The risk of developing any autoimmune condition is higher in families of

patientswithautoimmunediseasesthangenerally.

• Hypermobilityperse(notnecessarilyjointhypermobilitysyndrome)andFM

showastrongheritabilityintwinstudies.

Drughistory

• Thefollowingdrugshavebeenreportedtocauseamyopathy(thosemarked

aremorelikelytobepainful):lithium,fibrates,statins,penicillin,colchicine,

penicillamine

, sulphonamides, hydralazine, ciclosporin, phenytoin,

cimetidine

 (musclecramps), zidovudine, carbimazole,TNFαinhibitors, and

tamoxifen.

• The myositis that occurs with penicillamine is not dose dependent or

cumulativedosedependent.Itcanbelife-threatening.

• Drug-inducedSLE,whichischaracterizedcommonlybyarthralgias,aching,

andmalaise,andlesscommonlybypolyarthritis,canoccurwithanumberof

drugs including hydralazine, procainamide, isoniazid, minocycline, TNFα

inhibitiontherapy.Quinidine,labetalol,captopril,phenytoin,methyldopa,and

sulfasalazinemayalsocausesimilarsymptoms.

• Mildmyalgiasandarthralgiasmaybecausedbyanumberofcommonlyused

drugs,e.g.protonpumpinhibitorsandquinoloneantibiotics.

• Alcoholinexcessandsomeillegaldrugsareassociatedwithtoxicmyopathy

occasionallyresultinginrhabdomyolysis.

Askaboutchestpain,dyspnoea,palpitations,cough,andhaemoptysis

• Cardiac abnormalities are features of autoimmune rheumatic and connective

tissuediseases, butare infrequentat initialpresentation.Cardiacinfectionis

associated with widespread aches and pains (e.g. rheumatic fever/post-

streptococcalmyalgias/arthralgias,infectiveendocarditis).

• Chroniceffort-relateddyspnoeaduetointerstitiallungdiseaseoccursinmany

patients with autoimmune connective tissue and rheumatic diseases. Up to

40%ofRApatientsmayhaveCTevidenceoflungdisease.Inmanysedentary

patients,however,symptomsarenotprominent.Dyspnoeamaybepresentat

presentation.

• Respiratory failure and aspiration pneumonia can occur as a result of a

combinationoftruncalstriated,diaphragmatic,andsmoothmuscleweakness

inPM.

• ThereisanassociationbetweenbronchiectasisandRA.

• Themostcommonneoplasminpatientsdiagnosedwithmalignancy-associated

myositis,isofthelung.

Askspecificallyaboutdysphagia,abdominalpain,anddiarrhoea

• Patients may not mention gastrointestinal symptoms if they have resolved.

Therearemanylinksbetweenboweldiseaseandinflammatoryarthritis(SpA

linkedtoIBDisprobablythecommonest).

• Ask specifically about previous severe diarrhoeal or dysenteric erythema

migransinLymedisease.

• Erythemamarginatuminrheumaticfever.

• UVsensitiverashonface/armsinSLE.

• Violaceousrashonknuckles/aroundeyes/baseofneckinDM.

• LivedoreticularisinSLEandAPS.

• Purpuricrashinvasculitis(e.g.HSP).

• Erythemanodosuminsarcoidosis.

• Illnesses such as those caused by Campylobacter, Yersinia, Shigella, or

Salmonella,willberelevanttodiagnosingreactivearthritis/SpA.

• Gutsmoothmusclemaybeaffectedinpolymyositisandgiverisetodysphagia

andabdominalpain.

Examination

Inpatientswithwidespreadpain,afullmedicalexaminationisalwaysnecessary.

Skinandnails

Inallpatientslookcarefullyattheskinandnails:

• Nails may show prominent ridges or pits in psoriatic arthropathy, splinter

haemorrhages in infective endocarditis, systemic vasculitis or APS, or

periungualerythemainsclerodermaandtheinflammatorymyopathies.

• Look for skin rashes in conditions characterized by widespread pain. For

example, lymphadenopathy may be present with either infection or

inflammation and is non-specific. However, if prominent it may denote

lymphoma.

• Signs of anaemia are a non-specific finding in many chronic systemic

autoimmunediseases.

• ClubbingofthedigitsmaybepresentinCrohn’sdiseaseandulcerativecolitis

(associatedwithSpA)andbronchiectasis(associatedwithRA).

• Oedemacanoccurinbothupperandlowerextremitiesinasubsetofpatients

presenting with inflammatory polyarthritis/tenosynovitis. The condition has

beentermedRS

PE(remittingseronegativesymmetricsynovitis withpitting

oedema).Thisconditionisstrikinginthatitoccurssuddenly,ofteninpatients

60–80 years old and is very disabling. It may be associated with other

conditions.ItmaybeamanifestationofpseudogoutinCPPDdisease.

Examinationofthejoints

Importantpointstonotewhenexaminingjoints:

• Eachjointshouldbecomparedtothejointontheoppositeextremity,firstby

observation, then palpation, then by its active and passive range of motion

exercises.

• Useful examination tools include a tape measure to record swelling

(circumferential)andagoniometer(protractorwitharms)tomeasuretherange

ofjointmovement.

Patternsofabnormality

Notethespecificcauseofjointswellingandsiteoftenderness,distributionof

affectedsites,andhypermobility:

• InnodalgeneralizedOA,osteophytes(bonyswelling—maybetender)canbe

notedatDIPJs(Heberden’s nodes)andPIPJs(Bouchard’s nodes).Periosteal

newboneatsitesofchronicenthesitismaybepalpableandtender.

• Nodules may occur in nodal OA, RA, polyarticular gout, ANCA-associated

vasculitis,multicentricreticulohistiocytosis,orhyperlipidaemia(xanthomata).

• Soft tissue swelling with tenderness and painful restriction of the joint on

movementsuggestsaninflammatoryarthritis.Thereisoftenadjacentmuscle

wasting.Thisismosteasilyappreciatedintheinterosseousmusclesinpatients

withhandarthritis,orthequadricepsinpatientswithkneearthritis.

• The ‘painful joints’ may be inflamed tendons or entheses. Tender tendon

insertionsandperiarticularbonetenderness,oftenwithoutanyjointswelling,

maydenoteenthesisinflammationassociatedwithSpA.

• Tendonitismaybepartofmanyautoimmunerheumatic orconnective tissue

diseases.Lookspecificallyforthickeningofthedigitalflexorsandswellingof

thedorsalextensortendonsheathinthehand,andtenderness/swellingofboth

peronealandposteriortibialtendonsinthefoot.

• GrossswellingwithpainfulrestrictionofsmalljointsisunusualinSLE.Often

thereislittletofindonexaminationofjoints.

• Generaljointhypermobilitymayleadtojointandothersofttissuelesions.An

examinationscreenfor hypermobility maybe helpful (Table2.9; also see

Chapter19).Checkalsoforassociatedfeatures.

Table2.9Featuresofhypermobility.Thesearethe‘Brighton’criteria

Examinationscreen

(scoredoutof9)

Abilitytoextendfifthfinger>90°atMCPJ

(score1+1forR+L)

Abilitytoabductthumb(withwristflexion)to

touchforearm(score1+1)

Extensionofelbows>10°(1+1)

Extensionofknees>10°(1+1)

Abilitytoplacehandsflatonfloorwhenstanding

withkneesextended(1)

Associatedfeatures

Prolongedarthralgias

Skinstriae,hyperextensibility,andabnormal

scarring

Recurrentjointdislocations

Varicoseveins

Uterine/rectalprolapse

Recurrentsoft-tissuelesions

Marfanoidhabitus

Eyesigns:droopingeyelids,myopia,down-

slantingeyes

Examinationofpatientswithwidespreadmyalgia

• Check for muscle tenderness and weakness. Document the distribution. Is

thereevidenceofneurologicorvasculardisease?

• The characteristic sites of tenderness in fibromyalgia should be confidently

recognized(Fig.2.1;seealso Chapter22).Despitediscomfort,themuscles

shouldbestrong.

• Examinethestrengthofbothtruncalandlimbmusclegroups(Fig.2.2).Inthe

presenceofpain,itmaybedifficulttodemonstratesubtledegreesofmuscle

weakness.

• Patternsofmuscleweaknessarenotdiseasespecific;however,therearesome

characteristic patterns: symmetric proximal extremities in PM and DM;

quadriceps and forearm/finger flexors in inclusion body myositis; limb

musclesinmitochondrialmyopathy.(Note:usingspecificapparatusphysical

therapists can help document isometric muscle strength in certain muscle

groups.)

• MusclesinPMRarenotintrinsicallyweak.

• Muscle wasting is not specific. If wasting is profound and rapid, consider

neoplasia.Wastingwilloccurinmostlong-standingmyopathies.

• Check for increased limb tone and rigidity—most evident by passive

movement atajoint—consistent with extrapyramidal disease. Theremaybe

restingtremorinthehand,facialimpassivity,and‘stiff’gait.Musculartonein

the limbs may also be increased in motor neuron disease; however, if

presentingwithmuscle pains,thepatientwithmotorneurondiseaseismore

likely to have a lower motor neuron pattern of neuronal loss (progressive

muscular atrophy) with muscular weakness/wasting, flaccidity, and

fasciculations.

• The fatiguability of myasthenia gravis can be identified by determining the

lengthoftime the patientcankeep theirarmsextended in frontofthem, or

maintainanupwardgaze.

• Muscle pains or cramps due to large-vessel ischaemia are likely to be non-

tenderatrestandstrong.Demonstrateabsentpulsesandbruitsandsubstantiate

findingswithUSDopplerexamination.

• In suspected cases of PM and DM, examine for cardiopulmonary

abnormalities. Other associated signs in DM include periungual

erythema/telangiectasia, erythematous violaceous rash and skin calcinosis.

DysphoniaandswallowingabnormalitiesoccurinbothPMandDM.

• Because of its associations, patients with myositis should be carefully

examinedforthefollowingsigns:dryeyes/mouth(Sjögren’ssyndrome;see

Chapter12), skin thickening/tendernessordiscoloration (scleroderma;see

Chapter 13), skin rashes (SLE; see  Chapter 10), thyroid tenderness or

enlargement(endocrinemyopathy;see Chapter4).

Fig.2.1Typicalsitesoftendernessinfibromyalgia.

Investigations:generalpoints

• ESR and CRP may be higher than normal in the setting of infection,

malignancy,oractiverheumaticdisease.AslightlyelevatedESRisacommon

findinginhealthyelderlypeople.

• ApositiveANAmayoccurinassociationwithmanyautoimmuneconditions,

inotherdiseases(Table2.10),andinsomehealthypeople.Itis,therefore,not

diagnosticforSLEoranysinglecondition;however,high-titreANAmaybe

significantandconversely,ANA-negativeSLEisrare.

• ACPA is more specific for RA than RF (see  Chapter 5), which can be

positiveinanumberofinflammatoryconditions.

• Controversy exists about the diagnosis of FM. It is prudent to only make a

diagnosisofFMwhenotherdisorderscanbeconfidentlyexcluded.Consider:

psoriasis-related MSK disease, SAPHO, sarcoid, autoimmune connective

tissuediseasesincludingAPS,vasculitides.

Basictestsinpatientswithpolyarthropathy

• Urinalysis (dipstick) may show proteinuria or haematuria. Both glomerular

and tubular damage are possible. Glomerulonephritis (in SLE, vasculitis, or

endocarditis, for example) is usually associated with significant proteinuria

andhaematuriasimultaneously.Thesepatientswillneedurgentevaluationby

anephrologist.

• ESRandCRParenon-specificandmaybenormalintheearlystagesofthese

conditions.Ifveryhigh,thenconsiderinfectionormalignancy.Thereisoften

no evidence of an acute-phase response in patients with enthesitis (even

though pain and bony tenderness may be widespread). A mild anaemia and

thrombocytosismayaccompanyinflammation.

• Throat swab, ASOT, anti-DNAaseB antibodies may be useful to identify a

recent post-streptococcal condition, but levels may remain mildly elevated

long-termandindicatepreviousinfection(IgG).

• Othertestswhichcanbeconsideredintheappropriatesetting:

• randombloodsugar(diabetes).

• TFTs/thyroidantibodies(hyper/hypothyroidism).

• prostatic-specificantigen(malignancy).

• fecalcalprotectin(screeningforinflammatoryboweldiseaseinSpA).

• Jointfluidaspirationandcultureismandatoryforpatientsinwhomsepsisisa

possibility. Fluid should be examined by polarized light microscopy in

suspectedcasesofcrystal-inducedsynovitis.

• InpatientswhoareANA-positive,testforextractablenuclearantigens(ENAs)

tohelpcharacterizethetypeofautoimmuneprocess.

• In many patients presenting with a short history of widespread joint pains,

radiographswillbenormal.Anearlysignofjointinflammationisperiarticular

osteopenia, but this is not specific. Recognized types of erosions, and bone

reactionlesionsandtheirdistributioncanbenotedbyexperiencedradiologists

inspecificconditions(e.g.RA,psoriaticarthritis,gout,CPPDarthritis).

• Referraltoasexualhealthclinicforfurtherdetailedinvestigationsifthereisa

suggestionofrecentorrecurrentgenitalinfectionmayhelptostrengthenthe

evidenceforadiagnosisofsexuallyacquiredreactivearthritis.

Laboratorytestsinpatientswithwidespreadmusclepain/weakness

• Dipstickurinalysis:toscreenforhaematuriaormyoglobinuria.

• FBC,ESR.

• Initial screening tests to consider: urea/electrolytes (U&E), creatinine,

TFTs/TSH, bone profile, and 25-hydroxyvitamin D, liver function tests

(LFTs), angiotensin-converting enzyme (ACE), CK, parathyroid hormone

(PTH),ANA/ENAs,RF,myositisspecificantibodypanelandconsiderrandom

cortisoland24-hoururinarycortisol.

Table 2.10. Examples of the prevalence of antinuclear antibodies (ANAs) in some diseases using

ELISA,orHep2cellsassubstrate

Populationgroup PrevalenceofANAs

(‘upto’)(%)

Normalpopulation 8

SLE 100

Otherautoimmunejoint,

vasculitis,orCTDs

Systemic

sclerosis

Sjögren’s

syndrome

70–80

Psoriatic

arthritis

Polymyositis 40

Polyarteritis

nodosa

Examplesfromotherdiseases Chronicactive

hepatitis

100

Drug-induced

lupus

100

Myasthenia

gravis

Sarcoidosis 30

Diabetes 25

• ElevatedCKoraldolaseoccursinmostcasesofPM.ALT,AST,andlactate

dehydrogenase(LDH)arenon-specificmarkersofmuscledamage.Notethat

specificmuscleisoenzymesofCKandLDHexistandthenormalrangeofall

enzymesmayvaryindifferentpopulations.Muscleenzymesmaybeelevated

afternon-inflammatorycausesofmuscledamage,e.g.exercise/trauma.

• Check for ANA and, if positive, screen for ENAs. Antibodies to certain

(cytoplasmic)tRNAsynthetases(e.g.Jo-1,SRP)aremyositis-specific.

• Think of checking for urinary myoglobin in cases where acute widespread

muscle pain may be associated with myolysis—causes include excessive

alcoholoringestionofcertaindrugs(cocaine,amphetamines,ecstasy,heroin),

exercise,ortrauma.Suchpatientsmaybeatriskofrenalfailure.

• PM can be a presenting feature of HIV. In HIV-positive patients, infections

causingmusclediseaseincludeTBandmicrosporidia.

• Viral myositis may be clinically indistinguishable from PM. Serology may

yielddiagnosticclues.

Electrophysiologyandimaginginpatientswithmuscleconditions

• Electromyography (EMG) abnormalitiesoccur in two-thirds ofpatientswith

muscleinflammation.Moreinformationislikelyifstudiedintheacuterather

than the chronic phase of the illness. In the acute phase, denervation and

muscledegenerationgivefibrillationpotentialsin74%ofPMand33%ofDM

patients (see  Chapter 14). Other features include low-amplitude short-

durationmotorunitandpolyphasicpotentials.

• EMGispooratdiscriminatingongoingmuscleinflammationinmyositisfrom

steroid-inducedmyopathy.

• TherearecharacteristicMRIpatternsofabnormalityinPMandDM.MRIcan

beusedtoidentifypotentialmusclebiopsysitestoavoidfalse-negativeresults

associatedwithpatchymuscleinflammation.

Fig.2.2Screeningexaminationforproximalmyopathy.(a)Functionalmovementsrequiringtruncaland

proximallowerlimbmusclestrength.(b)Resistedmovementtestingofdeltoid(i),longitudinalflexorsof

theneck(ii),andiliopsoas/quadriceps(iii)strength.

Musclebiopsy

• MusclebiopsyshouldbeconsideredinallpatientsevaluatedforPMorDM.

• In PM, inflammatory infiltrates predominate in the endomysial area around

muscle fibres without perifascicular atrophy. In DM, inflammation is more

prominentintheperimysialareaandaroundsmallbloodvesselsandthereis

typicallyperifascicularatrophy.

• Routine tests do not reliably distinguish PM from cases of viral myositis.

Some of the glycogen storage diseases will become apparent from light

microscopyofbiopsymaterial.

• An autoimmune myositis is unlikely in the absence of positive HLA

immunohistochemistryonbiopsymaterial.

Investigationsformalignancy

Investigations in adults with widespread bony pain should aim to rule out

malignancy, particularly myeloma, gonadal tumours, and malignancies from

breast,renal,andprostatecancers:

• Investigationsshouldincludemammography,urinecytology,PSA,renalUS,

serumandurinaryproteinelectrophoresis.

• Hypercalcaemia may accompany these conditions; check blood calcium,

phosphate,25-hydroxyvitamin-D,PTH,PTH-relatedprotein.

• PTHshouldalsobecheckedinsuspectedcasesofosteomalacia(raiseddueto

calcium/vitaminDdeficiency)togetherwith25-hydroxyvitaminDlevels(low

orlow/normal),alkalinephosphatase(high/normal),24-hoururinarycalcium

willbelow.

• Radiographsofaffectedsitesareimportant.IncludeaCXR.

• Bonescintigraphycanidentifysitesofneoplasia,Paget’sdisease,osteoporotic

fractures,severePTHbonedisease,orosteomalacia.Characteristicpatternsof

abnormalityexist.

• Whole-body CT scan is often the best single investigation to rule out deep

tissuemassesinabdomenandpelvis.

• Bonebiopsy(maintainedundecalcifiedbyplacingsamplein70%alcohol)of

affected sites will be diagnostic in some, but not all, cases of osteomalacia,

osteoporosis,andrenalosteodystrophy.Thebestsamplesareobtainedfroma

transiliacbiopsy.Bonemarrowcanbeaspiratedforexaminationatthesame

time.

• PET-CTisnowusedtoscreenforsuspectedsmalltumourswhereothertests

arenegative,forlocatinglymphomatissueforbiopsyandinidentifyingdeep

tissueinflammationorsepsiswherediagnosisisotherwiseunclear.

Chapter3
Regionalmusculoskeletalsymptoms:makinga
workingdiagnosis
Introduction
Neckpaininadults
Neckpaininchildrenandadolescents
Shoulderpaininadults
Shoulderpaininchildrenandadolescents
Painaroundtheelbowinadults
Elbowpaininchildrenandadolescents
Wristpaininadults
Symptomsinthehandinadults
Wristandhandpaininchildrenandadolescents
Upperlimbperipheralnervelesions
Thoracicbackandchestpaininadults
Thoracicbackandchestpaininchildrenandadolescents
Lowbackpaininadults
Lowbackpaininchildrenandadolescents
Pelvic,groin,andthighpaininadults
Pelvic,groin,andthighpaininchildrenandadolescents
Kneepaininadults
Kneepainandlowerlimbdevelopmentinchildrenandadolescents
Lowerlegandfootdisordersinadults
Lowerlegandfootdisordersinchildrenandadolescents
Introduction
Thischapteraimstoprovideaguidetoconstructingadifferentialdiagnosisin
the patient who presents with regional musculoskeletal (MSK) symptoms. It
doesnotmakereferencetoallpossiblediagnoses,onlythemostcommon.

Generalconsiderations(adults)

• Findings from conventional clinical examination and imaging of the MSK

systemusuallyoccurwhenthepatientisatrest,andthereforeonlyminimally

symptomatic.

• Examinationinthecontextoffunction(i.e.carrying,lifting,walking,bending,

etc.) is not easy, although it is arguably more appropriate. Therefore, a

thoroughhistoryutilizingagooddepthofknowledgeoffunctionalanatomyis

thebestalternativeandaninvaluablewayofobtaininggoodinformationabout

abnormalfunctionanditscauses.

• Time spent obtaining a detailed account of onset of symptoms is helpful

whetherornotthesymptomsareofrecentonset,orchronic,orassociatedwith

trauma.Patientsusuallyhaveaclearerconceptofinjury-induceddiseaseand

may try to rationalize the appearance of non-trauma-related symptoms by

associationwithaneventorinjury.

• Lay terms may reflect lay understanding. For example, the term ‘repetitive

straininjury’iscommonlyusedby thelaypersontodenoteadiagnosis.Itis

not a diagnosis, merely a description of a (unlikely!) mechanism by which

injuryhasoccurred.Itisimportanttoidentifyanatomicallywheretheproblem

liesandtothenenquireastoactivitiesthatmayhaveinducedorperpetuated

theproblem.

• Considerthepossibilitythattheproblemisa‘work-relateddisorder’(WRD).

A WRD may not just be MSK; consider the possibility of associated

respiratory (asthma, fibrosis), dermatological (dermatoses), neurological

(neuropathy, behavioural), psychosocial (anxiety, depression), and infective

(sewage, carcasses, needlestick) pathologies. Examples of MSK WRDs are

giveninthischapter.

• Withchildren,itisimportanttoobtainahistoryfromboththechildandacare

provider.Second-handinformation,evenifprovidedbyaparent,maybeless

reliable than direct information from someone who has the opportunity to

observethechildduringtheday.

• Regional MSK lesions may be a presenting feature of a systemic disorder,

suchasanautoimmunerheumaticdisease,malignancy,orinfection.Clinical

suspicionshouldguidetheevaluation.

• Screening for disseminated malignancy, lymphoma, myeloma, and infection

should at least include a FBC, metabolic screen, serum and urine protein

electrophoresiswithimmunofixation,ESR,andCRP.

• Weakness(asasymptom)maybeduetoaneuropathicormyopathiccondition

or it may be perceived according to the impact of other symptoms such as

pain.

Generalconsiderations(childrenandadolescents)

Regional MSK assessment in children and adolescents differs from adult

assessment, in the need to account for developmental variation, and motor

‘competence’.

• Though MSKproblemsfromcongenitaldeformities canpresent forthe first

time in adults—to adult rheumatologists—it is more likely that congenital

anomaliesaredisclosed initially inchildren.Regional MSK assessmentina

childrequiresconsiderationofthis.

• AlthoughMSKpainisanubiquitousexperienceinchildhood,responsetopain

by an individual child depends on various states of anxiety, stress, and past

experiences and can be influenced by the role of parents or other family

members.

Neckpaininadults

Backgroundepidemiology

• About 10%ofthe adultpopulationhas neckpainat any onetime, although

manypeopledonotseekmedicalhelp.

• About1%ofadultpatientswithneckpaindevelopneurologicaldeficits,but

overalllevelsofdisabilityarelowerthanforpatientswithlowbackpain.

• A continuum of radiological appearances exists in relation to age:

intervertebraldiscnarrowing,marginalend-plateosteophytes,andfacetjoint

changes. Appearances are often termed ‘degenerative’; however, the

correlationwithpresenceandseverityofpainispoor;Table3.1liststhemajor

causesofneckpaininadults.

Functionalanatomy

• Theneckisthemostmobile(37separatearticulations),butleaststablepartof

the spine. There are seven vertebrae (C1–C7) and five intervertebral discs

(C2/3–C6/7).TheC5/6discismostoftenassociatedwithradicularsymptoms.

If it occurs, cord compression is most likely in this region, although

atlantoaxial (C1–C2) subluxation may produce the same picture, especially

amongpatientswithRA.

• Minor congenital abnormalities are not infrequent and increase the risk of

degenerativechanges.

• NerverootsC2andC3coversensationoverthebackofthehead,thelower

jawline,andtheneck.

• Nerve roots (C4–T1) leave the spine in dural root sleeves, traverse the

intervertebralforamina,andformthebrachialplexus.

• Cervicalnerveshaveadermatomalrepresentation(Fig.3.1)andsupplyupper

limbmusculatureinapredictableway.

Fig.3.1Dermatomaldistributionofthecervicalandupperthoracicnervesreflectingtheradicularpatternof

nerverootlesions.

Table3.1Themajorcausesofneckpaininadults

Softtissuelesions(posture,

psychogenic,andoveruseas

modifiers)

Neckstrain

Torticollis

Myofascialpain

Trauma(e.g.acuteflexion-extension

injury(‘whiplash’))

Cervicothoracicinterspinousbursitis

Degenerativeandmechanical

lesions

Spondylosis

Discprolapse

Thoracicoutletsyndrome

Diffuseidiopathicskeletalhyperostosis

(DISH)

Inflammatoryconditions Rheumatoidarthritis(see Chapter5)

Spondyloarthropathy(±fracture

±inflammatorydiscitis)

Juvenileidiopathicarthritis(see

Chapter9)

Polymyalgiarheumatica(PMR)

Myelitis

Bonelesions Traumaticfracture

Osteomyelitis(e.g.TB)

Osteoporosis(fracture)(see Chapter

16)

Osteomalacia(bonediseaseormuscle

pain)

Paget’sdisease

Non-osseousinfections Generalsystemicinfection

(general/cervicalmyalgias)

Meningitis

Discitis

Malignancy Primary(rare)orsecondarytumours

(±pathologicalfracture)

Myeloma,lymphoma,leukaemia

Brachialplexuslesions Trauma

Thoracicoutletsyndrome(e.g.cervical

rib)

Referredpain Acromioclavicularor

temporomandibularjoint

Heartandmajorarteries(e.g.angina,

aortadissection)

Pharynx(e.g.infection,tumours)

Lunganddiaphragm(e.g.tumour,

subphrenicabscess)

Abdomen(e.g.gallbladder,stomach,

oesophageal,orpancreaticdisease)

Shoulder(e.g.adhesivecapsulitis)

Takingahistoryofneckpaininadults

Thesite,radiation,anddescriptionofpain

• Nerveroot(radicular)pain isusuallysharpandreasonablywelllocalized in

thearms.Itisoften‘burning’andassociatedwithparaesthesiaandnumbness.

• Nerve root irritation and compression by an intervertebral disc are common

causes of radicular pain. However, in older adults and those who suffer

recurrentboutsofpainitisusuallyduetoencroachmentofvertebralend-plate

or facet joint osteophytes, or thickened soft tissue or fibrosis on the nerve

leadingtostenosisoftheexitforamen.

• Painfromdeepcervicalstructuresiscommon.Itoftenlocalizespoorlyacross

theupperback.Itcanbereferredtotheupperarms,istypicallydescribedas

‘heavy’or‘aching’andismorediffusethannerverootpain.

• Musclespasmcanaccompanyanylesion.Itcanbeverypainful.

• Pain from the upper cervical spine (C1–C3) can be referred to the

temporomandibularjoint(TMJ)orretro-orbitalregions.Conversely,painfrom

bothTMJdisordersandasaresultofdentalmalocclusioncanbereferredto

theneck.

• Pain from the lower neck may be referred to the interscapular and anterior

thoracicwallregions.Thelattermaymimiccardiacischaemicpain.

• Floriddescriptionsofthepainandofitsextentandseverity(‘catastrophizing’)

areassociatedwithprominentpsychologicalmodulatorsofpain.

• Evaluation of the shoulder joint is often necessary as pathology there often

coexistsandsymptomsaroundtheshoulderoftencomplicateneckevaluation.

• Occipitalheadacheisacommonmanifestation.

Acuteneckpainwithtrauma

Acute neck pain with trauma requires urgent assessment, even if there are no

obviousneurologicalsymptoms:

• Acutetraumarequiresurgentevaluationforfracture,spinalcorddamage,and

vertebralinstability.About80%ofseriousinjuriesoccurfromanaccelerating

headhittingastationaryobject.

• An abrupt flexion injury may fracture the odontoid (less common with

extension); however, <1 in 5 injuries at C1/C2 produce neurological deficit

becauseofthewidecanalatthislevel.

• Ifnottraumaticorosteoporotic(thelatterbeingrelativelyrareinthecervical

spine),fracturesmayoccurinboneinvadedbymalignancy.

Newand/orassociatedsymptoms

Askaboutassociatedlegweakness,andnewbladderorbowelsymptoms.New-

onset acute neck pain with neurological features needs urgent evaluation.

Neurologicalsymptomsmayalsoaccompanychronicneckpain:

• Spinalosteomyelitis,meningitis,discitis(infectionorinflammation),myelitis,

andfracturemayallpresentwithacuteorsubacuteneckpain.Allmaycause

cord compression. Myelopathy due to spondylosis typically presents with a

slowlyprogressivedisabilityoverweekstomonths,althoughitcanbeacute,

particularlyifassociatedwithcentraldiscprolapse.

• Subacute pain,flaccidparalysis, andprofounddistal neurological signsmay

suggest myelitis, a condition caused mainly by infections and autoimmune

diseases.

• Tinnitus,gaitdisturbance,blurringofvision,anddiplopiaassociatedwithneck

painareallascribedtoirritationofthecervicalsympatheticnerves.

• The vertebralarteriespass close tothefacet joints justanteriorto emerging

nerveroots.Disruptionofvertebralbloodflowmaycausedizzinessinsevere

casesofneckspondylosis.

Previoustrauma

Askaboutprevioustrauma.Itcanprecedeandinfluencechronicpain:

• Acuteandoccupational(chronicoveruse)traumaisacommonantecedentof

chronicneckpain.

• Cervical dystonia (torticollis) can occur 1–4 days after acute trauma, it

respondspoorlytotreatment,andcanbelong-standing.Itmayalsocomplicate

arthropathy,suchasinRAorParkinson’sdisease.

• Whiplashinjuryisassociatedwithchronicmyofascialpain.

• Insomepatientswithchronicpainfollowing(sometimestrivial)trauma,there

may be dissatisfaction with the quality of care received at the time of the

injury.

• Unresolvedlitigationassociatedwithtraumacorrelateswiththepersistenceof

neckpainandreporteddisability.

Occupationalandleisureactivities

Someoccupations,sportsandactivitiesareassociatedwithrecurrentneckpain:

• Neck pain (andearlyspondylosis) is prevalentinpeople whose occupations

requirepersistentawkwardheadandneckpostures,e.g.professionaldancers.

• Although biomechanical factors may be an important influence in initiating

and aggravating neck pain, there may also be an underlying genetic

predispositiontoOAand/orhypermobility.

Otherpoints

Establishwhetherthepainstartedorvarieswithnon-MSKsymptoms:

• Cardiacischaemia,dyspepsia,orabdominalpaincanresultinreferredpainto

theneck(Table3.1).

Examinationoftheneck:adults

Theneckispartofthefunctionalupperlimbandsymptomsinthearmsandlegs

mayberelevant.Neurologicalexaminationofthearmsisimportant:

• Anadequateexaminationcannotbeperformedinaclothedpatient.Despitethe

inconvenience,itisimportanttohavethepatientchangeintoanexamination

gowntoavoidmissingrelevantclues.

• Inspectionfromfrontandbackmayrevealspecificmusclewastingorspasm

andpoorposture.

• Observing active movements reveals little if the patient has severe pain or

musclespasm.Inabilitytomovetheneckevensmalldistancesischaracteristic

inaxialspondyloarthritis(axSpA;see Chapter8).

• Tenderness often localizes poorly in degenerative disease. Exquisite

tendernessraisesthepossibilityofadisclesion,osteomyelitis,ormalignancy

(thelattertwoarerare).

• There may be ‘trigger points’ in neck stabilizer and extensor muscles.

Activation of a trigger point elicits myofascial pain in a zone that is

stereotypicalfortheindividualmuscle.

• Tender points (localized, non-radiating pain elicited by pushing with the

thumb), notably at the occipital origin of the trapezius, the medial scapular

border,andthemid-bellyofthetrapezius,arefeaturesoffibromyalgia(FM;

see  Chapter 22). It is not clear whether tender and trigger points are the

same.

• Examinationofpassivemobility maybehelpfulprimarilyif itrevealsgross

asymmetry.Thenormalrangeofmovementvariesdependingonage,sex,and

ethnicity.Generally,atleast45°oflateralflexionand70°ofrotationshouldbe

achieved in a middle-aged adult. Global loss of passive mobility is non-

specific and occurs with increasing age. The range of movement that might

indicatehypermobilityhasnotbeenestablished.

• Care should be taken if neck instability is a possibility (e.g. fracture, RA).

Vigorouspassiveexaminationofforwardflexionmayexacerbatedisclesions.

• Examination of the shoulder is important to evaluate any referred pain or

associatedarticularlesion(e.g.adhesivecapsulitis).

• Neurologicalexaminationofupperandlowerlimbsisimportantinall cases

where pain is referred to the arms and/or the legs if cord compression is a

possibility:lookforincreasedtone,clonus,pyramidalweakness,andextensor

plantarresponse.Checkforacervicothoracicsensorylevel.

Investigationofneckconditionsinadults

Radiographs

Radiographsshouldberequestedwithspecificobjectivesinmind:

• A lateral neck film may demonstrate soft tissue thickening in infection or

synovium in RA (see  Chapter 5), will document spondylitis

(syndesmophytes, discitis, and periosteal apposition in posterior elements

associatedwithpsoriasis),andtheseverityofspondylosis.

• Oblique viewscentred onthe suspectedlevelmayshownerve rootforamen

stenosisfrombonyencroachmentinpatientswithradiculopathy.Theremaybe

underlyingOA(see Chapter6).

• High cervical flexion and extension views and a ‘through-the-mouth’

(odontoid)viewareusefultoseeodontoidpathology.

• InanadultwithRA,ifthedistancebetweentheanteriorarchoftheatlasand

odontoidprocessis >3mm on alateral (flexion)image thereislikely tobe

C1/C2subluxationinthesagittalplane.

• Onalateralimage,superiorodontoidsubluxationinRAcanbejudgedfroma

reduced distance from the antero-inferior surface of C2 to a line drawn

between the hard palate and base of the occiput (McGregor’s line). The

distanceshouldbe>34mminmenand>29mminwomen.Lateralodontoid

subluxationisbestdemonstratedwithmagneticresonanceimaging(MRI).

• Stepwisevertebralsubluxationthroughoutthecervicalspinedemonstratedon

alateralimageischaracteristicofadvancedRA.

• Theremaybeonlyafew,butimportantsignsofspinalinfection,suchasasoft

tissuemassorisolatedlossofjointspace.

Magneticresonanceimagingandcomputedtomography(CT)

• MRI has largely superseded CT, arthrography, and CT arthrography in

assessing cervical spine/nerve, dural, vertebral, disc, and other soft tissue

lesionsintheneck.

• InmanycasestherelevanceofsomeMRIfindingsisstillbeingestablished—

patterns of signal abnormality do occur in asymptomatic people. The

frequencyoftheseeffectsincreaseswithage.

• MRIisthetechniqueofchoiceforimagingdiscprolapse,myelopathy(see

Plate2),myelitisandforexcludinginfectionortumours.MRIisusedtohelp

evaluate the need for, and plan, neurosurgical intervention in high cervical

instabilityinRApatients.

• MRI may show soft tissue swelling around the odontoid in calcium

pyrophosphatedeposition(CPPD)disease(see Chapter7),butthediagnosis

isbestmadewithCT,whichshowscalcificationaroundtheodontoidandof

adjacentligaments(‘crowneddenssyndrome’).

• In patients with the combination of unexplained radiographic signs and

generalized symptoms MRI is an important investigation. Cases of spinal

infectionsuchas tuberculosis(TB)orbrucellosisandlymphomaandcanbe

pickedup(see Chapter17).

Bonescintigraphy

• Despiteimprovedimagequalityandtomographicimages,theneckispoorly

imagedusingbonescintigraphy.

Treatmentofneckpaininadults

Fig.3.2showstheprinciplesoftreatingmechanicalcervicalsyndromesinadults

andthetimingofMRIscanning:

• Remember to review the diagnosis if pain persists despite treatment and

symptomsseemdisproportionatetotheresultsofimaging.

• In our experience, inflammatory spondyloarthritis (SpA)-related neck pains

canbemistakenasaresultof‘cervicalspondylosis’.Thismaybebecausethe

clinician too readily assumes the latter diagnosis and/or radiologists report

degenerativechangesonlyonradiographs.

Fig.3.2TheprinciplesoftreatingmechanicalnecksyndromesinadultsandthetimingofMRIscanning.

Neckpaininchildrenandadolescents

Generalconsiderations

Neckpainin children iscommon.See Table3.2. Though there are conditions

specifictochildhoodbelow,thissectionshouldbereadinassociationwithneck

painassessmentin adultsp. 74includingfunctional anatomyand examination

(foradolescents).

• Theprevalenceofneckpaininsecondaryschool-agedchildrenis~11%.

• Inonestudy,60% ofchildrenexperiencedatleastoneepisodeofneckpain

overa2-yearperiodand9%experiencedneckpain‘often’.

• OfthosechildrenwithneckpainwhopresenttoA&E,62%havehadtrauma,

19% presented following infection, in 18% neck pain is related to adverse

posture,andjust1.2%hadneckpainassociatedwithotherconditions.Neck

painresolvesin96%within2weeks.

Clinicalfeatures

• Inyoungerchildren,neckproblemsaremostcommonlymanifestastorticollis

orstiffness.

• Subacute or chronic infectious aetiology includes lymphadenitis, including

tuberculousretropharyngealabscess,anddiscitis.

• Bonepathologyisveryrarebutcausesincludeeosinophilicgranuloma,non-

bacterialosteomyelitis,andosteoidosteoma.Malignancyisusuallyassociated

withcharacteristicMRIfindings.

• SystemiconsetandotherformsofJIAareassociatedwithneckstiffnessmore

thanwithpain.

• Studiesinadulthoodhaveindicatedcervicalspineinvolvementinupto80%

casesofpolyarticularJIA.

• InJIA,neckinvolvementisoftenassociatedwithTMJinvolvement.

Examinationoftheneck:childrenandadolescents

• Generalguidelinesfortheassessmentofpainshouldbefollowedasoutlined

in Chapter1.

• There should be full exposure of the spine for the examination and a

neurologicalexaminationundertakeninallcases.

• A full examination includes assessment of posture and biomechanics of the

shouldersandlowerspineandpelvis.

• Examinationoflymphnodes,pharynx,eyes,andjointsisimportant.

• ImagingofchoiceisMRI.

Table3.2Thecausesofneckpaininchildren

Softtissue

injury

Neckstrain,congenitaltorticollis,traumaincludingwhiplash,

andsportinginjury

Inflammatory

conditions

JIA,juvenileSpA,non-bacterialosteomyelitis,myelitis

Skeletal

conditions

Osteomyelitis(includingTB),osteoidosteoma,histiocytosis,

malignancy,insufficiencyfracture(e.g.idiopathicjuvenile

osteoporosis)

Non-skeletal

infection

Lymphadenitis,meningitis,discitis,retropharyngealabscess

Neurological

conditions

Posteriorfossatumour,benignparoxysmaltorticollis,syrinx

Other Oculartorticollis(Duanesyndrome,refractiveerror,

nystagmus,visualfielddefect),chronicpainsyndrome,

thoracicoutletsyndrome

Shoulderpaininadults

Anatomyoftheshoulder

(SeeFig.3.3.)

• Theglenohumeraljointisaballandsocketjoint.Theshallowglenoidcavity

permitsawiderangeofmovement.Thecircularfibrocartilaginouslabrumsits

on theglenoid,increases the articularsurfacearea, and acts asastatic joint

stabilizer.

• Normalglenohumeralmovementsincludedepression,thenglideandrotation

ofthehumeralheadunderthecoraco-acromial(CA)archtoenableelevation

ofthearm.Asthearmelevates,thereissmoothrotationandelevationofthe

scapulaonthethoracicwall.

• Shoulder movements are a synthesis of four joints: glenohumeral,

acromioclavicular(AC),sternoclavicular(SC),andscapulothoracic.

• Movements at AC and SC joints enable slight clavicular rotation, shoulder

elevation/depression,andprotraction/retraction.

• TherigidCAarchprotectstheglenohumeraljointfromtraumaandit,andthe

overlying deltoid, are separated from the capsule by the subacromial

(subdeltoid)bursa.

• A cuff of muscles surrounds the glenohumeral joint capsule. These ‘rotator

cuff ‘muscles are the supraspinatus, infraspinatus, teres minor, and

subscapularis.

• The supraspinatus initiates abduction by depressing the humeral head, then

elevating the arm alone for the first 10° of movement. The more powerful

deltoid then takes over abduction. Infraspinatus/teres minor and the

subscapularis externally and internally rotate the arm in the anatomical

positionrespectively(Fig.3.4).

• Production of powerful shoulder movements requires some degree of arm

elevation as the larger muscles, such as deltoid, latissimus dorsi (extensor),

andteresmajor(adductor),workinefficientlywiththearmintheanatomical

position. Rotator cuff muscles act synchronously as joint stabilizers through

therangeofshouldermovement.

• The long head of the biceps tendon originates above the glenoid usually

attached to the labrum and runs within the glenohumeral joint capsule

anteromediallyinabonygroove.

Painandshoulderlesionsinadults

(Seealso Chapter20.)

• Shoulderpainiscommonandmayhaveitsorigininarticularorperiarticular

structuresormaybereferredfromtheneckorthoracicspine,thoracicoutlet,

orsub-diaphragmaticstructures(Table3.3).

• Shoulderlesionsoftenproducepainreferredtothehumeraldeltoidinsertion

(patientpointstoupperarm).

• Periarticular disorders, mainly shoulder subacromial impingement (SAI)

disorders, are the most common cause of shoulder pain in adults (>90% of

cases).

• Traumaticorinflammatorylesionsofmanydifferentshoulderstructuresand

conditions that result in neuromuscular weakness of the rotator cuff or

scapularstabilizersmayresultinimpingementpain.

• Painfromsubacromialimpingementsyndromeisthoughttobegeneratedby

the‘squashing’ofsubacromialstructuresbetweenthegreatertuberosityofthe

humeralheadandtheCAarchduringrotation/elevationofthehumeralhead.

Fig.3.3(a)Majorshoulderstructures.(b)Therelationshipofthejointcapsuletoitsbonysurroundandthe

coracoacromialarch.

Fig.3.4Themusclesoftheshoulder:(a)anteriorview;(b)posteriorview.

Table3.3Themostcommoncausesofshoulderpaininadults

Periarticularlesions(oftenmanifestas

subacromialimpingementpain)

Rotatorcufftendonitis/tears

(common>40years)

Calcifictendonitis

Bicipitaltendonitis

Subacromialbursitis

Enthesopathyassociatedwith

SpA,e.g.PsA

Periarticularmuscleweakness

Articularlesions

Synovitis(glenohumeralor

ACjoints)

OA(glenohumeralorAC

joints)

Glenohumeralinstability(e.g.

labraltears)

Adhesivecapsulitis(‘frozen

shoulder’)

Neurologic Cervicalnerverootand

radicularreferredpain

Neurologicalamyotrophy

Spinalcordlesions:tumours,

syringomyelia

Brachialneuromyopathy

Thoraciclesions(referredpain) Mediastinaltumours

Angina

Systemicanddiffuseconditions Polymyalgiarheumatica

Myositis(see Chapter14)

Chronicpainsyndromes(see

Chapter22)

Polyarticularinflammatory

arthritis

Bonedisorders

(see Chapter16)

Tumours

Osteonecrosis

Paget’sdisease

Takingahistoryaboutshoulderpaininadults

Whendidthepainstart?

Shoulderinjuriesarecommon,andmaybeacuteorchronic(overuse).

• Rotatorcufflesions(inflammation,degenerativeweakness,ortear)areoften

associated with activities and occupations that involve straining the arm in

abduction or forward flexion. A history of an acute injury, however, is not

always obtained. Subsequent calcification in the tendon following a

supraspinatusinjurycanbeasymptomaticorpresentwithacutepain.

• Manual labour is a risk factor for rotator cuff lesions. There is typically no

acute injury, but a history of repetitive movements over years that lead to

injury.

• Athleteswhotakepartinthrowingandracketsportsareatriskofrotatorcuff

tendinopathy and labral tears. Rugby and American Football players and

cyclistsareatriskofclaviclefracture,shoulderdislocationanddisruptionof

theACjoint.

• Pain from degenerative glenohumeral or AC joint arthritis might be a long-

termsequelaofaboneorjointinjury.

• Myofascial pain of the shoulder girdle is common and may mimic the

symptomsofcervicalradiculopathyandevenrefluxoesophagitisorischaemic

heartdisease.

• Severe,persistent,sleep-disturbingpainofrecentonsetmaybeindicativeof

avascularnecrosis,osteomyelitis,orbonytumours.

Whereisthepain?

• Painfromtheshouldermaybereferredtothedeltoidinsertion.

• Well-localized pain may occur with AC joint arthritis (e.g. patient places a

fingerontheaffectedjoint),butrememberthatreferredC4nerverootpainand

painfrombonelesionsofthedistalclavicleismaximalinthesamearea.

• Glenohumeral articular and capsulitis pain is not well localized (e.g. the

patientcoverstheirshoulderwiththeirhand).

• Pericapsular pain may be associated with SAI, but may also be myofascial

(typically)orreferredfromthecervicothoracicspine.

• Bilateral shoulder pain should increase suspicion of the presence of an

inflammatory polyarthritis such as RA (see  Chapter 5), psoriatic arthritis

(see Chapter8) orCPPDarthritis (see Chapter 7)—but these would be

rarewithoutotherjointsymptoms.

• Diffusepainacrosstheshouldergirdlemusclesinthose>55yearsoldraises

thepossibilityofPMR.Painisoftenassociatedwithimmobilityandstiffness,

particularlyearlyintheday.

• A deep aching pain associated with stiffness is characteristic of adhesive

capsulitis (frozen shoulder). The useofthetermfrozenshoulderis popular,

butoftenincorrectlyapplied.Itisaconditionthatisrareinpatients<40years

of age. The condition occurs in three phase: a painful phase, an adhesive

(‘frozen’)phase,andaresolutionphase.Phasesoftenoverlapandtheduration

variesbutlong-termlimitationofshouldermovementremainsinupto15%of

patients.Itisassociatedwithdiabetes.

Doesthepainvary?

Movement-orposture-relatedpainmaybeacluetoitscause:

• Rotator cuff lesions often present to rheumatologists with a subacromial

impingementpatternofpain—thatis,painreproduciblyaggravatedbyspecific

movements during each day such as reaching up (overhead) with the arm.

Articular,bone,andadhesivecapsulitispainismorelikelytobepersistent.

• A history of recurrent bouts of shoulder pain in young adults may suggest

glenohumeralinstabilityduetohypermobilityorprevioustrauma,e.g.alabral

tear.

• In an unstable shoulder, pain may result from synovitis, subchondral bone

damage,oranSAIdisorder.Thefrequencyofrecurrentanteriorsubluxationis

inverselyproportionaltotheageatwhichtheinitialdislocationoccurs.

Aretherespinalsymptoms?

There is an association between neck conditions and shoulder pain. C4 nerve

root pain is referred to the shoulder, adhesive capsulitis is associated with

cervical nerve root symptoms (the nature of the link is unknown), and

inflammatoryconditions,suchasCPPDandpsoriaticspondylitisformscanbe

associatedwithbilateralshoulderpainreferralandcanmimicPMR.

Examinationoftheshoulderinadults

Visualinspection

Inspect the neck, shoulders, and arms from the front, side, and back with the

patientstanding.

• Abnormalityofthecontourofthecervicothoracicspinecouldindicatemuscle

imbalance/spasmormightbeassociatedwithanerverootoriginofpain.

• Scapularasymmetryatrestisespeciallyrelevantwhenexaminingchildrenand

may indicate a congenital bony deformity. Subtle degrees of asymmetry are

common and are not usually due to specific pathology, nor are they of

consequence.

• Diffuse swelling of the whole shoulder may suggest a shoulder

effusion/haemarthrosis or subacromial bursitis. In the elderly, Milwaukee

shoulder should be considered. Swelling of the AC joint occurs with joint

diastasis,arthritis,anddistalclavicularbonelesions.

• Armswellingandskinchangesdistallycouldindicateacomplexregionalpain

syndrome.

Elicitanytenderness

Elicitingtendernessofshoulderstructuresisoftenunrewarding:

• TendernessoftheACjoint,humeralinsertionofthesupraspinatustendon,and

thelongheadofbicepstendonmaybecluestopathology,butpalpationwill

notbespecificfordiagnosis.

• ThedeltoidoriginisatypicalenthesisinvolvedinactivePsA.

• Anappreciationoftriggerpointsassociatedwithmyofascialpainandtender

pointsinfibromyalgia(see Chapter22)isimportantintheinterpretationof

regionalsofttissuetenderness.

Documentbilateral(active)shouldermovements

This aids diagnosis but also gives an indication of the level of functional

impairmentandcanhelpinmonitoringchangesovertime.Themovementsare

first tested actively (the patient does the movement) and then passively (the

cliniciansupportsthelimb).Musclestrengthcanalsobeassessedwhiletesting

activemovement.

• Observe active arm elevation in the scapular plane from behind, noting

symmetryofscapularmovement,thepatternofpainduringelevation,andthe

range of elevation. Hunching of the shoulder at the outset of arm elevation

often occurs with an impingement problem. A painful arc may suggest a

rotator cuff lesion. Inability to lift the arm suggests a rotator cuff tear or

weakness, capsulitis, or severe pain, e.g. acute calcific supraspinatus

tendonitis.

• Observe and compare active internal rotation of shoulders, which can be

judgedbyhowfarupthebackthehandcanreach.Poorperformancemaybe

duetorotatorcuffweakness,weaknessofthescapularstabilizingmuscles,or

pain (generally from impingement syndrome). This manoeuvre assumes

normalelbowfunction.

• Observe theactive rangeof externalrotationofthehumerusfromthefront.

Ask the patienttoflex their elbows as if theywereholdinga tray and then

rotatethearmsoutwards.Minordegreesofrestrictioncausedbypainarenot

specific,butsevererestrictionischaracteristicofadhesivecapsulitis.

• Passiverangeofmotionshouldbetestedwithtwohands:onehandguidesthe

movement, while the second rests on the shoulder. Many patients will

subconsciouslyflexthespinetocompensateforrestrictedrangeofmotionat

theshoulder;usingbothhandscanhelpdetectthisandotherabnormalitiesin

movementatthejoint.

Testforsubacromialimpingement

• Always compare the affected with the non-symptomatic side and make

conservative judgements about muscle weakness if there is pain impeding

voluntaryeffort.

• Most tests rely on their ability to narrow the distance between the humeral

headandtheCAarch,bydrivingthegreatertuberosityundertheCAarchas

thehumerusrotates(Fig.3.5).

• Whetherthetestsarespecificforlesionsofthesubacromialstructuresorfor

thesiteofimpingementisunknown.

Movementoftheglenohumeraljoint

Movetheglenohumeraljointpassivelyinalldirectionsbymovingtheupperarm

with one hand and placing the other over the shoulder to feel for ‘clunks’,

crepitus,andresistancetomovement:

• Ifthehumeralheadcanbeslidanteriorly(oftenwitha‘clunk’)clearlywithout

rotationintheglenoiditsuggestsinstability.

• Grosslyreducedpassiveshouldermovement(notablyexternalrotation,withor

withoutpain)isthehallmarkofadhesivecapsulitis.

• Pull down on both (hanging) arms. If the humeral head moves inferiorly

(sulcussign)theremaybeglenohumeralinstability.

Stresstheacromioclavicularjoint

StressingtheACjointmayreproducethepain.Thisisconventionallydoneby

compressionorsheartests:

• These tests should not normally be painful. Although painful tests have not

provedtobespecificforACpathology(painfromSAImayalsobepresent),a

positive test may provide a clue that the AC joint is arthritic, dynamically

unstable,orthatimpingementofstructuresinthesubacromialspaceunderthe

ACjointisoccurring.

• Holdthepatient’sarminforwardflexion(90°)anddrawitacrossthetopof

the patient’s chest. The resulting compression of the AC joint may produce

pain.ACjointpaincanalsobeelicitedbypassivelyelevatingthearmthrough

180°,bringingthehandtotheceiling.Painisexperiencedintheupper10°or

soofmovement.

Gaugestrengthinrotatorandothershouldermuscles

Oncethepotentialactiverangeofmovementhasbeenascertainedinthecontext

ofpainandyouknowwhichmovementshurt(bytestingactivelyandpassively)

thenyoucanjudgethevalidityoftheexaminationofisolatedmuscleresistance

testing(Table3.4):

• Rotatorcuffmusclesneedtobetestedsub-maximallyinregardofstrengthfor

strengthagainst resistance—explaintothepatientnottopushtoohard—see

Table3.4.

• Knowledge of nerve supply is important to know whether there might be a

neuromyopathic cause for weakness and where a lesion might be (post-

infectivebrachialneuritis cancausefocalrotatorcuffneuromyopathyandis

notuncommon).

Table3.4Isolatedmuscletestingofshouldergirdlemuscles

Muscle:nerve

root,peripheral

nerve,supply

andmuscle

action

Muscleposition Isolatedmuscle

test

Pathology

affectingmuscle

strength/bulk

Supraspinatus:

C5/C6.

Suprascapular

nerve.Initial

humeral

abductionand

stabilityofraised

upperarm

Frombehind,

seenandfelt

abovethe

scapularspineat

restandwhen

activated

Abductarmfrom

neutralagainst

resistance

Tearordisuse

followingdamage,

e.g.afterafall,

chronicoveruse

stress,orin

athletes(throwing

arm)

Infraspinatus:

C5/C6.

Suprascapular

nerve.External

rotationand

stabilityof

humeralhead

Frombehind,

seenandfelt

arisingfrom

medialscapular

borderpassing

laterally(below

thescapular

spine)

Externalrotation

ofarminneutral,

elbowsupported

andflexedat90°

Tearordisuse

followingchronic

damage

Serratus

anterior:C5–C7.

Appreciatedfrom

behindwhen

Testbypushing

wallwithan

Damagetolong-

thoracicnerve

Long-thoracic

nerve.Pullsthe

scapulaforward

onthethoracic

wall(extends

forwardreachof

arm)

patientispushing

againstawall

witharms

outstretchedin

front,inthat

scapularemains

fixed

outstretchedarm

orpush-up.If

paralysedthere

willbeliftingand

lateralexcursion

ofthescapula

fromtrauma.

Patientmayalso

haveSAI

Deltoid:C5/C6.

Axillarynerve.

Flexion,extension

butmainly

abductionof

humerus

Arisesfromthe

scapularspine

andacromion,

thenswathesthe

shoulderinserting

intothehumerus

laterally

Wastingmaybe

obvious.

Weaknessin

isometricstrength

ofanarm

abductedto90°

Lesionsofaxillary

nervedamagedby

anteriorshoulder

dislocation

(externalrotation

mayalsobeweak

fromdenervationof

teresminor)

Fig.3.5Testsusefulforelicitingsubacromialimpingement.

Shoulderexaminationwiththepatientsupine

Examinetheshoulderswiththe patientsupineto testwhetherthereis anterior

cuff deficiency, glenohumeral joint laxity, or a labral tear: this is especially

important in young adults and adolescents to identify an ‘unstable shoulder’.

Holdandsupport the upper armheld in slightabductionand external rotation

(theelbowisflexed).Movethearmgently(craniallyinthecoronalplane)and

applygradualdegreesofexternalrotation.

• Deficiencyofanteriorstructuresissuggestedbypatientapprehensionthatpain

isimminentorthattheshoulderwillslipforward.Withalabraltear,theremay

beanaudibleorpalpable‘clunk’.

• Pressure down on the upper arm (taking the pressure off anterior shoulder

structures by an anteriorly translocated humeral head) may relieve

apprehensionorpainassociatedwithit(+verelocationtest).

• An unstable shoulder identified with the above tests may denote previous

traumaticinjury(e.g.shoulderdislocation)orahypermobilitydisorder.

Investigationsofshoulderdisordersinadults

Optimum initial imaging for investigating undiagnosed shoulder pain is

disputed.Managementofshoulderproblemsbasedonhistoryandexamination

alone isapracticalapproach to a common problem,sincemanyproblems get

betterintheshortterm.Thelong-termsequelaeofsuchmanagementstrategies,

however,areunknown.Studiesofshoulderpainprimarilysuggestthatchronic

shoulderproblemsarecommon,oftendespiteinitialimprovement.

Radiographs

• The standard projection for screening purposes is anteroposterior (AP),

although the AP axial–lateral view taken with the arm abducted may add

informationabouttherelationshipoftheglenoidandhumeralhead.Lookfor

calcific deposits in soft tissue basic calcium phosphate crystals: Milwaukee

shoulder(see Chapter7).

• Supraspinatusoutletviewsareoftenusedtoassessacromialconfigurationand

identifyinferioracromialosteophytesinpatientswithSAI.

• Ifrecurrentdislocationissuspected,associatedhumeralheaddefectsmaybe

identified by an AP film with internal humeral rotation or a Stryker view.

Bilateralfilmsdistinguishanomaly(invariablybilateral)fromabnormality.

• BilateralAPACjointviewswiththepatientholdingweightsmayidentify,and

gradedegreesof,ACjointdiastasis(separation).Distalclavicularerosionmay

be due to RA, hyperparathyroidism, myeloma, metastases, or post-traumatic

osteolysis.

• AlthoughcharacteristicpatternsofabnormalityareassociatedwithSAI(see

Plate3),minorage-relatedradiographicabnormalitiesarenormal.

Otherimaging:ultrasound,arthrography,CTarthrography,MRI,isotope

bonescan

• Ultrasound (US) scoring systems for locating and grading rotator cuff tears

now exist. US permits examination of the rotator cuff with the shoulder in

differentpositions,butishighlyoperatordependent.

• Patterns of rotator cuff abnormality and subacromial impingement are well

recognizedwithbotharthrographyandMRI.However,thereisnoconsensus

aboutwhichofultrasound,MRI,orarthrographyismostaccuratefordetecting

rotatorcufftears.

• Children, adolescents, and young adults suspected of having unstable

shoulders should have an MRI examination, since detailed views of the

humeral head, glenoid labrum, periarticular glenohumeral soft tissues, and

subacromialareaareimportant.

• MRIisthemodalityofchoiceinyoungadultswheninstabilityisdiagnosed.

Rotator cuff lesions and labral abnormalities are best assessed with MRI.

EnhancementwithIVcontrastmay increasethechanceofdetectingalabral

tear.

• No specific patterns of bone scan abnormality have been consistently

recognized for isolated shoulder lesions, although a phase study may be

diagnosticforcomplexregionalpainsyndromeinthearm.

Otherinvestigations

• Local anaesthetic injection may help disclose the site of shoulder pain,

although it is possible that by the time anaesthesia occurs, the injected

anaesthetichasspreadtoareasnotintendedasatarget.

• Jointaspirationisessentialifinfectionispossible.Fluidis usuallyaspirated

easily from a distended shoulder capsule. Haemarthroses can occur in

degenerateshoulders,with haemophilia, trauma,and pigmented villonodular

synovitis(PVNS).

• Electrophysiological tests (electromyography (EMG)/nerve conduction study

(NCS)) may confirm muscle weakness and help establish the presence of

neuromusculardisease,e.g.myositisorneurologicalamyotrophy.

• Bloodtestsarerequiredifconsideringinfectionorinflammation.

• A normal creatine kinase (CK) and aldolase will rule out myositis in the

majorityofcases.

• Bloodurea,electrolytes,creatinine,alkalinephosphatase,calcium,phosphate,

thyroidfunctiontests,andmyelomascreenshouldbeconsideredifmetabolic

boneormyopathicdiseaseisconsidered.

Treatmentofshoulderdisordersinadults

• Physicaltherapyshouldplay afocalpartinencouragingmobilizationofthe

joint,andearlyassessmentisprudent.

• Know whether there is an additional neck/spinal generated pain component

(physicaltherapistsareindependentdiagnosticiansandsomemayerroneously

aimtherapyatcervicothoracicsegmentsforindividualshoulderlesions).

• Donotrefertophysiotherapywithoutknowledgeofwhowillseethepatient,

andtheapproachthatwillbetakenforinstabilityandrotatorcuffweakness.

• Simpleanalgesicsareoftennecessary.

• Steroid injections can be considered in the following situations (see also

Chapter24):

• Tendonitisoftherotatorcuff.

• Adhesivecapsulitis(see Plate4).

• ACjointpain.

• Subacromialbursitis(see Plate5).

• The principles of steroid injection and rehabilitation are dealt with in

Chapter24.

• Thereareseveralsituationswherelocalsteroidsshouldbeavoided:

• Bicipitaltendonitis(rest,analgesia,physicaltherapy).

• Thefirst6weeksofanacuterotatorcufftear.

• When symptoms have become chronic and conservative therapy has not

helped for a presumptive clinical diagnosis (this requires reassessment,

imagingassurgerymayberequired).

• Surgical intervention may be: subacromial decompression arthroscopy,

synovectomyoftheSCjointandACjoint,orexcisionofthedistalendofthe

clavicle:

• Subacromial decompression may be necessary for chronic rotator cuff

tendonitis especially when imaging has shown inferior acromial

osteophytes.

• Otherinterventionsincluderepairofarotatorcufforbicepstendonrupture

andjointreplacement (forpain reliefratherthan improvementin function

mainly).

• Lithotripsy does not offer advantages over steroid injection and physical

therapyforcalcificsupraspinatustendonitis.

Shoulderpaininchildrenandadolescents

Generalconsiderations

Theprevalenceofchronicshoulderpaininadolescentsis7–11%.

• Theprincipalcauseofshoulderpainisbiomechanicalimbalanceeitherfrom

deconditioning, sporting injury (e.g. labral tear or rotator cuff lesions),

overuse,orsecondarytodirecttrauma.

• TheshouldercanbeinvolvedinJIA.

• Examinationfollowstheprinciplesofadultexaminationalreadydescribedand

paediatricguidelinesonexamination—see Chapter1.

Table3.5Causesofshoulderpaininchildrenandadolescents

Softtissue

injury

Biomechanicalimbalanceanddeconditioning:adverse

neuromuscularpatterning/glenohumeralorscapularinstability;

subacromialimpingement;bicepstendinopathy;rotatorcuff

tendinopathy;trauma;myositis

Joint

pathology

ACjointinjury;juvenileidiopathicarthritis;labraltear

Skeletal

lesions

Proximalhumeralstressinjurytophysis(includinglittle

leaguer’sshoulder);osteomyelitisandnon-bacterialosteomyelitis

(especiallyofclavicle);osteoidosteoma;osteosarcoma

(especiallyinadolescent);fracture;distalclavicularosteolysis

Other Brachialplexusinjury;chronicpainsyndrome;referredpain

(fromtheneck);thoracicoutletsyndrome;periphrenic

inflammation

Painaroundtheelbowinadults

Functionalanatomy

• The humero-ulnar articulation is the prime (hinge) joint at the elbow. The

radius also articulates with the humerus and allows forearm and hand

supination/pronation,withtheulnaattheelbow(Fig.3.6).

• Normalextensionresultsinastraightarm,butsomemuscularpeoplelackthe

last5–10°ofextensionandsome(especiallywomen)haveuptoanextra10°

ofextension(hyperextension).

• Normal flexion is to 150–160° and forearm supination/pronation range is

around180°.

• Duetoobliquityof thetrochlea,extension isassociatedwitha slightvalgus

thatcanbeaccentuatedinwomen(upto15°).

• Unilateral acute traumatic or chronic overuse lesions of the elbow are

common.Bilateralsymptomsmayoccurinthesesituations,butalsoconsider

the possibility of an inflammatory arthritis affecting the elbows or referred

painfromtheneck.

Takingahistoryofelbowpaininadults

Ispainexclusivelylocatedintheelboworreferredfromelsewhere?

Establish whether the pain is associated with neck pain and whether it has

neurogenicqualitiesorisassociatedwithparaesthesiasornumbness.Painmay

bereferredfromproximalneurologiclesions(e.g.C6,C7)orfromdistallesions

suchascarpaltunnelsyndrome(CTS).

Isthereahistoryofacuteorchronic(overuse)trauma?

• Pain at the lateral epicondyle 1–2 weeks after a weekend of ‘home

maintenance’ might suggest lateral epicondylitis (tennis elbow) following

excessiveuseofascrewdriver,forexample.

• Othercommonsitesofpain,wherecharacteristicconditionsrelatedtooveruse

arerecognized,includethemedialhumeralepicondyle(‘golfer’selbow’)and

theolecranonbursa(repetitivepressure/friction).Althoughtypicallyacutein

onset,theseconditionsmaydevelopinsidiously.

• Fractures around the elbow and fractures/dislocations in the forearm are

common.

• Dislocation of the radial head alone is rare and is usually associated with

concurrentfractureoftheulna(radiographsmaynotidentifythefracture).If

notassociatedwith fracture(and especiallyifrecurrent), dislocationmay be

associatedwithgeneralizedhypermobility(see Chapter19)orshorteningof

theulnaduetobonedysplasia.

Fig.3.6Bonyconfigurationatthe(right)elbow(anteriorview).

Doesthepainradiatedistally?

• ForearmpainmaybeanadditionalcluetoC6orC7radicularpain,butmay

alsobedueto thespreadof MSKpainalongtheextensorgroupofmuscles

fromlateralepicondylitisorfromentrapmentofthemediannerveintheelbow

region.

• Peritendonitis crepitans is pain, tenderness, and swelling in the forearm

associatedwithoccupationaloveruse.Itisthoughttobeduetodamageofthe

longwrist/handflexorsandextensorsatthemuscle–tendonjunction.

• Diffusepainintheforearmcanoccurasaresultofoveruseinjury,particularly

in musicians and typists, although there is overlap with regional pain

syndromes.

• Painaroundtheforearmmayalsoarisefrominflammationatthewrist(see

‘Wrist pain in adults’, pp. 106–109) particularly in De Quervain’s

tenosynovitis.

Isthereprominentstiffnesswiththepain?

• Stiffnessisoftennon-specificbutmaydenoteinflammationsuchassynovitis

of the joint or olecranon bursa. It raises the possibility of an autoimmune

rheumaticorcrystaldepositiondisease.

• Inthemiddleagedandelderly,gout(see Chapter7)oftheolecranonbursa

andsurroundingsofttissues,particularlyoverlyingtheborderoftheulna,is

commonandisoftenmisdiagnosedasacellulitis.

Askaboutlocking

Locking of the elbow either in flexion or supination/pronation may be due to

loose intra-articular bodies. A single loose body is most commonly due to

osteochondritis dissecans of the capitellum and multiple loose bodies are

associatedwithOAorsynovialchondromatosis.

Isthepainunremittingandsevere?

Thistypeofpainsuggestsbonypathology:

• Althoughnon-fracturebonepathologyisrareintheelbowregion,localbony

painmightsuggestosteochondritisoravascularnecrosisor,ifpartofawider

patternofbonypain,metabolicbonedisease.

• Intheelderlyandothersathighriskforosteoporosis,supracondylar,andother

fracturesmayoccurwithsurprisinglylittletrauma.

Aretheresymptomsinotherjoints?

Askaboutotherjoints,lowback(sacroiliac)painsandrisksforgout:

• ElbowsynovitisisanuncommonpresentingfeatureofadultRA.

• Periarticularenthesitisisarecognizedfeatureofspondyloarthritis(SpA)(see

Chapter8)andmaymimictenniselbow.

• Theperiarticulartissuearoundtheelbowisacommonsiteforgout.

Examinationoftheelbowinadults

Lookforabnormalitythenpalpatewiththethumb.Observetheactive,passive,

andresistedactive rangeofjoint and relatedtendon movements, andconsider

examining for local nerve lesions. A complete assessment should include

examinationofneck,shoulder,andwrist.

Visualinspection

Lookforobviousdeformityorasymmetryintheanatomicalposition:

• Upto10°ofextensionfromastraightarmisnormal.Moreextensionmight

suggestahypermobilitydisorder.

• A child with an elbow lesion typically holds the extended arm close to the

body,ofteninpronation.

• Swellingduetojointsynovitisisdifficulttoseeintheantecubitalfossaunless

itisflorid:itismosteasilyseen(andmoreeasilyfelt)adjacenttothetriceps

tendoninsertion.

• Theolecranonbursa,whichmaybeinflamed,overliestheolecranonanddoes

not as a rule communicate with the joint. Overlying erythema, though non-

specific,maybeasignofinfectionorgout.

• NodulesovertheextensorsurfaceorulnabordermaybeassociatedwithRA

(see Chapter5).

• Psoriaticplaquesarecommonlyfoundattheelbowextensorsurface.

Observeactiveflexionandsupination/pronationwiththeelbowsheldin90°of

flexion

• Althoughtherangeofmovementmaybeaffectedbyextra-articularpain,loss

ofrangeusuallyimpliesanintra-articulardisorder.

Palpatethelateralepicondyleofthehumerus

• Inlateralepicondylitis(tenniselbow),thereistenderness,whichmayextend

distally. Resisted wrist and finger extension with the elbow in extension or

passivelystretchingthetendons (makefist,flexwrist,pronateforearm,then

extendelbow)mayreproducethepain.

• Lateralepicondyletendernessmaybeduetoinflammationoftheradiohumeral

bursathatliesundertheextensortendonaponeurosis.

• Notethattendernessoflateralandsometimesmedialepicondylescanoccurin

chronicpainsyndromes.Inthesecases,therelevantextensororflexortendon

provocationtestsarelikelytobenegative.

Palpatethemedialhumeralepicondyle

• Tenderness suggests traumatic medial epicondylitis (‘golfer’s elbow’), a

regionalorchronicpainsyndrome,orenthesitis.Confirmthesiteofthepain

by stretching the wrist flexors—supinate the forearm then passively extend

boththewristandelbowsimultaneously.Resistedpalmarflexionofthewrist

or forearm pronation with elbow extension may also cause pain. Tasks that

relyonthisrepetitivemovementareoftentheprovokingcause.

• Consider osteochondritis of the medial humeral epicondyle as a cause of

persistentpainfollowinganinjury.

Passivelyflexandextendtheelbowjoint

Passivelyflexandextendthejointand notetherangeof movementand‘end-

feel’(thefeelofresistanceattheendoftherangeofpassivejointmovement):

• ‘End-feel’maytell youwhetherthere isablock to fullflexion or extension

from a bony spur or osteophyte (solid end-feel) or from soft tissue

thickening/fibrosis(springy,oftenpainful).

• Noteanycrepitus(oftenassociatedwithintra-articularpathology)andlocking

(mayhaveloosebodiesinthejoint).

Supinateandpronatetheforearm

Passively supinate and pronate the forearm supporting the elbow in 90° of

flexionwithyourthumbovertheradioulnararticulation:

• There may be crepitus or instability/subluxation associated with pain.

Instabilitymightsuggestatear/damagetotheannularligament(duetotrauma

orchronic/aggressiveintra-articularinflammation).

Testperipheralnervefunctioniftherearedistalarmsymptoms

• Givenitscoursearoundthelateralepicondyle,theintegrityoftheradialnerve

shouldalwaysbetestedwhenalateralelbowlesionissuspected.

• The median nerve runs in the antecubital fossa and may be affected in

traumaticelbowlesions.Itisparticularlysusceptiblewhereitrunsbetweenthe

twoheadsofpronatorteres(frommedialepicondyleandthecoronoidprocess

oftheulna)andseparatesintoanteriorinterosseousandterminalmediannerve

branches.

• Theulnarnerveliesinthegroovebehindthemedialepicondyle.Bonyorsoft

tissueabnormalityinthisareamayaffectnervefunctionandleadtoreduced

sensationinthelittlefingerandweaknessinthesmallmusclesofthehand,the

flexorcarpiulnaris(FCU),theextensorcarpiulnaris(ECU),ortheabductor

digiti minimi (ADM). The median and ulnar nerves are dealt with in more

detailinthelatersectionsonwristandhanddisorders.

Investigationofelbowconditionsinadults

Radiographsandotherimaging

• Standard AP and lateral radiographs are the most straightforward way of

imagingtheelbowinitially.CTorMRImaythenbeneededifthediagnosisis

stillobscureandreferredpaincanberuledout.

• Look for periosteal lesions and enthesophytes (new bone spurs at clear

entheseslikethetricepsinsertion).Periostealnewboneandenthesophytesare

typicalinpsoriaticarthritis(see Chapter8).

• A lateral radiograph may identify displacement of the anterior fat pad

associatedwithajointeffusion(sailsign).

• Dislocations of the radial head and associated ulna fractures in children are

easilymissed.Tomakethisdiagnosisahighdegreeofsuspicionandfurther

imagingareoftenneeded.

Needlearthrocentesis/olecranonbursocentesis

• Arthrocentesis/bursocentesiswithfluidsentformicroscopyandcultureshould

alwaysbedoneinsuspectedcasesofsepsis.

• Fluid should be sent for polarized light microscopy in cases of bursitis that

maybeduetogout.Serumurateisworthrequestingbutmaynotberaisedin

acutegout.

• Examination of fluid for crystals should always be considered in cases of

monoarthritisintheelderlyorpatientsondialysis.

Electrophysiology

If nerve entrapment is suspected and there is some uncertainty after clinical

examination, then electrophysiological tests may provide useful information.

Testingcanhelpidentifythedegreeandlikelysiteofnervedamageandcanhelp

todiscriminatebetweenaperipheralandnerverootlesion(ifEMGofselected

musclesrequestedalso).

Treatmentofelbowconditionsinadults

• Themanagementoffracturesisbeyondthescopeofthistext.

• Epicondylitisisbestmanagedearlyonwithrest,splinting,analgesia,andlocal

steroidinjections.Theefficacyofphysicalmanipulationhasnotbeenproven,

although there are theoretical reasons why ultrasound therapy could be of

value (e.g. it passes through the myofascial planes and concentrates near

bone).Resistantcasesmaybenefitfromsurgery—a‘lateralrelease’.

• Steroid injections (see  Chapter 24) may be of value in the following

situations:

• lateralormedialepicondylitis(hydrocortisone).See Plate6.

• inflammatoryarthritis(usuallylongactingsteroid).

• olecranonbursitis.

• ulnarnerveentrapment.

• Surgicalprocedures include excisionof nodules andbursae,transposition of

the ulnar nerve, synovectomy, excision of the head of the radius, and

arthroplasty.

• Arthroplasty in inflammatory arthritis is best reserved for severe pain and

shouldbeundertaken byan experiencedsurgeon. Lesserprocedures suchas

proximalradialheadexcisioncanbeeffectivetoimprovepainandfunctionif

forearmpronation/supinationarepoor.

• Radiation synovectomy of the elbow (Re-186) for inflammatory arthritis,

PVNS, or synovial chondromatosis requires ultrasound guidance (see

guidelinesavailableat http://www.eanm.org).

Elbowpaininchildrenandadolescents

Generalconsiderations

Theelbowisacommon siteof injuryin childrenandadolescents;thegrowth

plateandenthesealattachmentsarevulnerabletooveruseinjurybeforeskeletal

maturity.

• Characteristic injurious lesions are associated with specific activities (e.g.

baseballpitchingorthrowingsports,gymnasts).

• Thetwomainenthesesattheelbow—originoflongtendonstothefingersat

medial andlateralhumeral epicondyles—can become inflamed orpainfulin

peoplewithjuvenilePsAorSpA.

• Examinationoftheelbowinyoungpeopleisasforadultssee p.100.See

alsofunctionalanatomysee p.98.

Table3.6Causesofelbowpaininchildrenandadolescents

Lateral

elbow

Lateralhumeralepicondylitis/enthesitis(causedbytraumaorJSpA

orJPsA);osteochondritisandosteochondritisdissecans(adolescent

gymnasts);Panner’sdisease(osteonecrosisofcapitellumseenin

childrenaged5–10yearsandmayberelatedtothrowinginjuries)

Medial

elbow

Medialhumeralepicondylitis/enthesitiscausedbytrauma—seen

inchildren9–12yrsfromthrowingsportsincludingpitchingin

baseball—andenthesitisinJSpAandJPsA;medialcollateral

ligament(MCL)injury;ulnarneuritis;pronatorstrain

Posterior

elbow

Olecranonenthesitis;olecranonosteochondritis;olecranon

impingement(overheadarmuseinracketsports,swimming,

boxing,etc.);tricepsavulsion

Other JIA;fracture;loosecartilaginousbody;skeletaldysplasia

Wristpaininadults

Functionalanatomyofthewrist

• The wrist includes radiocarpal (scaphoid and lunate) and intercarpal

articulations.Theulnadoesnottrulyarticulatewiththelunate,butisjoinedto

it,thetriquetrum,andtheradius(ulnarsideofdistalaspect),bythetriangular

fibrocartilagecomplex.

• Theintercarpaljointsarejoinedbyintercarpalligamentsandaremoststable

whenthewristisinfullextension.Anteriorcarpalligamentsarestrongerthan

posterioronesandarereinforcedbytheflexorretinaculum.Wristandfinger

flexor tendons, the radial artery, and the median nerve enter the hand in a

tunnelformedbythecarpalbonesandtheflexorretinaculum(carpaltunnel).

• Flexion(70°),extension(70°),radialandulnardeviation(about20°and30°

frommidline,respectively)occuratthewristbutsupination/pronationofthe

wristandhandisduetoradiohumeralmovementattheelbow.

• Flexorcarpiradialis(FCR)andulnaris(FCU)arethemainflexorsofthewrist,

although palmarislongus(PL)also helps (Fig.3.7). They all arise from the

medialhumeralepicondyle.

• Allcarpalextensorsarisefromthelateralhumeralepicondyle(Fig.3.7).

• Radial deviation (abduction) occurs primarily when radial flexors and

extensors act together. Ulnar deviation (adduction) occurs primarily when

ulnarflexorsandextensorsacttogether.

Takingahistoryofwristpaininadults

Table 3.7 details the major diagnoses for painful conditions of the wrist and

hand.

Determinetheexactlocationofthepain

• Painlocalizingonlytothewristmostlikelycomesfromlocaltissuepathology.

CervicalnerverootpainasaresultofaC6,C7,orC8lesionandpainfrom

peripheralnervelesionsislikelytobelocatedchieflyinthehand.

• Painatthebaseofthethumb,aggravatedbythumbmovements,inmiddleand

oldageistypical ofOA (see Chapter6)ofthetrapezium-firstmetacarpal

joint.Paininthisareamightalsobeduetotenosynovitisofthumbtendons.

Traumahistory

Injury/post-injury conditions are common. Taking a history of trauma is

important.

• Common fractures in adults are scaphoid and base of the first metacarpal

(Bennett’s),andheadoftheradius(Colles’).

• Post-traumatic chronic wrist pain following injuries may be due to

ligamentousinjuryandchroniccarpalinstabilityorosteonecrosis(lunate).

• Unusual or florid pain descriptors suggest a regional pain syndrome (e.g.

CRPS;see Chapter22).

Fig.3.7Flexor(a)andextensor(b)tendonsheathscrossingthewrist.Flexorcarpiradialis(FCR)inserts

intothesecondandthirdmetacarpals.Flexorcarpiulnaris(FCU)insertsintothepisiform,hamate,andfifth

metacarpal.Extensorcarpiradialislongus(ECRL)insertsintothebaseofthesecond,extensorcarpiradialis

brevis(ECRB)intothethird,andextensorcarpiulnaris(ECU)intothefifthmetacarpal,respectively.

Table3.7Painfulconditionsofthewristandhand(adults)

Articular Chronicinflammatoryarthritis(e.g.PsA,RA,JIA,CPPD)

Osteoarthritis

Septicarthritis

Carpalinstability(e.g.lunatedislocation)

Periarticular

DeQuervain’stenosynovitis

Tenosynovitisofcommonflexor/extensortendonsheath

Flexorpollicistenosynovitis

Distalflexorstenosingtenosynovitis(triggerfingerorthumb)

Ganglia,subcutaneousnodules,tophi

Diabeticcheiroarthropathy

Dupuytren’scontracture

Bone Fracture

Neoplasia

Infection

Osteochondritis( Chapter16)

Neurologic Mediannerveentrapment(carpaltunneloratpronatorteres)

Anteriorinterosseousnervesyndrome

Ulnarnervelesions(cubitaltunnelorinGuyon’scanalin

wrist)

Posteriorinterosseousnerveorradialnerveentrapment

Brachialplexopathyorthoracicoutletsyndrome

Cervicalnerverootirritationorentrapment

Complexregionalpainsyndrome

Spinalcordlesions,e.g.syringomyelia

Aretherefeaturestosuggestsynovitis?

• Pain due to wrist joint synovitis may be associated with ‘stiffness’ and be

worse at night or early morning. Stiffness ‘in the hand’ may have various

causes including multiple tendon/small joint synovitis, diabetic

cheiroarthropathyorsystemicsclerosis(SScl;see Chapter13).

• WristsynovitisoccurscommonlyinadultRAandPsA.

• Intheelderly,wristsynovitismaybeduetoCPPDarthritis(see Chapter7).

Thequalityofthepain

• Althoughprimarybonepathologyisrare,localbonypain(unremitting,severe,

sleepdisturbing)mightsuggestosteonecrosisor,ifpartofawiderpatternof

bonypain,metabolicbonedisease.

• Radicular pain may be burning in quality and is typically associated with

numbnessandparaesthesia.Suchneurogenicpainiscommonlyduetonerve

rootirritationorcompression.

Otherjoint/MSKsymptoms

• Wristandextensortendonsheathsynovitisisacommonpresentingfeatureof

adultRA.Otherjointsmaybeaffected.

• CPPD arthritis commonly involvesthewrist, and can mimic RA in its joint

distributionandpresentationintheelderly.

• Wrist synovitis and enthesitis occurs in SpA. Pain may be considerable,

althoughswellingisminimal.Theremaybeinflammatory-typesymptomsof

spinalpainandenthesitiselsewhere.

Askspecificallyaboutjob/leisureactivities

• Repetitivelateralandmedialwristmovementswiththumbadductedcancause

tenosynovitis of the abductor pollicis longus (APL) or the extensor pollicis

brevis(EPB),commonlycalledDeQuervain’stenosynovitis.

• Ifthereisnoobvioushistoryoftrauma,tendonitismaybeapresentingfeature

ofasystemicautoimmunerheumaticdiseaseorevengonococcalinfectionin

adolescentsandyoungadults.

• Overusepainsyndromesmayoccurasaresultofrepetitiveactivity.Theterm

‘repetitive strain injury’ is controversial. Objective assessment of pain,

location of swelling, etc., from the outset is invaluable in assessing the

response to treatment. Lack of objective findings (if imaging is normal)

suggestsaregionalpaindisorder.

Examinationofthewristinadults

Visualinspection

Inspectthedorsalsurfaceofbothwristslookingforswelling,deformity,orloss

ofmusclebulk(see Plate7a):

• Diffuseswellingmaybeduetowristjointorextensortendonsheathsynovitis

orboth.

• Aprominentulnastyloidmayresultfromsubluxationatthedistalradioulnar

jointowingtosynovitisorradioulnarligamentdamage.

• Prominence (‘squaring’) of the trapezoid–first metacarpal joint commonly

occursinOAofthisjoint.

• Loss of muscle bulk in the forearm may be due to a chronic T1 nerve root

lesionordisuseatrophy.

Flexion/extensionrangetestsformajorwristlesions

• The normal range of both flexion and extension in adults is about 70°.

Synovitisinvariablyreducesthisrange.

• Substantial common flexor or extensor tendon swelling will probably block

thefullrangeofwristmovements.

• There is normally an additional 20° of flexion and extension to the active

rangewithpassivemovement.

• Painandcrepitusareunlikelytobespecificforanytypeoflesion.

Examinethedorsumofthewristindetail

• Noteanyabnormalexcursionoftheulnarstyloidassociatedwithpainand/or

crepitussuggestingsynovitis.

• Post-traumatic carpal instability, particularly scapulolunate dissociation, is

relativelycommon.Thelatterisdemonstratedbyelicitingdorsalsubluxation

oftheproximalscaphoidpolebyfirmpressureonitsdistalpoleasthewristis

deviated radially from a startingpositionwiththeforearm pronated and the

wristinulnardeviation.Noteanygapbetweenscaphoidandlunate,andany

associatedtenderness.

• Noteanytendernessorthickeningofthecommonextensortendonsheathand

tendonsheathofAPLandEPB.

• Tendernessatthebaseofthethumbmaybeduetowristsynovitis,carpalor

carpometacarpalOA,tenosynovitis,aganglion,oraligamentlesion.

• Finkelstein’s test for De Quervain’s tenosynovitis may be used to elicit

APL/EPBtendonpain.Withthethumbadductedandopposed,thefingersare

curledtoformafist.Passiveulnardeviationatthewriststretchestheabnormal

tendons andelicitspain. Although it is asensitivetest, it is notspecificfor

tendonpain.

• Protrusionofthethumboutofthefistontheulnarsideofthehandduringthe

first part of this test is unusual and suggests thumb, and perhaps general,

hypermobility.

Testtheintegrityofthetendons

Many muscles/tendons that move both the wrist and digits originate at the

elbow; therefore, the quality of information gained from isolated tendon

resistancetests(eitherforpainorstrength)maybeaffectedbypainelsewhere

aroundthewrist,wristdeformity,orelbowlesions.

• Interpretfindingscautiously.

• Usefulinformationmightbeobtainedbypassivemovementofatendon,rather

than by resisted active movement, and also by feeling for thickening or

crepitusofthetendons.

Investigationandtreatmentofwristconditionsinadults

Theinvestigationandtreatmentofwristconditionsiscoveredin ‘Symptoms

inthehandinadults’,pp.112–121.

Symptomsinthehandinadults

Symptoms in the hand are a common presenting feature of some systemic

conditions,andlocalizedneurologicalandMSKlesionsarecommon,especially

in adults. Detailed knowledge of anatomy is beyond the scope of this text.

Functional anatomy is important and the more common abnormalities are

summarizedhere.

Functionalanatomyofthehand

Thelongtendons

• Digitalpowerisprovidedprimarilybyflexorandextensormusclesarisingin

theforearm.Theiractionissupplementedandmodifiedbysmallmusclesin

thehand.Precisemovementsofthehandaremainlyduetosmallmuscles.

• Powerful flexors (Fig. 3.7): flexor digitorum superficialis (FDS), flexor

digitorumprofundus(FDP),andflexorpollicislongus(FPL).

• FDS flexes proximal interphalangeal joints (PIPJs) and, more weakly,

metacarpophalangealjoints(MCPJs)/wrist.

• FDP flexes distal interphalangeal joints (DIPJs) and, increasingly weakly,

PIPJs,MCPJs/wrist.

• FPLflexes(at90°tootherdigits)mainlythePIPJ,butalsothewholethumbin

apowergrip(seelater).

• Powerful digital extensors (Fig. 3.7 and Fig. 3.8): extensor digitorum (ED)

arises from the lateral epicondyle splitting at the wrist to insert into each

digitaldorsalexpansion(digitstwotofive)thatattachestoallthreephalanges.

The fifth digit has an additional tendon, extensor digiti minimi (EDM) that

alsoarisesatthelateralepicondyle.

• APLabductsthethumbattheMCPJ,providedthewristisstable.

• EPBandEPLextendthethumb.

• Extensorindicis(EI)arisesfromtheulnaposteriorborderdistaltoEPLand

joinstheindexfingerEDtendon.

• Themusclesofthethenareminence(Table3.8)actsynchronously.Allexcept

adductorpollicis(ulnarnerve,C8/T1)aresuppliedbythemediannervefrom

C8/T1nerveroots.Allthreemusclesaresuppliedbytheulnarnerve(C8/T1).

Theintrinsicmuscles

• Thelongitudinalmusclesofthepalm(fourdorsalandfourpalmarinterossei

andfourlumbricals)allinsertintodigits.

• Palmarinterosseifrommetacarpals1,2,4,5,insertintodorsaltendons.

• Eachdorsalinterosseousarisesfromoriginsontwoadjacentmetacarpals.The

muscles abduct the second and fourth fingers and move the middle finger

eithermediallyorlaterally.

• Thefourlumbricals(Fig.3.9andTable3.9)arisefromtendonsofFDPinthe

palm passing to the lateral side of each MCPJ inserting into the dorsal

expansions.

• Theinterosseicombinewithlumbricalstofacilitatefinecontrolofflexionand

extensionofMCPJsandPIPJs.

Fig.3.8Extensorexpansionofafinger.

Table3.8Musclesofthethenareminence

Muscle Origin Insertion

Abductor

pollicis

brevis

Flexorretinaculum,scaphoid,and

trapezium

Thumbproximal

phalanxanddorsal

expansion

Flexor

pollicis

brevis

Flexorretinaculum,trapezium,

trapezoid,andcapitate

Thumbproximal

phalanx(baseofradial

side)

Opponens

pollicis

Flexorretinaculumandtubercleof

thetrapezium

Firstmetacarpal(lateral

border)

Adductor

pollicis

Capitate,basesofsecond/third

metacarpalsanddistalthird

metacarpal

Thumbproximalphalanx

(medialside)

Grip

• Forpower,thewristextendsandadductsslightly,andthelongdigitalflexors

contract.

• A modified power grip, the hook grip,isusedtocarryheavy objects like a

suitcase. The thumb is extended out of the way and extension at MCPJs

accompaniesflexionatPIPJs/DIPJs.

• More precision in the grip can be obtained using varying degrees of thumb

adduction,abduction,andflexion.Thethumbcanbeopposedwithanyofthe

fourotherdigitsdependingontheshapeoftheobjecttobeheldandthetype

ofmanipulationrequired.

Fig.3.9(a)Lumbricalmusclesandmusclesofthethenarandhypothenareminences.(b)Dorsalinterossei.

Table3.9Musclesofthehypothenareminence

Muscle Origin Insertion

Abductor

digitiminimi

Flexorretinaculum(FR),

pisiform,andpisohamate

ligament

Baseofthefifthproximal

phalanxanddorsal

expansion

Flexordigiti

minimi

brevis

FlexorretinaculumandHook

ofhamate

Baseofthefifthproximal

phalanx

Opponens

digitiminimi

FlexorretinaculumandHook

ofhamate

Medialsideofthefifth

metacarpal

Takingahistoryofhandsymptomsinadults

A history of acute or overuse trauma with subsequent localized symptoms

requires a straightforward application of anatomical knowledge, precise

examination, and judicious choice of imaging techniques for diagnosis.

However,therearesubtlerorlesseasilydelineatedpatternsofsymptomsinthe

hand,particularlywhenpainisdiffuseorpoorlylocalized.

Isthepainassociatedwithimmobilityorstiffness?

• Stiffnessmaybeassociatedwithjointortendonsynovitisbutisnotspecific.

Promptingmayprovidemoreaccuratelocalizationofsymptoms.

• Ifunilateral,especiallyonthedominanthand,besuspiciousthatdiffusehand

painmaybeduetoaregionalpainsyndrome.

Isstiffnesslocalordiffuse?

• Patterns of joint involvement in autoimmune rheumatic disease and

polyarticulararthritisaresummarizedin Chapter2.

• Iflocalizedinthepalm,theremaybeDupuytren’scontracture(associatedwith

diabetes). If diffuse, there may be thickening of soft tissue from a systemic

process,e.g.hypothyroidism,SScl,diabeticcheiroarthropathy,ordisordersof

mucopolysaccharide metabolism (the latter especially in infants, although

Fabry’s disease can present in adulthood with acroparaesthesias and palmar

telangiectasia).

• Stiffnessduetoanuppermotorneuronlesion(aninterpretationofincreased

tone)isunlikelytobeconfinedtothehandandislikelytobeassociatedwith

weakness. The pattern of symptoms over time should give a clue to its

aetiology.

Arethereneurologicqualitiestothepainorcharacteristicstypicalofa

commonnervelesion?

• ‘Burning’ or‘deep’ episodicpainvarying with head, neck, andupperspinal

positionistypicalofcervicalnerverootpain.Askaboutoccupationandother

activitiesthatare associated withneckproblems, the relationshipwithsleep

posture,andfrequentheadaches.

• Pain on the radial side of the hand waking the patient at night and often

relieved, at least partially, by shaking the hand is typical of median nerve

entrapment in the wrist. However, pain in this condition is often poorly

localizedatinitialpresentation.Rememberotherlesionsthatproducepainin

the area around the thumb base: trapezoid–first metacarpal joint OA,

tenosynovitisofAPL/EPB(DeQuervain’s)orEPL,referredpainfromaC6

nerverootlesion,andligamentlesions(e.g.ulnarcollateralligamentoffirst

MCP—‘skier’sthumb’).

Tingling/pinsandneedles/numbness

Make sure bothyouandthepatient understand what you each mean by these

terms:

• Symptomsusuallydenotecervicalnerverootorperipheralnervecompression,

althoughtheycanreflectunderlyingischaemia.

• Tingling in the fingertips of both hands, however, is recognized to occur

commonlyinpatientsdiagnosedwithfibromyalgia.

• Symptomsassociatedprimarilywithspecificpositionsofthewholearmmay

beduetothoracicoutletcompressionofneurovascularstructures.

Painarisingfrombone

Pain in the hands arising from bones may be difficult to discriminate.

Radiographswilloftenleadtoconfirmationofthediagnosis:

• The most common tumour in the hand is an enchondroma. It is usually

painless.Iftheyarepainful,thenoneshouldsuspectinfarctionor malignant

change.

• Secondary metastases and malignant bone tumours in the hand are rare, but

must be ruled out in children, adolescents, and young adults with persistent

localizedbonepain.

• Paget’sdiseaseofhandbonescanoccur,butisrelativelyrare.

• Digital bone pain from osteomalacia/rickets occurs, but is unusual at

presentation.

• Digitalpainmayrarelybeduetosarcoidosis,hyperparathyroidbonedisease,

thyroid acropachy, hypertrophic (pulmonary) osteoarthropathy (HO), or

pachydermoperiostitis.Lookforclubbing.

Ischaemicpain?

A history suggestive of ischaemic pain in the hands is rare in rheumatologic

practice.Persistentischaemicdigitalpaincancomplicatesystemicsclerosisand

severeRaynaud’s(see Chapter13):

• Digitalvasomotorinstability(e.g.Raynaud’sdisease(RD);see Chapter13)

isepisodic,triggeredbycoldandemotion,andcharacterizedbydigitalcolour

changes:white/bluethenred.

• Pain fromvasculitis islikelyto bepersistent andassociatedwith apurpuric

rash,nailfoldinfarcts,orsplinterhaemorrhages.

• Ischaemic pain associated with cervicothoracic posture or prolonged arm

elevationmaybeduetoalesionofthethoracicoutlet.

• Pain may be due to thromboembolism (e.g. antiphospholipid syndrome),

infectiveendocarditis,orthromboarteritisobliterans(Buerger’sdisease).

‘Swelling’

Examinationismorereliablethanahistory:

• Apartfromisolatedlesions,suchasganglia,patients’descriptionofsofttissue

or joint swelling may be unreliable and should be substantiated by

examination.

• Nerve lesionscangive theimpression thatswellingis present(think whata

dentist’s local anaesthetic does for your lip!). Patients with carpal tunnel

syndrome,forexample,cancomplainofthehandswellingatnight.

‘Weakness’

Askabouttrauma,neck,andmediannerveentrapmentsymptoms:

• Acutetendoninjuriesarecommonindustrialaccidents.Chronicoccupational

overusemayalsoleadtorupture.

• If weaknessis profoundandtherehasbeen noobvious trauma,thecauseis

likelytobeneuromuscular.

• If not associatedwith pain, weaknessismore likely tobeneurological than

MSKinorigin.

• WeaknessassociatedwithpainmaybeduetoaneurologicorMSKlesion,the

lattersituationoftenduetoaninabilitytousethehand(orpartofit)because

of pain or an alteration in biomechanical function as a result of deformity,

whichmayonlybeslight.

• Trueweaknessassociatedwithstiffnessisassociatedwithmyelopathyoreven

motorneurondisease.

• Adetailedhistoryoftheprogressionofsymptomsisimportantandneurologic

examinationshouldbethorough.

Triggerfinger

Thismaydenotetenosynovitisofadigitalflexortendon.Damagetothetendon

anditssheathcanresultinafibrousnoduleattachedtothetendonthatmoves

andcatchesundertheproximalannularligamentjustdistaltotheMCPJ.Itmay

notbepainful.Thismostcommonlyaffectsthemiddleandringfingers,andis

prevalent among professional drivers, cyclists, and those in occupations

requiringrepeateduseofhand-heldheavymachinery.

Examinationofthehand:adults

Thefollowingsequenceiscomprehensive,butshouldbeconsideredifageneral

conditionissuspected.Oftenanexaminationonlyneedstobemorespecifically

directed.

Inspectionofthenailsandfingers

• Pits/ridgesanddactylitisareassociatedwithpsoriaticarthritis(see Plate8

and Chapter8).

• Splinter haemorrhages may be traumatic, but are associated with infective

endocarditisorvasculitis(see Chapter13).

• Obvious cuticle damage and punctate cuticle erythema (dilated capillary

loops)arefeaturesofsecondaryRDorSScl(see Plate9).

• Periungual erythema is associated with a number of autoimmune rheumatic

andconnectivetissuediseases.

• MultipletelangiectasiasareassociatedwithlcSScl(see Chapter13).

• Diffusefinger thickening(dactylitis) maybedue togrosstendon thickening

(e.g. SpA or sarcoid), or connective tissue fibrosis/thickening (SScl,

cheiroarthropathy). Bony or soft tissue DIPJ or PIPJ swelling should be

discriminated.

• Ashiny/waxyskinappearancemayindicatescleroderma/morphoea.

• Scattered, tiny, non-blanching dark red punctate lesions are typical of

cutaneousskinvasculitis.

• Erythematousorviolaceousscalypapules/plaquesoverMCPJsorPIPJsmay

suggestdermatomyositis(see Chapter14).

Noteanydiffuseswellingofthehand

• Diffuse soft tissue/skin swelling, may occur in association with RA, CPPD-

pseudogout,CRPS,andSScl.

• RS

PE (remitting seronegative symmetric synovitis with pitting oedema),

whichpresentsmainly in adultsintheir 70s, maybe a distincttypeof non-

erosivepolyarticular/tendonsynovitis,butmaybeassociatedwithother,often

haematological,conditions.

• SwellingassociatedwithCRPSmaybelocalizedordiffuse(see Plate10).

Skin may be shiny and later there is often a dark red or blue mottled

appearance.

• Typical skin appearances are critical to making a clinical diagnosis of

scleroderma. The skin may be initially puffy, but later shiny and tight and,

withprogression,atrophicwithcontractures.

Noteanymusclewasting

Wastingmaybeduetoadegreeofchronicdenervation(e.g.thethenareminence

in CTS), disuse atrophy (e.g. painful polyarthropathy, joint hypomobility), or

catabolismofmuscle(e.g.polymyositis,RA).Intheelderly,theremaybeage-

relatedmuscleloss(‘sarcopenia’).

Noteanydeformityofdigits

• Deformities tendto occurwith long-standingpolyarticular jointdisease, e.g.

OA,severeRA,andpsoriaticarthritis.

• Isolated deformities may be due to previous bone or tendon trauma, severe

neurological lesions and Dupuytren’s contracture. A mallet finger (loss of

active DIPJ extension) is due to rupture of the distal extensor tendon

expansionusuallyduetodirecttrauma.

Inspectthepalmanddorsumofthehand

• Palmarerythemaisnotspecific,butisassociatedwithautoimmunedisorders

ofconnectivetissueandjoints.

• CheckforDupuytren’sdisease(fascialthickeningonulnarside).

• On the dorsum of the hand, ganglia and swelling of the common extensor

tendonsheathareusuallyeasilynoted.Swellingoftheextensortendonsheath

iscommonlyassociatedwithRAinadults.

Palpationofjointsandnodules

Palpationofjointsandnodulesisbestdoneusingthumbpadswiththepatient’s

wristsupported:

• Swelling should be noted for site, consistency, tenderness, and mobility.

Osteophytes and exostosis are periarticular or at sites of pressure, may be

tender,butarealwaysfixed(see Plate7d).

• Gangliaarehardandusuallyquitemobile(canoccuranywhere).

• Rheumatoidnodules(occuranywhere,buttypicallyonthedorsumofthehand

andtheextensorsurfaceoftheelbow)andtophi(usuallydistal)arerubbery,

hard,relativelyfixed,butmaybemoved(see Plate7a).

• Synovitisisoftenrepresentedbysoft(‘boggy’),oftenspringy,swellingaround

ajoint.Itmaybetenderandwarmbutthisisnotinvariable.

• Synovitisinasinglejointmaybeduetoautoimmunerheumaticdisease,OA,

infection,orforeign-bodysynovitis(e.g.rosethornsynovitis).

Palpatetendonsinthepalmoronthevolaraspectofthephalanges

• Thickening,tenderness,andcrepitussuggesttenosynovitis,buttenosynovitis

canbehardtospotifitismild.

• Tethering and thickening of tendons in the palm associated with excessive

digitalflexionwhenthehandisatrestandablocktopassivefingerextension

suggestschronicflexortenosynovitis(takecaretonoteanycontributoryjoint

damage).

• Passive tendon movement by gently flexing/extending a proximal phalanx

maydisclosepalpabletendonnodules,crepitusandtenderness.

DiscriminateDupuytren’sdiseasefromflexortendinopathy

Dupuytren’sdisease(afasciacontracture)typicallyinvolvesthefourthandfifth

fingers (40% bilateral). It is common in males aged 50–70 years. The fascia

extendstothesecondphalanx,thus,ifsevere,theconditioncausesfixedflexion

ofMCPJsandPIPJs.Itisassociatedwithepilepsy,diabetes,andalcoholism,and

usuallyisnotpainful.

Investigationofwristandhanddisorders:adults

Radiographs

• An AP view of the hand and wrist is a useful screening investigation to

characterize a polyarthropathy and diagnose traumatic and metabolic bone

lesions(Table3.10).

• Radiographsmayrevealsofttissueswellingaroundjointscompatiblewitha

diagnosisofsynovitis.

• Radiographsareinsensitiveforidentifyingerosionsinearlyautoimmunejoint

disease.

• Anobliqueviewofthehandmayaddinformationaboutjointerosionsifan

erosiveMCPJarthritisisconsidered.

• Lateralandcarpaltunnelviewsofthecarpuscanbeobtainedbyvaryingthe

degreeofX-ray projectionangle; however, unlesssearchingfor evidenceof

fracturetheseviewsarerarelyneeded.

Table3.10Someconditions/featurestypicallydiagnosedonsimpleAPhand/wristradiographs

Bone

conditions

Fractures(e.g.scaphoid,baseoffirstmetacarpal)

Tumours

Metabolicbonediseases(e.g.rickets,hyperparathyroidism—

lookforcorticallossandtunnellinginphalanges)

Osteonecrosis(e.g.post-traumatic—lunate,sicklecelldisease)

Sarcoidosis( Chapter18)—typicallybonecysts

Specific

features

Cartilagedamage(jointspacelossandsubchondralbone

changes—primaryorsecondaryOA)

Articularerosions

Osteophytes

Infection(cortexloss,patchyosteolysis)

Calciumdepositioninjoint(e.g.triangularligament

chondrocalcinosisinCPPDdisease)

Softtissueswelling(e.g.overulnarstyloidinwristsynovitis)

Periarticularosteoporosis(associatedwithjointinflammation)

Carpaldislocation(e.g.lunatedisplacementinchroniccarpal

pain)

Polyarticular:

overall

patternsof

radiological

abnormality

OA(distributionofosteophytesandsubchondralbone

changes)

RA(e.g.deformities,erosionappearance/distribution)

Psoriaticarthritis(e.g.deformities,juxta-articularnewbone,

enthesophytes,erosionappearance—DIPJs)

CPPD:carpal—particularlyscapho-trapezial,trapezio-

metacarpaland2ndand3rdMCPJs—degenerativechanges,

intenselinearperiarticularsclerosisandosteophytes

Gout:erosionappearance—‘punchedout’bites,likeLulworth

Cove.Basesoferosionssclerosed

Furtherimaging:US,MRI,andbonescintigraphy

• Inexperiencedhands,UScanbeausefulwayoflookingforearlysynovitis

andpatternsofabnormalityinassociationwithmediannerveentrapment.

• MRImaydemonstrateatornoravulsedtriangularcartilageinpatientswitha

post-traumaticpainfulwristorwithcarpalinstability.

• MRI images of the carpal tunnel are useful in confirming median nerve

compression/tethering and soft tissue wrist pathology, particularly when

symptomsrecuraftercarpaltunnelreleasesurgery.

• MRI can provide valuable information about the degree and distribution of

inflammatory disease in joints and tendons, particularly in children and

patientswherehistoryandexaminationaredifficult.

• MRI is more sensitivethanradiography in identifying jointerosionsin RA.

ChoosingMRIoverUSdependsonavailabilityandsonographerexperience.

• Bonescintigraphyisnotspecificforanysinglecondition,butinyoungadults

(after closure of epiphyses and before OA is likely) it may be useful for

disclosingpatternsofinflammationatandaroundjointsandentheses.

99m

Tc-

labelled human immunoglobulin is more specific for detecting patterns of

synovitisinchildrenandadults.

Laboratoryinvestigations

• FBC, ESR, CRP: the characteristic, though non-specific, picture in patients

with a systemic inflammatory condition such as RA is mild anaemia with

normal (or slightly hypochromic, microcytic) red cell indices, high or

high/normalplatelets,andincreasedacutephase.

• Notably in PsA and in SpA the acute phase measures may be low, even

normal,evenwhenthereiswidespreadpain/diseaseactivity.

• Lymphopeniafrequentlyaccompaniesautoimmunedisease.

• Neutrophilsareraisedininfection,withsteroids,withcrystal-inducedarthritis,

andinadult-onsetStill’sdisease(see Chapter18).

• Bloodurea,electrolytes,creatinine,anduratewilldetecthyperuricaemiaand

renalimpairmentassociatedwithgout.

• Bloodcalcium,phosphate,albumin,vitaminD,alkalinephosphatase,andPTH

willscreenformetabolicbonedisease.Testallcomponentstointerpretfully

themetabolicpicture.

• Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (ACPA) are

usefulfordiagnosingrheumatoidarthritis.

• Antinuclear antibody (ANA) and a screen of extractable nuclear antibodies

(ENAs)maybehelpfulfortheevaluationofanumberofdisorders,including

SLEandscleroderma.

• Otherinvestigationstoconsider:serumangiotensinconvertingenzyme(ACE)

for sarcoidosis, glycosylated haemoglobin in diabetics, serum, and urinary

proteinelectrophoresisformyeloma.

Otherinvestigations

• Neurophysiology (EMG/NCS) is a useful adjunct to clinical examination in

diagnosisofupperlimbneuropathies.

• Joint/bursa fluid aspiration is mandatory in suspected cases of sepsis and

shouldbesentforcultureandmicroscopy(requestGramstainandpolarized

lightmicroscopyoffluidfromthelab).

Treatmentofwristandhanddisordersinadults

TreatmentsforspecificdiseasesareconsideredintherelevantchaptersinPartII

ofthisbook.Managementofthesofttissuelesionsinthehandandwrist,like

elsewhere,combinesperiodsofrestandsplintingwithactivephysicaltherapy,

avoidanceofrepetitiveactivity,andanalgesia.Inmostcases,theconditionwill

resolvespontaneously,butsevereorpersistentpainanddisabilitymaywarrant

inputfromahandoccupationaltherapist,localsteroidinjections,oroccasionally

surgicalsofttissuedecompression:

• Conditionsthatrespondtolocalsteroidtherapy(see Chapter24):

• tenosynovitis,e.g.DeQuervain’s.

• tendonnodulesandganglia.

• flexortenosynovitis(andtriggerfinger).

• Dupuytren’scontracture.

• carpaltunnelsyndrome.

• synovitis: radiocarpal and radioulnar at the wrist, MCPJs and PIPJs, first

carpometacarpal.

• TheaccuracyofneedleplacementislikelytobeimprovedbyUSguidance;

however,greaterefficacyfromanUSprocedureversusblindinjectionhasnot

yetbeenshown.

• Theprinciplesofsteroidinjectionaredealtwithin Chapter24.

• Functionalevaluation(fromaphysicalandoccupationaltherapist)islikelyto

be of use in cases of polyarthropathy. Early use of splints, orthotics, and

exercisesmayleadtogreaterfunctionalabilityandadecreaseinsymptoms.

• Surgicaloptionsforthehandandwristmayinclude:

• fusionorresectionofthecarpalbones.

• ulnastyloidectomyandwristsynovectomy(RA).

• tendonrepairandtransferoperations(RA).

• synovectomyofjointsand/ortendons(RA).

• fusionofsmalljoints.

• PIP/MCPjointreplacements.

• Dupuytren’srelease/fasciectomy.

• carpaltunnelrelease.

• trapeziectomyforthumbCMCjointOA.

Manyoftheseproceduresprimarilyreducepain;functionmaynotberestored.

Wristandhandpaininchildrenandadolescents

Generalconsiderations

IsolatedMSKlesionsinthewristandhandsofchildrenarerare.Afewnotable

conditionsexist.

• Smallswellingsmaybeganglia—resolvespontaneouslyin50%.

• Congenitaltriggerthumborfingerisnotrareandcanaffect1in300children.

Spontaneousresolutionoccursinupto60%within2years.

• Swelling in wrists and fingers may denote JIA. US is a relatively easy and

acceptablewayofconfirmingsynovitisispresentinjointsinyoungchildren,

thougholderchildrenmaytolerateMRI.

• Wrist pain and swelling may be the key presenting feature of rickets,

especiallyinachildoradolescentwithaseverelyrestricteddiet.

• Digital vasomotor instability is more commonly seen in children with

neurologicalconditionsincludingcerebralpalsy.

• AssessmentofRaynaud’sDisease,typicallyinadolescents,issimilartothatin

adults(see Chapter13)anderythromelalgia,whichcausesmarkedredness

ofhandand feetassociated withdiffusepain,swelling anddistress, ismore

commonlyseenintoddlersthanolderchildren.

• Digitalulcersandischaemiclesions,Gottron’spatchesandnailbedvascular

changesmayindicateSLE,JDMorSScl.

• AlthoughCRPS(see Chapter22),isoccursinchildren,itislesscommon

thaninadults.

• Wrist pain may be the presenting feature of a skeletal dysplasia—a wrist

radiograph should be obtained. Specialist centre radiologist input can be

helpfulinsuchcases(e.g.dREAMS: http://www.d-reams.org)

• Assessment of the wrist and hand in children and adolescents is essentially

similartotheassessmentinadults.

• Forfunctionalanatomyofthewristsee pp.106–107,andforthehand,see

pp.112–115.

Upperlimbperipheralnervelesions

Background

• Upper limb peripheral nerve lesions are common. Most are entrapment

neuropathies. Occasionally, nerve trauma may present to primary care

providersorrheumatologistswith(primarily)regionalmuscleweakness.

• Althoughnotspecificforitsdiagnosis,thecombinationofpain,paraesthesia,

numbness,andweaknessissuggestiveofnerveentrapment.Featuresmaybe

consideredmorespecificfornerveentrapmentifthereisahistoryofacuteor

overusetraumaproximaltothedistributionofthesymptoms.

• Lesions may characteristically occur in association with specific activities,

occupations,orsports(e.g.ulnarneuropathyincyclists).

• Accuratediagnosisreliesondemonstrationoftheanatomiclesion.Usefulin

thisrespectisknowledgeoflikelysitesofentrapmentordamageand,inthe

case of entrapment, the ability to elicit a positive Hoffman–Tinel sign (i.e.

pressureorpercussionoverentrapednervecourseelicitingsensorysymptoms

inthenervedistribution).

• Alwayscompareexaminationfindingsinbothupperlimbs.

• Neurophysiologicexaminationisanadjuncttoclinicaldiagnosis.Itshouldnot

bereliedontomakeadiagnosisintheabsenceofgoodclinicalassessment.

• MRIofnerveroots/spineandpotentialsitesofdistalnerveentrapmentcanbe

used, with clinical assessment and neurophysiology, to pinpoint with high

accuracy,anynervelesionintheupperlimb.

Thelongthoracicnerve

• Entrapmentisinthedifferentialdiagnosisofpainlessshoulderweakness.The

nerve origin is at C5–C7, and its course runs beneath the subscapularis and

intotheserratusanterior.

• Muscleparalysisisoftenpainlessandimplieslossofthelast30°ofoverhead

arm extension, disrupted scapular rhythm, and scapula winging. Winging is

demonstrated by inspection from behind with the patient pressing against a

wallwithanoutstretchedarm.

• Damagetothenerveoccurstypicallyfromananteriordirectbloworbrachial

plexusinjury.Damagesometimesoccursaftercarryingheavybackpacks(e.g.

armyrecruits)oraftersurgicalresectionofacervicalrib.

• Itcanalsooccurspontaneouslyafterinfection.Thereisnospecifictreatment.

Thesuprascapularnerve

• The nerve origin is at roots C4–C6; its course is lateral and deep to the

trapezius, through the suprascapular notch, terminating in the supraspinatus

and posteriorly in the infraspinatus. It carries pain fibres from the

glenohumeraljointandACjoint.

• Impingementofthenerveatthesuprascapularnotchshouldbeconsideredina

patient complaining of shoulder pain despite a normal examination and

imagingtests.

• Injury to the nerve often gives diffuse shoulder pain, although painless

paralysisofthemusclescanoccur.

• Injury isoftenthought tooccurfrom repeatedstretchingof thenerveat the

notch.Weightliftersarepronetobilateralinjuryandvolleyballplayersprone

todominantsideinjury.

• Neuromyopathy (acute weakness, pain, CK+, muscle wasting on MRI?

secondarytoinfection)ofsupraspinatusorinfraspinatusisnotuncommon.

• Compressionbygangliaortumours(andevenpossiblygouttophi)occursand

canbeconfirmedbyMRI.

Ulnarnerve

TheulnarnerveoriginatesfromC8andT1.Itliesalongthemedialsideofthe

brachial artery in the upper arm, then above the medial humeral epicondyle

where it passes posteriorly, piercing the medial intermuscular septum. It then

runsbehindtheelbowinagroovebetweentheolecranonandmedialepicondyle,

coveredbyafibroussheathandarcuateligament(cubitaltunnel).Followingthe

lineoftheulnaintheflexorcompartmentoftheforearm,branchessupplythe

flexordigitorumprofundus(FDP)andtheflexorcarpiulnaris(FCU).Thenerve

entersthehandontheulnarsidedividingintosuperficial(palmarisbrevisand

skinoverthemedialoneandahalfdigits)anddeep(smallmusclesofthehand)

branches:

• Lesionsareusuallyduetoentrapment.

• The ulnar nerve is occasionally damaged in the relatively exposed cubital

tunnel(cubitaltunnelsyndrome)resultinginpainandparaesthesiaalongthe

medialforearm,wrist,andfourth/fifthdigits.Damagemayoccurfromdirect

trauma,compression,orrecurrentsubluxation.TheTineltestattheelbowmay

bepositiveandtheremightbesensorylossoverthepalmaraspectofthefifth

digit.

• Thereareanumberofsiteswhereentrapmentof theulnarnerve mayoccur

aroundthewrist,eitherproximaltothevolarcarpalligamentorbeneathitor

thepisohamateligament.Externalcompression,acuteorrecurrenttrauma,and

gangliaaretheusualcauses.Symptomshavebeennotedincyclists,usersof

pneumaticorvibratingtoolsandinavidvideogameplayers.Entrapmentofthe

purelysensorycutaneousbranchcanoccurfromexcesscomputermouseuse.

• Motorweaknessmaybemostevidentbyobservinggeneralmusclewastingin

the hand (hypothenar eminence, interossei, adductor pollicis) and flexion

deformityofthefourthandfifthdigits—thelattercausedbythirdandfourth

lumbricalweakness(see Plate11).

• Flexionofthewristwithulnardeviation(FCU)andthumbadductionmaybe

weak(adductorpollicisweaknesswillbeevidentifyouaskthepatientto‘run

the thumb across the base of the fingers’ as normally it can sweep across

touchingtheskin).

• Froment’s sign also signifies weakness of the adductor pollicis, and is

demonstrated by a weakness in holding paper between the thumb and the

indexfingerwhenbothareinthesagittalplane.

• Discriminationofawristsitefromanelbowsiteofnerveentrapmentishelped

by the site of a positive Hoffman-Tinel test, preservation of power of wrist

flexion/medialdeviation(FCU)inawristlesion,andelectrophysiology.

• Rest, analgesia, and occasionally local steroids are helpful. A review of

posture, repetitive activity, and a biomechanical assessment with changes in

activitiesandtechniquearerecommended.Surgicaldecompressionmayalso

benecessary.

Radialnerve

ThenerveoriginisatrootsC5–C8,anditscourserunsanteriortosubscapularis

then passes behind the humerus in a groove that runs between the long and

medialheadsoftriceps.Itthenwindsanteriorlyaroundthehumeralshafttolie

betweenbrachialisandbrachioradialis.Intheflexorcompartmentofthearmit

divides at the level of the lateral epicondyle into superficial branch

(cutaneous/sensory) and the posterior interosseous nerve (PIN), which runs

through the supinator muscle into the forearm to supply the extensor

compartmentmuscles:

• Entrapment needs to be considered in those cases of shoulder or upper arm

trauma,wheresubsequentpresentationincludesarmandwristweakness.

• Compressionoftheradialnerveintheupperarmcausesstiffnessinthedorsal

armandforearm,weaknessofthewrist,andlittlefingerextension.Thetriceps

isusuallyunaffectedasthenervesupplytothemuscleleavestheradialnerve

proximally.

• Transientcompressionofthenerveatthesiteofthemedialheadoftricepshas

beendescribedintennisplayers.

• Compressioncanoccurasthenervepiercesthelateralintermuscularseptum

justdistaltotheradialheadandalsowherethePINpiercesthesupinator.

• At this lower site, compression is often a consequence of trauma, may be

associated with a positive Hoffman-Tinel test and local tenderness, and the

painmaybereproducedbyextremepassiveforearmpronationcombinedwith

wrist flexion. Symptoms may mimic those of lateral epicondylitis. Surgical

explorationmaybenecessarytoconfirmadiagnosis.

Mediannerve

ThenerveoriginisfromC6–T1nerveroots.Itscoursefromthebrachialplexus

runstogetherwiththebrachialarteryintheupperarm(supplyingnothing)then

enterstheforearmbetweenthetwoheadsofpronatorteres(frommedialhumeral

epicondyle and coronoid process of the ulna). It runs deep in the forearm

dividing into median and anterior interosseous branches. The median branch

entersthehandbeneaththeflexorretinaculumontheradialsideofthewrist.All

pronatorandflexormusclesintheforearm(exceptFCUandthemedialhalfof

FDP)aresuppliedbythetwobranches.Themediansuppliessensorynervesto

theradialsideofthehand:

• Entrapmentsyndromeatthewristisverycommon;CTS.

• Intherarepronatorsyndrome,trauma, swelling,ormassesbetweenthe two

pronatorheadscancauseentrapmentgivinglowerarmpain,paraesthesias,and

weaknessofforearmpronation.Thereislocaltendernessandreproductionof

painfromresistedforearmpronationorwristflexion.

• Pain in CTS is often present at night and relieved by exercising the hand.

Daytimesymptomscan persist.Paincan bereferredup thearmeven tothe

shoulder.Sensorysymptomsareconfinedtotheradialthreeandahalfdigits.

• ClumsinessisacommonearlyfeatureofCTS.

• Symptoms reproduced by a positive Tinel’s sign (percussion over the volar

aspectofthewrist)andPhalen’smanoeuver(volaraspectofthewristrested

onthebackofachairandthehandallowedtofalllooselyundergravity,held

for1min)indicatesnervecompression.

• Asevereorchroniclesionisassociatedwithsensorytestingabnormality(Fig.

3.10) and motor weakness of the abductor pollicis brevis (APB), opponens

pollicis,andthefirstandsecondlumbricals.

• NCSsareindicatedifthediagnosisisuncertain,theconditionisprogressive,

motorneurondiseaseissuspected(thenarmusclewastingmarked/progressive

with minimal sensory symptoms), dual pathology is suspected, surgical

decompression is being considered, and in cases of surgical failure. False-

negativeresultsoccurin10%ofcases.

• MRI appears to be more sensitive than US for detecting abnormalities

involvingthemediannerveinoraroundthecarpaltunnel.

• Aetiology ofCTS isdebated,but probablymultifactorial. Thefollowingare

associated: Colles’ fracture, trauma, carpal OA, diabetes, inflammatory

joint/tendon disease (e.g. RA, SScl), ganglia, menopause and pregnancy.

Hypothyroidism,acromegaly,amyloid,andbenigntumoursarealsoassociated

withCTS.

Treatmentofcarpaltunnelsyndrome(CTS)

( Chapter24hasfurtherinformationonsteroidinjectiontechniques.)

• Nightsplintingmaybecurative,especiallyearlyinthecondition.

• NSAIDsarehelpfulifthereisunderlyinginflammatorydisease.

• Localsteroidinjectionsareofvalue.Ifpartialremissionisachieved,consider

repeatingtheinjection(see Chapter24).

• Surgical decompression is indicated when there is failure of conservative

therapy, progressive/persistent neurological changes, or muscle

atrophy/weakness.

• Failureofsurgicalreleaseofthecarpaltunnelrequiresfurtherconsiderationof

underlying causes such as a ganglion or other soft tissue lesion. Reconsider

alsowhethertherereallyisamechanical/localorperhapsasubtlercause(e.g.

mononeuritis or peripheral neuropathy, entrapment at the pronator or nerve

rootlesion).

Fig.3.10Approximatedistributionofdermatomesontheanterior(a)andposterior(b)aspectsofthe(right)

upperlimb.Approximateareaofsensorychangeinlesionsofthemedian(c)andulnar(d)nerves.

Thoracicbackandchestpaininadults

Background

• Thethoracicsegment(T1–T12)moveslessthanthelumbarandcervicalspine.

Segmentalmovementinanydirectionisabout6°.However,giventhenumber

ofsegmentsthiscanadd upto appreciablemobility overall.Less segmental

movement results in reduced frequency of problems overall (only 6% of

patientsattendingaspinalclinichavethoracicspineproblems).

• Ribs (1–10) articulate posteriorly with vertebrae at two points: the articular

facetoftheribheadwiththecostovertebralfacetoneachvertebralbodyand

the articular facet of the rib tubercle with the costotransverse facet on each

vertebrallateralprocess.Thesearebothsynovialjoints.Ribs11and12donot

havecostotransversejoints.

• The ribs, each continuous with its costal cartilage, articulate anteriorly by a

synovialjointwiththemanubrium(1–2),sternum(2–7),eachcostalcartilage

above(8–10),ordonotarticulate(11/12‘floatingribs’).

• Amassiveblockofspinalextensormusclesisresponsibleformaintainingthe

body against gravity. Some extend over some distance (e.g. the spinalis

thoracisfromtheupperthoracictothemid-lumbarspinousprocesses).

• DermatomesarecircumferentialandextendfromT2attheclaviclestoT10at

theumbilicus.However,uptofivenerverootsmaycontributeinnervationof

anyonepointinatruncaldermatome.

Takingahistoryinadults

The interpretation of cardiac, oesophageal, or pleural chest pain as MSK in

origin can occur. It may result in missing a serious condition (Table 3.11 and

Table3.12). Similarly, theinterpretation of neurogenicorMSK chest pains as

cardiogenic, oesophageal, or pleural can occur and may lead to unnecessary

investigations.

Table3.11Characteristicsofchestpaininadults:fromnon-neurologicalandnon-MSKpathology

Process Characteristicsofpain

Angina Gradualonsetoftenrelatedtoexercise,aheavymeal,or

emotion.Squeezing,strangling,orconstrictioninchest,can

beachingorburninginnature.Commonlysubsternal,but

radiatestoanyofanteriorchest,interscapulararea,arms

(mainlyleft),shoulders,teeth,andabdomen.Reduceswith

restandsublingualnitrates

Myocardial

infarction

Similartoaboveregardingqualityanddistribution.Longer

duration.Lesseasilyrelieved

Pericardial

inflammation

Sharporsteadysubsternalpain.Canbereferredtoshoulder

tip,anteriorchest,upperabdomen,orback.Oftenhasa

pleuralcomponentandisalteredbychangeinposition—

sharpermoreleft-sidedwhensupinebuteasedbyleaning

forward

Aortic

dissection

Acuteonsetwithextremelyseverepeak.Feltincentreof

chestorback.Lastsforhours

Pleuritic

inflammation

Common.Sharp,knife-like,superficial.Aggravatedbydeep

inspiration,sneezing,orcoughing.Ifaccompaniedby

haemoptysisconsiderpulmonaryembolism

Mediastinal

conditions

Empyemaorsurgicalemphysemamaybeintenseandsharp

andradiatefromsubsternaltoshoulderarea.Associatedwith

crepitus.Mediastinitisandtumourpainresemblespleural

pain.Mayhaveconstantfeelingofconstriction/oppression

Peptic

disease

Penetratingduodenalulcerscancauseintense,persistentmid-

thoracicbackpain

Oesophageal

reflux

Persistentretrosternalburningistypical.Oftenpost-prandial,

whenlyingoratnight/earlymorning.Oesophagealspasmcan

besimilartoanginaandcancausemid-thoracicbackpain,but

refluxsymptomsoftencoexist

Table3.12PainfulneurologicalandMSKconditionsofthethoracicspineandchestwallinadults

Thoracic

vertebraldisease

Osteoporoticorpathologicalfracture

Tumours,e.g.osteoidosteoma,metastasis

Osteomyelitis

Paget’sdisease

Osteomalacia,rickets

Costovertebraljointdysfunction

Nerveirritation

Rootirritation/compressionfromdiscprolapseor

osteophyteatexitforamen,fromstructuredistaltoexit

foramen,orfromneuroma

Biomechanical/

degenerative

Scoliosis(non-structuralcompensatory,structural)

Diffuseidiopathicskeletalhyperostosis(DISH)

Calciumpyrophosphatedihydratedisease

Herpeszosterofintercostalnerve

Chest

wall/superficial

lesions

Ribfracture

Otherriblesions,e.g.tumours,fibrousdysplasia,

osteomalacia

Costochondritis/enthesitis(e.g.PsA)

Intercostalmuscletear/strain

Mastitisorfibrocysticdiseaseofthebreast

Myofascialpainandfibromyalgia

Parietalpleuralinflammation/infection/infiltration

Spondyloarthritis

(SpA)

Spinalinflammation

Acutediscitis

Chronicindolentdiscitis

Scheuermann’s

osteochondritis

Inadolescentsonly

• Areviewofthequalityandradiationofcardiacandoesophagealpaininthe

clinicalcontextshouldalwaysbeconsidered.

• Pleuriticpainiscommon.Chronicpulmonaryembolimaybeunderdiagnosed

and have serious consequences. Any inflammatory, infective, or infiltrative

pleurallesionwillbepainful.

• Lesionsconfinedtopulmonaryparenchymadonotproducepain.

• PericardialpaincanbemisinterpretedasMSKorpleuritic.

• Mediastinalabnormalitiescanproducepainthatisoftenreferred.

• Thoracicspinelesionscanresultinreferredanterolateralchestpain.

• Costovertebralandcostotransversejointdysfunctionisrelativelycommonand

isgenerallyage-related,butcanoccurinanyonewithspinaldeformity.Itmay

producethoracicspinepainaloneorresultinanextensivepatternofradiation

ofpainovertheback,lateral,andanteriorchestwall.

• Lowercervicalspinelesionscanreferpaintotheanteriorchestwall.

• Manypainfulchestconditionsareassociatedwithradiationofthepaindown

theleftarm.Thispatternisnotspecificformyocardialischaemia.

• Lowercervicalpainmaybereferredtotheinter-scapularregion.

• Inter-scapularpainmayalsobeassociatedwithmechanicallumbardisorders.

Unlikeinfection,tumours,andfracture,referredpainiseasedorabolishedby

changesinpositionorposture.

• If there is thoracic back pain alone and it is acute and/or severe consider

osteoporoticfracture,tumours,andinfection.

• Osteoporotic vertebral collapse is common in postmenopausal women. An

acute,non/minimal-trauma-associatedseverepainistypical.Fracturesoccurin

manyothersituations,e.g.ASoraneoplasticbonelesion.

• Spinalinfectionsshouldnotbemissed.ThemostcommonareStaphylococcus

aureus,Brucella,andMycobacteriumtuberculosis.

Askaboutthequalityofpain

• MSK pain (local or referred) generally associates with specific movements,

positions,orpostures,andisreproducible.

• Painthatincreaseswithcoughing,sneezing,ordeepinspiration,issuggestive

of pleural lesions. Rib and intercostal lesions or costovertebral joint

dysfunctionmayalsocausethissortofpain.

Askaboutothersymptomsandriskfactors

• Thepainfromafracture/lesion(osteoporotic,malignancy,infection)isoften

localizedandextreme,wakingthepatientatnight.

• Acute or chronic thoracic spine lesions may be associated with cord

compression.Askabout recent changein sphincter functionandprogressive

lowerlimbstiffnessorheaviness.

• Risksforosteoporosis(see Chapter16).

• Systemicsymptomsoffever(osteomyelitis).

• Bonepainelsewhere(metastases,osteomalacia,Paget’sdisease).

• Spinalpaininadolescence(foranadultwithkyphosis/spinalpain).

• A positive family history is recognized in idiopathic scoliosis, osteoporosis,

andgeneralizedosteoarthritis(see Chapter6).

• Depressionandanxietyareimportantmodulatorsofpain.However,although

thoracicbackandchestpainsmaybepsychogenic,itisunwisetosettleonthis

diagnosiswithoutexcludingMSKconditionsanddiseasesofviscerathatcan

causereferredpain.

Examinationofthe(MSK)thoraxinadults

Visualinspection

Observethepatient(whohasundresseddowntotheirunderwear)fromtheback

and front. Look for deformity, asymmetry, swellings, and note the respiratory

pattern:

• Any scoliosis should be noted. Non-structural scoliosis is frequently due to

posture, severe back or abdominal pain, leg length discrepancy, and, rarely,

canbepsychogenic.Structuralscoliosismaybeduetovariouslesionsatany

age.

• There is a normal mild thoracic kyphos; however, marked kyphos in adults

(particularly postmenopausal women) might suggest multiple osteoporotic

vertebralfracturesordegenerativediscdisease.Alossofnormalkyphosis(flat

spine)maybeseeninspondylitisorpossiblyseveremusclespasm.

• Loosefoldsofskinonthebackcandenoteheightlossfrommultiplevertebral

fractures.

• Costochondral swelling occurs in some cases of costochondritis or SAPHO

(synovitis, acne, pustulosis (palmoplantar), hyperostosis, and (aseptic)

osteomyelitis)syndrome.Lookforlesionsofcostosternalorsternoclavicular

joints(whicharealsofoundinPsA).

Palpation

Palpateoverthevertebrae,paravertebraljoints,andbackmusculaturewiththe

patientprone.Palpatetheanteriorchestwall:

• Spinal osteomyelitis may be associated with obvious skin swelling and

erythema,exquisitefocaltenderness,andextensorspasm.Tumoursmaygive

similarsigns,thoughskinerythemaisnotlikely.

• Costotransverse joints may be tender (4–5 cm from midline). Discomfort at

anycostovertebraljointanditsreferredpaincanbeelicitedbyindividualrib

manipulation(downwardpressureontheriblateraltoitsvertebraljointswhen

thepatientisprone).

• Identifyanytriggerpointsthatreproducemyofascialpaininbackmuscles.

• Tenderswellingofthesternoclavicular,costomanubrial,orsternocostaljoints

maysuggestspondyloarthritis(axSpA)orSAPHOsyndrome.See Chapter

• Inflammationofcostalcartilagesisoftenassociatedwithpainfulswellingand

tenderness. Rib and intercostal lesions should be easily discriminated from

referredpainbyelicitinglocaltenderness.

Checkthoracicspinalmovement

Movementsofthethoracicspineshouldbechecked.Askthepatienttositonthe

couch with their arms folded in front of them. Guided by movements of the

spinousprocesses,gaugetherangeofthoracicspinemovement:

• Approximatenormalrangesofmovementintheabove-mentionedpositionare

extension30°,lateralflexion30°,flexion90°,androtation60°.

• Scoliosisisoftenassociatedwithrotationthatisaccentuated,onexamination,

onflexion.

• Abnormalmobilitywillnotbespecificforanyunderlyingcondition,butmay

draw attention to the major affected spinal segment. Painful segments are

‘guarded’andmayappearhypomobile.

• AxSpA/ankylosingspondylitis(AS)maybecomeobviousifthereisextensive

spinalhypomobility.

• Chest expansion should be measured from forced expiration to complete

inspiration measuring at expansion, with a tape, at the level of the

xiphisternum.

Otherexamination

• Given the range of serious conditions causing chest pains, a full medical

examinationisimportantandshouldalwaysbeconsidered.

• Neurologicalexaminationofthelegsshouldbeconsideredinanyonewhoisat

riskofspinalcordcompression.Lookforincreasedtone,weakness,andbrisk

reflexes.

• Breastandaxillarylymphnodeexaminationshouldbedone.

Investigationsofthoracicconditionsinadults

Radiographs

• Lateral view radiographs generally provide more information about thoracic

spinelesionsthananteroposteriorviews;however,together,bothviewsshould

confirm osteoporosis, degenerative disease (e.g. previous Scheuermann’s

osteochondritis,ochronosis,DISH),andPaget’sdisease(see Chapter16).

• Look for vertebral squaring (in axSpA/AS) and either marginal or non-

marginal syndesmophytes as in psoriatic spondylitis or other SpAs (see

Chapter8).

• DiscriminateenthesitisinSpAfromDISHatthecornersofvertebraebythe

presence of erosions with bone reaction (enthesitis) compared with bone

proliferation alone (DISH). Spondylodiscitis is part of the SpA spectrum of

diseases.

• Radiographsofthespine,orCTimages,areprobablyabetterindicatedofPsA

inthespinecomparedwithMRI.

• Normalradiographsdonotexcludemalignancy.

• BonelesionscanbewellcharacterizedbyCT(e.g.osteoidosteoma).

MRI

• MRIisimportantindiscriminatingtumourfrominfection.

• Disclesions,spinalcanal,andcordarewellvisualizedwithMRI.

• Fatsuppressedorcontrast-enhancedMRsequencesmaybenecessarytodetect

enthesitisorspondylodiscitisassociatedwithSpA.

Bonescintigraphy(

99m

Tc-diphosphonate-MDP)

• Bonescintigraphyisasensitivetestforinfectionandmalignancy.

• In suspected cases of malignancy, it is more sensitive than radiographs, can

often confirm the lytic or sclerotic nature of a lesion and will identify any

otherskeletalsitesofdisease.

• ThepatternofabnormalitiesinSAPHOsyndromearecharacteristic.

• Itisausefulinvestigationinpatientswithmalignancywhopresentwithback

pain. A lack of additional lesions strongly suggests against a single spinal

abnormalitybeingmalignancy-related.

• Scintigraphic tomography can detect abnormality in the pars interarticularis,

facetjoint,anddisc/vertebralbody.

• Scintigraphy sensitively identifies rib and, in most cases, inflammatory

intercostal lesions. The differential diagnosis is of a metastasis, primary

malignant or benign bone tumour, healed rib fracture, fibrous dysplasia,

Paget’sdisease,hyperparathyroidism,orinfection.

Otherinvestigationstoconsiderinpatientswithchestpain

• CXR, then consider pulmonary ventilation-perfusion scan and spiral CT to

evaluateforpulmonaryembolism.

• CTofthechestinpatientswithunexplainedpleuralpain.

• ECGandanexercisestresstestifpossiblecardiacischaemia.

• Transthoracicechocardiographytoshowthickenedpericardiumoraneffusion

associatedwithpericarditis.

• UpperGIendoscopyinsuspectedcasesofpepticulceration.

• Diagnostictrialofaprotonpumpinhibitorincasesofrefluxoesophagitis.

Thoracicbackandchestpaininchildrenand

adolescents

Generalconsiderations

Chest pain is a common paediatric presentation to primary care and A&E in

patientsaged10–21years.Acutechestpainiscardiacin<6%ofpatients.

• Chest pain is often alarming to parents and patients, but rarely caused by a

seriouscondition(Table3.13).

• Inastudyof300patientswithchronicchestpaintherewasacardiaccausein

justonepatient.

• Differentiating cardiac pain and other serious parenchymal pathology, from

musculoskeletalandotherbenignpainremainsimperative.

• PaediatricchestpaincanbeclassifiedintoMSK,respiratory,GI,cardiacand

otherconditions(seeTable3.13).

• For assessment of: thoracic back pain in children and adolescents see

Chapter 21 p. 618; low back pain in children see  p. 154; and thoracic

assessmentinadults,see p.130.

Historyandexamination

Generalconsiderations

• Focalchestpaininchildrenisusuallychest-wall(MSK)orpleuralinorigin.

• Diffusechestpainismostlikelytobereferredfrominternalorganpathology.

• A third of adolescents with chest pains who present to outpatients have a

historyofstressfulevents.Theirchestpainsymptomsaretypicallyassociated

with other somatic complaints and sleep disturbance. Hyperventilation,

dyspnoea,dizziness,orparaesthesiamayindicatepanicattacks,unrecognized

bythepatientorparent.

Cardiachistoryandexamination

• Exertionalchestpainwithchesttightnessandsyncopemightbeduetoatrial

flutterortachycardia whichin turnmaybe duetostructuralcardiacdisease

(e.g.hypertrophicordilatedcardiomyopathy).

• Angina chestpain isusually associatedwithexertion,afeelingoftightness,

andradiatestotheneck,throat,jaw,teeth,orshoulder.

• Pericarditispresentsassharpretrosternalchestpainoftenradiatingtotheleft

shoulder,aggravatedbylyingsupineordeepbreathsandrelievedbybending

forward.

• Severeandtearingmidsternalchestpainradiatingtothebackmaybedueto

aorticdissectioninMarfansyndrome,Turner’ssyndrome,Ehlers–Danlostype

IV,andhomocystinuria.

• Though non-specific, chest pain with fatigue and exertional dyspnoea or

syncopecanindicatepulmonaryhypertension.

• PastmedicalhistoryshouldbetakentonoteanypreviousKawasakidiseaseor

cardiacsurgery.

• Takeafamilyhistoryforarrhythmias,tonotefamilialsuddendeath,genetic

conditionsorhyperlipidaemia.

• Cardiac signs on examination: a harshejectionsystolicmurmur radiating to

theneckin aorticstenosis; anejectionclick froma stenosedbicuspidaortic

valve;abnormalperipheralpulses(e.g.previousKawasakidisease).

Musculoskeletalfeatures

• Chestwallpainexacerbatedbydeepbreathinglastingsecondstominutesmay

be due to costochondritis (e.g. secondary to infection or intercostal muscle

enthesitis in ERA or JSpA). Chest-wall tenderness may be present (usually

unilateralalongtheuppertwoormorecontiguouscostochondraljoints).

• Tietzesyndromeisatermusedtodescribeanteriorchestwallpainusuallyina

singlejoint(commonlyatthesecondorthirdribarticulationatthesternumor

sternoclavicularjoint).DifferentialdiagnosisSAPHOsyndromeinadolescent

andenthesitis(see Chapter16).

• Intense pain in thelowerchest or upper abdomenmaydenote‘slipping-rib’

syndrome, which is secondary to trauma and dislocation of ribs 8, 9, 10.

Noting a history of physical strain, sports-related injury, or direct trauma is

important.

• Slipping ribsyndrome paincan bereproducedbyhookingfingers underthe

inferior rib margin and pulling the rib edge outward and upward (hooking

manoeuvre).Thismanoeuvremayproduceaclick.

• A history of sickle cell disease may be relevant given any MSK pains and

pulmonarydisease(e.g.thromboembolism).

Pulmonarydiseasefeatures

• Pulmonarydiseaseis chieflyidentifiablefromahistoryofdyspnoea,cough,

andconventionalrespiratorysymptoms.

• Severe pain, dyspnoea, and low oxygen saturations require both pulmonary

embolismandpneumothoraxtobeexcluded.

Other

• Abdominal pathology can present with chest pain (e.g. typical ‘heartburn’

symptomsinthethroat; cholecystitis-relatedchestpainradiatingto theright

shoulder).

• Throbbing or burning focal chest pain locating to breast tissue is typical of

mastitis,fibrocysticdisease,orpregnancy.

• Burningpainorparaesthesiainadermatomal pattern,precedinga rashbya

fewdayssuggestsherpeszoster.

Table3.13Causesofchestpaininchildrenandadolescents

Tissue/organ Diagnosis/syndrome Frequency

Musculoskeletal Trauma,injury

Costochondritis/Tietzesyndrome,xiphydynia

Slippingribsyndrome

Sicklecelldisease

15–30%

Cardiac Pericarditis,coronaryarteritis(Kawasaki

disease),aorticdissection,anginasecondaryto

structuralcardiacdisease

Veryrare

(<2%)

Respiratory Pleuralinflammation(infectionandsterile

pleuritis(SLE)),pneumonia,PE,asthma,acute

chestsyndrome

2–11%

Gastrointestinal GORD,IBD,cholecystitis 8%

Neurological Herpeszoster

Nerverootsymptoms

Rare

Other Idiopathic

Anxiety,panic-hyperventilation

Breast-relatedconditions

>50%

Lowbackpaininadults

(Seealso Chapter21.)

Epidemiology

• The lifetime prevalence of back pain is 58% and the greatest prevalence is

between45and64yearsofage.

• Most recent statistics report in the order of 12 million primary care

consultationsandover2.4millionadultspecialistconsultationsannuallyinthe

UKforlowbackpain(population64million).Lowbackpainisthefifthmost

commonreasonforallphysicianvisitsintheUSA.

• 2%oftheworkforceintheUSAiscompensatedforbackinjurieseveryyear.

• EstimatedannualcosttotheUKNationalHealthServiceis£500millionwith

over £5 billion lost annually due to absence from work. The financial

healthcare and indirect employment costs of low back pain in the USA are

estimatedtobemorethan$24billion.

Lumbarandsacralspineanatomy

• Therearenormallyfivelumbarvertebrae.Anomaliesarenotuncommonatthe

lumbosacraljunction.

• Thetransitionbetweenthemobilelumbarspine(flexion,extension,andlateral

flexion)andfixedsacrumtogetherwithhighweight-loadingcombinetomake

theregionhighlypronetodamage.

• The facet joints are sharply angled, effectively reducing rotation in lumbar

segments.

• Thesacroiliacjoints(synovial)areheldfirmlybyastrongfibrouscapsuleand

tough ligaments. The amount of normal movement (essentially rotation) is

normallyinverselyproportionaltoage.

• The spinal cord ends at L1/L2. Nerves then run individually, are normally

mobileinthespinalcanal,andtogetheraretermedthecaudaequine.

• Each nerve exits its appropriate lateral intervertebral exit foramen passing

initially superior and then laterally to the disc, e.g. L4 from L4/L5 exit

foramen. However, in the spinal canal each nerve descends immediately

posterior to the more proximal intervertebral disc before it exits. Thus, for

example, L4 root symptoms can occur from either lateral herniation of the

L4/5discorposteriorherniationoftheL3/L4disc(orfromboth).

• Facetjointinnervationisfromposteriorprimaryrami,eachofwhichsupplies

thecorrespondingjointatitslevel,onehigherandonelower.

Basicprinciplesofassessment

• Low back pain can arise from damage or inflammation of the thoracic or

lumbar spines or from the posterior pelvis. Pathology in retroperitoneal

abdominalandpelvicvisceracanresultinreferredpaintothelowback.

• A simple way of categorizing back pain is to consider its cause to be

mechanical, inflammatory, neurologic, referred, or due to bone pathology

(Table3.14).

• Over90%ofepisodesoflowbackpaininadultsaremechanical,self-limiting,

anddonotrequireinvestigation.

• Indicatorsforfurtherinvestigationincludeage>55years,stiffness,focalpain,

pain that disturbs sleep, nerve root symptoms, and chronic persistent (>6

weeks)pain.

• The low back is often a focus for those who may use pain (consciously or

unconsciously) as a protective deviceinthefaceofdomestic,emotional, or

occupational stress. These stresses commonly influence the description and

impact of pain but rarely act alone in causing pain—there is usually some

underlyingorganicpathology.

Table3.14Commonand/orseriouscausesoflowbackpaininadults

Mechanical/degenerative

(verycommon)

Intervertebraldiscdisease(annulartear,internal

disruption,prolapse)

Facetjointarthritis

Spondylolisthesis

Scoliosis/kyphosis

Spinalstenosis

Inflammatory(common)

AS/axSpA( Chapter8)includingsacroiliitis

DISH

Infection(rare) Osteomyelitis(e.g.Staphylococcusaureus,

TB,brucellosis)

Bonedisease(common) Osteoporoticfracture

Paget’sdisease

Osteomalacia

Neoplasia(rare) Secondarymetastases

Multiplemyeloma

Other Sicklecellcrisis

Renaldisease(e.g.tumours,infection)

Gynaecologicaldisease

Fibromyalgia( Chapter22)

Takingahistoryoflowbackpaininadults

Differentiate whether the pain is likely to be primarily mechanical or

inflammatory,duetobonepathologyorreferred:

• The site and extent of the pain does not easily discriminate the cause. All

disordersmaybeassociatedwithmechanicaldeformityand/ormusclespasm

thatmaycausepaininadiffusedistribution.

• Generally, pain due to mechanical lesions is often acute in onset, while

patients with pain from inflammatory lesions often present after symptoms

havebeenpresentforsometime.

• Inflammatorypainisoftenassociatedwithmorningstiffnessthatcanlastfor

severalhoursandiseasedbymovement.Mechanicallesionstendtoworsen

with use. Many ‘mechanical’ or ‘degenerative’ lesions may have an

inflammatorycomponent,e.g.internaldiscdisruptioncausingdiscogenicpain.

• Intrinsicbonepathologyoftencausessevere,unremitting,focalpain.Sleepis

disturbed.Paindoesnoteasesubstantiallywithmovement.

• About 3% of patients presenting with back pain have non-MSK causes. A

significantproportionofwomenhavepelvicconditionssuchasovariancysts

orendometriosis.Painmaybecyclical.

• For those aged >55 with no previous similar episodes of pain increase

suspicionofanunderlyingneoplasticlesion.Investigationisrequired.

• Associated systemic symptoms are common in osteomyelitis and may be

presentifamalignancyhasdisseminated.

Askaboutpainradiationandsymptomsinthelegs

• Progressiveneurologicallegsymptomssuggestaworsening/expandinglesion

suchasatumour,infection/vertebralcollapse,Paget’sdisease,orlumbosacral

spinalstenosis.

• Pressure on the cauda equina sufficient to cause a disturbance in perineal

sensationand/orbowel/bladderparalysisisaneurosurgicalemergency(cauda

equinasyndrome;see Chapter21).

• Legpaincausedbynerverootirritation/compressionisoftenclearlydefined

and sharp, often accompanied by numbness or paraesthesias. The most

commonlyinvolvednerverootsareL4,L5,orS1.Paingenerallyradiatesto

belowthekneeandoften,butnotalways,totheheelandbigtoe.

• Sciatic nerve entrapment at the piriformis muscle can produce identical

radicularsymptomstoL5orS1nerverootentrapment.

• Neurological symptoms in the distribution of the femoral nerve (primarily

anterior thigh musculature) might suggest a high lumbar nerve root lesion

(L1–L3,forexample).

• Disc prolapse is the most common cause of nerve root pain, but bony

encroachment at the nerve root exit foramen by vertebral end-plate or facet

joint osteophytes, and/or soft tissue thickening or fibrosis can cause similar

pain(foramenalstenosis).

• Annulardisctearsandinternaldisruption(i.e.microfracturesinvertebralend-

plates)cancauseapatternofpain,termeddiscogenicpain,characterizedby

lowbackandreferredbuttock/posteriorthighpainaggravatedbymovement.

• Generally, all mechanical lesions of the lumbar spine can result in referred

painaroundthepelvisandanteriorthighs.However,painfromlumbarfacet

jointsandprobablyothersegmentalstructurescanbereferredtothelowerleg.

• Aching in the back and posterior thighs after standing is typical of, but not

specific for, spondylolisthesis. There are often added spasms of acute pain,

especiallyifthereissegmentalinstability.

• The symptoms of spinal stenosis are often relieved by sitting bent slightly

forward,sincethespinalcanaldimensionsincreaseinthisposition.

• Sacroiliitis often causes referred pain to the buttocks and back of thighs. It

occurscommonlyinSpA(see Chapter8).

• Sacroiliac pain can occur in multiparous women—the condition may be

associatedwithhypermobility.

Notethedescriptionofthepain

• Painmaybe‘severe’whateverthecause;however,notewhetherthepatient’s

descriptorsofitsuggestnon-organicinfluences.

• Sharp, lancinating leg pains suggest nerve root irritation/compression

(radicular pain), whereas leg pain referred from other structures within a

lumbarsegmentisgenerallydeepandaching.Thedistributionmaybesimilar

(see earlier in section). More persistent, rather than episodic, radicular pain

maydenotestenosisofthenerverootexitforamen.

• A description of bilateral buttock/leg pain that worsens on walking is

consistent with spinal stenosis, especially in those with normal peripheral

pulsesandnobruits.

• A change in the description of pain in someone who has an established

diagnosismaybeimportant,e.g.subacute,severe,unremittinglocalizedpain

in a patient with axSpA who normally has mild inflammatory pain might

reflectasuperaddeddiscitis;or,acutesevereunremittingsleep-disturbingpain

inanelderlywomanwithknownchronicmechanicalpainassociatedwithOA

mightsuggestosteoporoticfracture.

• Florid descriptions of the pain and its severity are associated with

psychologicalmodulatorsofpain.

Previousbackpainandtrauma,occupation,andfamilyhistory

• Scheuermann’sdisease(whichisassociatedwithirregularvertebralendplates)

causes spinal pain in adolescence. It is a risk for spinal degeneration and

kyphosisinadults.See p.514.

• Previoustraumamayhavecausedparsinterarticularisfractures(anantecedent

of spondylolisthesis),vertebralfracture (risk offurthermechanical damage),

orligamentrupture(subsequentsegmentalinstability).

• Itisgenerallyacceptedthatthehighprevalenceofdiscdiseaseamongmanual

workers at a relatively young age provides some evidence for a causal

relationship.

• Itisoftenthecasethatpatientswithchronicpainfollowing(sometimestrivial)

traumamaybedissatisfiedwiththequalityofcarereceivedatthetimeofthe

injury.Beawarethatmanybelieve,andthereissomeevidencetosupportthis,

that the way in which spinal pain is handled at its onset significantly

influencesitssubsequentcourse.

• Sacroiliitis is an early part of Brucella arthritis (20–51% of patients). Poor

animal- or carcass-handling hygiene or ingestion of infected foodstuffs/milk

can lead to infection. Spondylitis is a late feature and is characterized by

erosions,discinfection,andabscesses.

• Apositivefamilyhistoryoflowbackpainmight,incontext,suggestSpAor

generalizedOA.

Examinationofanadultwithlowbackpain

Inspecttheundressedpatientfromthesideandbehind

• Notethefluidityofmovementwhenthepatientisundressing.

• Check the skin for redness, local swelling, and skin markings. Redness and

swellingoccasionallyaccompanyosteomyelitis.

• Lipoma, hairy patches, café-au-lait patches, or skin tags often reflect

underlying structural nerve or bone abnormality, e.g. spina bifida,

diastematomyelia,neurofibromatosis.

• Skinfolds often suggest an underlying significant structural change, such as

osteoporoticfractureorspondylolisthesis.

• Noteanydeformity:hyperlordosis(associatedwithL5/S1damageandweak

abdominal musculature), prominent thoracolumbar kyphosis (multiple disc

degeneration or vertebral fractures), scoliosis (degenerative, compensatory

musclespasmforunilateralpain).

• Look from the side. A gentle lordotic curve is normal. Flattening suggests

musclespasmorfusioninSpA.Withmajorspondylolisthesis,astepbetween

spinousprocessescansometimesbeseen.

Observeactivemovementswhilethepatientisstanding

Lumbarforwardflexion(‘...withyourlegsstraight,slowlyreachdowntotry

and touch your ankles . . .’), lateral flexion (‘. . . with your legs and back

straight,tipsidewaysandrunyourhanddownyourlegtowardsyourknee...’)

andextension(‘...withyourlegsstraight,slowlybendbackwards...’).Note:

flexion can be mediated by the hip joints; extension can be affectedbyslight

pelvic tilt and body sway. Ask what can be achieved normally and what is

painful:

• Abnormalmovementsarenotspecificforanyconditionthoughtheymayhelp

tolocalizeaproblem.

• Pain in extension is characteristic of retrolisthesis, facet joint arthritis, or

impingingspinousprocesses.Mayberelievedbyflexion.

• Failure of the spinous processes to separate in a patient who manages good

forward flexion would be consistent with permanent spinal stiffness, e.g.

axSpA/AS,withflexionmediatedbythehipjoints.

• ForwardflexioncanbemeasuredusingthemodifiedSchöbertest.Whenerect,

marktheskinatthepointmidwaybetweentheposteriorsuperioriliacspines

(Venus’ dimples) and again 10 cm above and 5 cm below. Measure the

increase in distance between the outer marks at full forward flexion—in a

youngadultthisisnormally>6cm.

• Ask the patient to stand on one foot then lift onto their toes a few times.

WeaknessmightimplyanL5nerverootentrapment(gastrocnemius/soleus).

Observethegaitpattern

Abnormalityofgaitmayreflectanyspinalorlowerlimbproblem:

• Anantalgicgait;aself-protectivelimpduetopain,typicallycharacterizedby

ashortstancephaseontheaffectedleg.Thecommonestcauseispathologyat

thehip.

• Awide-basedgaitsuggestsunsteadiness(duetodizziness,muscularweakness,

proprioceptive,orcerebellardeficit,etc.).

• Leaningforwards/stifflegged—althoughnotspecific,inolderpeoplethismay

denotespinalstenosis.

• Shuffling, which could suggest parkinsonism (back pain/stiffness is a

recognizedearlysign).

• Footdrop,whichcouldsuggestL5orS1nerverootcompression.

• Flat feet, hind feet valgus, and genu recurvatum on stance phase, might

suggestgeneralhypermobility—associatedwithvariouslowbacklesions.

Checkextensionandlumbarrotation(patientseated)

Withthepatientseatedonthecouch,checklumbarextensionandrotation(the

pelvisisnowfixed):

• Typically,combinedrotationandextensioncanelicitpainfromarthriticfacet

joints.Itisasensitivethoughnotspecifictest.

• Slumpingforwards(Fig.3.11)stretchesthedura.Increasedlumbarpainmay

be elicited in cases of disc prolapse, but more importantly, leg pain can be

elicitedincasesofnerverootentrapment.Amoreprovocativetestcanbedone

by gently extending each knee in turn in the slump position. Look for

asymmetry.

Fig.3.11The(passive)slumptestidentifiespainfromlumbardiscandnerverootirritationorcompression.

‘Active’legextensioncanalsotriggerpain.

Examinethesacroiliacjointsandhips(patientsupine)

Withthepatientsupine,examinationofthesacroiliacjointsandanexamination

ofthehipsshouldbedonetoexcludepainarisingfromthesestructures:

• Testflexionandtherotationalrangeofeachhipbyliftingtheleg,flexedatthe

knee,sothattheupperlegisvertical.Passivemovementshouldnormallybe

pain-free.

• NoSIjointstresstestisspecific.Testsaredesignedtoreproducepainincases

ofSIjointdysfunctionorsacroiliitis.Herearetwo:

• Pressdown/outreasonablyfirmlyoverbothanteriorsuperioriliacspinesat

thesametime.

• Liftoneleg,flex,andabductthehipslightly.Exertanaxialforceintothe

acetabulumattwoorthreedifferentangles.Thistestisconsideredbymany

tobemoreusefulandprobablystressesboththejointandmanyofthesacral

ligaments,butislessspecificifthehipjointisabnormal.

Testingnerveroottension

(Alsosee Chapter21.)Usestraightlegraisewiththepatientsupine,Lasegue’s

test,andtheslumptest.

• Thenormalvariationinstraightlegraiserangesfrom60°tomorethan90°in

adults.Comparesides:

• Discomfort from normal tightening of the posterior thigh or calf muscles

mustbediscriminatedfromapositivetest.

• Apositivetest(legraisingrestrictedto40°orlessbytheradicularpain)is

mostspecificinpatientsaged<30yearsandforL5orS1nerverootlesions.

• A crossed straightlegraise(pain elicited by raising theunaffected leg) is

evenmorespecificfornerverootentrapment.

• Lasegue’stestisdonebyliftingtheaffectedlegwithkneefullyflexedatfirst

thenwiththeupperpartofthelegvertical,slowlyextendingthepatient’sleg

attheknee(passiveexamination).

• ApositiveLasegue’stestiswhenpainistriggeredinbuttockorbackasinthe

straightlegraise.

• Slumptestisparticularlyusefulwhenthepatientisunabletoliesupinefora

straightlegraiseorLasegue’stest.Withthepatientsitting,andslumped(Fig.

3.11)andlegshangingfreeofftheground,graduallyextendthelowerlegand

askifbuttockorlowbackpainistriggered(apositivetest).

• To identify more subtle cases of nerve root entrapment with all three tests,

apply additional foot dorsiflexion at the maximum possible extent of leg

raise/kneeextension(pain-free).

Neurologicalexamination

Neurologicalexaminationofthelegsisessentialinsuspectedcasesofnerveroot

entrapment, cord compression, spinal stenosis, and cauda equina syndrome.

Table 3.15 lists tests for muscle strength in the lower limbs—weakness may

denotenerverootentrapment—andTable3.16liststheprincipalsignsoflumbar

nerverootlesions.

Examinationofthepronepatient

Askthepatienttoturntolieprone.Palpatelowbackandoversacrum:

• Diffusetendernessmaybeduetomusclespasm.

• Superficial tenderness over the spinous processes or interspinous interval

mightsuggestinterspinousligamentdisruptionorimpingingprocesses.

• Paravertebralbonytendernessmaysuggestfacetjointarthritis.

• Costovertebralangle/lointendernesscouldindicaterenalpathology.

• TendernessovertheSIjointsisnotspecificforsacroiliitis.

• ApositivefemoralstretchtestreproducesL1–L4(especiallyL3)radicularpain

intheanteriorormedialpartofthethigh.Flexthepatient’skneeto90°and

passivelyextendthehip.

Otherexamination

• Insuspectedcasesofspinalstenosisorcaudaequinasyndrome,itisessential

to check for sensory loss in the sacral nerve dermatomes. Also check anal

sphinctertonebyrectalexamination(S5).

• In suspected cases of spinal stenosis, the patient can be asked to walk until

limitedbypainthenre-examined.Ifthereisanyischaemiaofthecaudaequina

or of a nerve root (from foramenal stenosis), nerve root signs may become

moreobvious.

Investigationoflowbackpaininadults

(Alsosee Chapter21.)

Therearetwoimportantinitialstepsininvestigatinglowbackpain.

Firstdecidingwhetherradiographswillhelp.Second,althoughrelativelyrarein

practice, the possibility of infection, malignancy, and cauda equina

compressionalwaysneedstobeconsidered.

• Simpleradiographicviewsareinsensitiveindicatorsoftheseconditionsand,

inmostcases,arenotspecificalthoughmostradiologistswouldagreetheyare

desirable in addition to CT or MRI. Laboratory tests are mandatory in all

suspectedcasesofinflammation,infection,andmalignancy.

Table3.15Testingmusclestrengthinthelowerlimbs(patientsupineunlessotherwisestated).Weakness

maydenotenerverootentrapment

Muscleormuscle

group

Nerve

roots

Test

Hamstrings(knee

flexion)

L5,

S1,

Askpatienttoflexthekneeto45°,hold

patient’sankleandaskthemtobendtheknee

furtheragainstyourhold

Iliopsoas(hip

flexion/internal

rotation)

L1,

L2,

Askpatienttoliftthelegwithabentknee,

holduptheupperlegandresistyourpush.Try

topushthelegdownandslightlyoutwards

Quadricepsfemoris

(hipflexion,knee

extension)

L2,

L3,

Holdthepatient’srelaxedupperlegabovethe

couch(holdunderneathabovetheknee).The

lowerlegshoulddroploosely.Askthemto

raisethelowerlegagainstyourresistance

Frompatientstandingtestrepetitivesquatting

formoresubtleweakness

Tibialisanterior

(ankledorsiflexion).

Tibialisposterior

(ankleinversionand

plantarflexion)

L4,

Withthekneestraightaskthepatienttopull

backtheirfoot(showthemfirst)againstyour

pull.Resistdorsiflexion

Standingorwalkingonheelstestsformore

subtleweakness.Note:ifthehindfootrestsin

valgusorthepatientsignificantlyevertsthe

footduringdorsiflexion,thetestmayalso

recruitperonealmuscles(L5,S1)

Extensorhallucis

longus

L5,

Askthepatienttopulltheirbigtoeback

againstyourfinger(atthebase)

Gastrocnemiusand

soleus(ankleplantar

flexion)

S1,

Askthepatienttopointtheirtoes.Resist

movementbypressingtheballofthefoot

Standingorwalkingonthetoestestsformore

subtleweakness

Comparesides.Scoreaccordingtoscale,forexample:0=nomusclecontraction;1=contraction

visible;2=activemovement,gravityeliminated;3=activemovementagainstgravity;4–/4/4+=active

movementagainstslight/moderate/strongresistance;5=normalpower.

Table3.16Principalcombinationsofsignsusedforidentifyinglumbarnerverootlesions

Nerve

root

Paraesthesiasandsensory

change

Muscleweakness Tendon

reflex

changes

L2 Upperthigh:anterior,

medial,andlateralsurfaces

Hipflexionandadduction None

L3 Anteriorsurfaceoflower

thigh

Hipadductionandknee

extension

Kneejerk

possibly

reduced

L4 Anteromedialsurfaceof

lowerleg

Kneeextension,foot

dorsiflexion,andinversion

Kneejerk

decreased

L5 Anterolateralsurfaceof

lowerlegand

dorsum/medialsideof

foot/toe

Hipextensionand

abduction.Kneeflexion.

Foot/toedorsiflexion

None

S1 Lateralborderandsoleof

foot.Backofheelandcalf

Kneeflexion.Plantar

flexionandeversionoffoot

Anklejerk

decreased

Radiographs:decision-makinginrequestingthem

(SeeTable3.17.)

• Lumbarspineradiographsarenotalwayshelpful.Rememberthatnineoutof

ten cases of back pain in the primary care setting are mechanical and self-

limiting.Featuresonaplainradiographofthelumbarspinecorrelatepoorly

withthepresenceorpatternofpain.

• Spondylosisiscommon,age-related,andoftenisn’tsymptomatic.

• MRIbestidentifiesaparsinterarticularisfracture,anyassociatedboneoedema

and spondylolisthesis seen in young people and athletes (see  p.620). CT

helpsclarifythehealingresponse(bridgingofboneacrossthedefect).

• Obtaining radiographs to help in the management of patients is a different

issuetoobtainingthemtoaiddiagnosisandonethatrequirescarefulthought,

e.g.isthepatientlikelytoperceivethattheyhavereceivedsuboptimalcareifa

radiographisnotrequested?

• Spondylolysis may be seen on a lateral view, but is seen better on oblique

view.Obliqueviewsmayalsoshowpediclestressfractures.

• Spondylolisthesismaybeidentifiedandgradedbyalateralfilm.

• Flexionandextensionviews maybe helpfulindelineating subtlecases,and

instability(spondylolytic).

• General osteopenia is a risk factor for low bone mass; however, it is not a

sensitiveindicatoroflowbonemass.

Table3.17Commonlyreportedpatternsofradiographicabnormalityinadultswithspinalsymptoms:the

interpretation,andsuggestedreaction

Radiographic

abnormalities

Lesion

suggested

Sensiblefurtheraction

Lumbosacral

anomalies

Riskforfuture

backpain

Maynotbeclinicallysignificant.Riskfor

lowbackpain(esp.ifhypermobile)

Generalized

osteopenia

Osteoporosis Measurementofbonedensity.Ruleout

secondarycauses,e.g.myeloma

Narrowed

discspace,

marginal

vertebralend-

plate

osteophytesor

both

Intervertebral

discdisruption

MRIifpersistentsymptomsorsignsof

samelevelnerverootentrapment,spinalor

nerverootexitforamenstenosis

Localized

lucentor

sclerotic

lesion,lossof

cortex

Tumour,

infection,or

fracture

Discusscasewithradiologist.MRIorCT

maybeadvised.Abonescanmaybe

helpful.Initiateappropriatelaboratorytests

immediately

Facetjoint

syndrome

Considerwhetherthereisassociated

spinal/nerverootexitforamenstenosis(?

radicularsymptoms)orsymptoms

suggestiveofspondylolisthesis.CTorMRI

isthenlikelytobeappropriate

Pars

interarticularis

defect

Spondylolysis/?

spondylolytic

Furtherobliquefilmcentredonsuspected

levelorCTshouldconfirm.Association

withsymptomsorsignsofdiscdiseaseor

spondylolisthesis.Flexionandextension

lateralviewradiographsmaydetailthe

lesionfurther.MRIcharacterizesbone

stress,softtissueinvolvementandnerve

impingment.

Shortlumbar

pedicles

Spinalstenosis ConsiderMRIifsymptomssuggestspinal

stenosis

Mixedpatchy

sclerosisand

lucencyin

entire

(enlarged)

vertebra(e)

Paget’sdisease Neurologicallegsymptomssuggest

spinal/exitforamenstenosisorvascular

‘steal’

• Lookforvertebralsquaring(inAS),non-marginalsyndesmophytes(inother

SpA,suchaspsoriatic—see Plate13),orflowingsyndesmophytes(inDISH

—atleastthreecontiguousvertebralbodies).

• Consider obtaining an AP view of the pelvis. Established (but not early)

sacroiliitiscanberuled-out.Afurther‘coned’viewisoftenhelpful.

• Sacroiliitis (periarticular osteoporosis, erosion, sclerosis of bone, widening

jointspace)occursinalltypesofSpA.Itcanbeunilateral.

• Sclerosis of the SI joint on the lower iliac side alone suggests osteitis

condensansilii.Jointspaceisnormalandjointmarginwelldefined.

• Patterns of metabolic bone disease, Paget’s disease and hip pathology are

usuallyreadilyidentifiableonapelvicfilm.

Bonescintigraphy(see Plate16)

• Bonescintigraphyisasensitivetestforinfectionormalignancy.Itisauseful

investigation in patients with previously diagnosed malignancy who present

with back pain, especially in those who have had no previous skeletal

metastases. No additional lesions strongly suggests against a single spinal

abnormalitybeingmalignancyrelated.

• Itisnotspecificforthevariousdegenerativelesions,butcanhelplocalizethe

siteofalesion.

• SI joint appearances can locate pathology but appearances may depend on

bothpreviouspathologyand/orcurrentinflammation.

CTorMR?

The choice of imaging depends on local availability and likely differential

diagnosis,althoughMRIispreferredinyoungpeople:

• For spondylolytic spondylolisthesis, CT shows bone bridging and size of

defectwhereasMRIshowsbonestressofanyrecentfracture.

• NerveimpingementcanbeshownbyCTorMRI.

• Intervertebraldiscprolapse,bothposteriorandposterolateral,canbeshownby

eithertechnique.ProlapsematerialisofsimilarCTdensityandMRsignalto

thedisc,andwell-definedagainstepiduralfat.

• Changesinthenormaldiscsignalpatternareassociatedwithage-relateddisc

degeneration. Discogenic pain has been associated with MRI abnormalities

classifiedaccordingtoModic.

• OnT2-weightedMRI,discmaterialisusuallyofhighersignalthan‘scar’(e.g.

fibrosisfromapreviouslesion),inwhichsignaldecreaseswithageing.Recent

scarring enhances immediately, but old scarring does so only slowly. This

discriminationrequiresgadolinium-enhancedMRI.

• CT or MRI shows early sacroiliitis in axSpA when radiographs are normal

thoughMRIwillshowcurrentinflammationbetterthan‘ever’involvementof

SIJs—forwhichCTisbetter.

• TheshapeandoutlineofthespinalcanalareideallyshownonCT,butarealso

seen withMRI.Itis difficultforMRI to distinguish fibrous structures from

sclerotic or cortical bone, though it shows intrathecal content more readily

whichisanadvantageinidentifyingintraduraltumours.

• Spondylodiscitis(partofaxSpA),ifchronic,maybedifficulttodiscriminate

from degenerative disc/vertebral end-plate disease. Fat-suppressed or

gadolinium-enhanced sequences may show high signal at the anterior disc

vertebralend-platejunctions.

Screeningforinfection,malignancy,ormetabolicbonedisease

• In cases where the history and examinationsuggestamechanical condition,

but where the clinician wishes to be more confident of excluding an

inflammatorycondition,ESR,andCRParesuggested.

• AraisedESRwouldpointtowardsfurtherlaboratoryinvestigation.

• An infection screen should include an FBC for anaemia and leucocytosis,

CRP,blood,andurinecultures.IfspinaltuberculosisissuspectedaplainCXR

shouldbetakenandserial(over3days)earlymorningurinesamplestaken.

• Serum and urine protein electrophoresis (with immunofixation) are essential

testsinthe‘work-up’formyeloma.Ureaandcreatininearealsoimportantas

hypercalcaemia, and acute renal impairment have prognostic significance in

thiscondition.

• Routinebloodtestsmaypointtoanunderlyingmetabolicbonedisordersuch

asPaget’sdiseaseorosteomalacia.Thesetestsarenormalinpostmenopausal

osteoporosis.

• Ifosteoporosisisdiagnosed(see Chapter16)ascreenforsecondarycauses

shouldincludeESR(andifraised,serum,andurineproteinelectrophoresis),

calcium, phosphate, sex hormones, but also serum 25-hydroxyvitamin D,

parathyroidhormone(PTH),thyroidfunctiontests(TFTs),andliverfunction

tests(LFTs).

Treatmentoflowbackpain:adults

(Seealso Chapter21forgreaterdetail)

• Animportanttherapeuticinterventioninthecaseofacutepainistotakethe

patientseriously,takeapositiveview,andintheabsenceofsinistersigns,e.g.

nerverootpain,urgeearlymobility.

• Analgesics and muscle relaxants can be used in the short term, initially

regularly,thenasrequired.

• Physicaltherapywithgraded-activityprogrammesmaybeofvalue,certainly

earlyindiscdiseaseorspondylosis.

• Cordcompressionduetobonecollapsefromatumourisanacuteemergency

and should be discussed immediately with an oncologist or radiation

oncologist,andaspinalorthopaedicorneurosurgeon.

• Caseswithdiscprolapsefailingtorespond toconservativetherapy,orcases

wherethereisongoingorrapidlyprogressiveneurologicaldeficit,shouldbe

referredforsurgery.

• Available surgical techniques for acute or persistent disc disease include

decompression (e.g. nerve root decompression and partial facetectomy),

prostheticintervertebraldiscreplacement,intradiscalthermocoagulation, and

intradiscal steroid injections, although evidence for long-term efficacy is

lackingforalltheseprocedures.

• Surgeryforspinalstenosisisusefulforrelievinglegneurogenicfeatures,but

notindicatedifthereisnosignificantneurologicalcompromise.Surgeryisnot

usuallydoneiftheonlyeffectofspinalstenosisisbackpain.

• In chronic back pain, aerobic exercises combined with behavioural methods

maybemoreeffectivethanexercisealoneandcanhelpmotivatethepatient.

Methods may also incorporate psychological and social assessment and

management.

• Thecommontreatmentsavailableforchronicbackpaininclude:

• analgesicsandmusclerelaxants.

• antiepileptics/antidepressantsforneuropathicpain.

• localanaesthetic/steroidinjections.

• acupuncture.

• transcutaneouselectricalnervestimulation(TENS).

• physicaltherapy.See p.609
• ergonomicadvice.
• multidisciplinary programmes—counselling, cognitive therapy, education,
relaxation,corsetsandbelts.
• Timelysurgeryforstructuralscoliosiscanlessenspinalcurvature.
Lowbackpaininchildrenandadolescents
Synopsis
Childrenandyoungpeoplepresentwithacombinationofbackpain,deformity,
limp, systemic or neurological features. Many of the features of adolescents
overlapwithyoungadultsandthereaderisreferredtotheassessmentofadults
onpp.140–152.Seealso Chapter21,pp.618–621.
• Backpaininchildren andadolescentsiscommon(lifetime prevalenceupto
80%by20y)and,asinadults,mostcasesarenon-specific,self-limitingand
donotpresenttothemedicalprofession.
• Backpainismorecommonattimesofrapidgrowthingirlsandwithhighand
lowlevelsofactivity.Itisespeciallycommoninyoungathletes.
• Times of rapid growth are also associated with: progression of idiopathic
scoliosis; other spinal deformities; and (if excessive) volume expansion of
vertebraewhichconfersthepotentialforadiscrepancybetweenbonesizeand
bonemass(areasonforcorrectingDXAscan-derivedBMDmeasures).
• Thelikelihoodoffindingunderlyingpathology(see Table21.6,p.618)is
low,butmorelikelyatyoungerages(especially<4yold).
• Low back pain in adolescence is a significant risk factor for back pain in
adulthood.
Takingahistoryoflowbackpaininchildren
• Itisimportanttoconsiderbackpaininrelationtoageanddevelopment.Loss
of developmental milestones, refusal to walk, or irritability in a non-verbal
child,especiallyif<4y,warrantsimmediateinvestigation.
• Systemicfeatures,intractableornightpaininchildren<6yrequireassessment
forinfectiousorneoplasticcausesincludingTBinrelevantpopulations.
• Backpainismorecommonattimesofrapidgrowthingirlsandwithhighand
lowlevelsofactivity.Itisespeciallycommoninyoungathletes.(seealso
Box21.1).
• Trauma,especiallysuddenorrepetitivetwistinginadolescentsmayaggravate
orcauseaparsdefectleadingtospondylolisthesis.
• Disability(includingschoolabsence)disproportionatetoexaminationfindings

may indicate pain amplification. Social history including stresses and sleep

patternshouldbeelicited.

• Incongruence of history and examination raises suspicion of non-accidental

injury.

• Asinadults,differentiationbetweenbiomechanicalandinflammatoryclinical

featuresshouldbeelicited.

Examinationofbackpaininadolescents

• Be opportunistic with a young child, observe play and review findings in

contextofdevelopmentalstage.

• Focalbonytendernessidentifiedbypalpationorpercussionshouldbeassessed

furtherthroughradiologicalinvestigation.

• Examinegait(see pp.37–39)andposture,forlossorexaggeratedlordosis,

pelvictilt(fromleglengthdiscrepancy),neckjut,andkyphosis.

• Scoliosisisrarelypainful.

• Reduced hamstring flexibility (determined by popliteal angle) and tight hip

flexors(Thomas’stest)arecommonlyassociatedwithbackpain.

• New,unilateralorpersistenttoe-walkingsuggestsspasticity,tetheredcord,or

muscleweakness.

• Survey the skin for possible bruising, mid-line hairy patches, café-au-lait,

axillary freckling (neurofibromatosis). Soft tissue swelling may denote

extensionofaspinaltumour.

• Neurologicalexaminationin20%ofchildrenwithboneorspinalcordtumours

willshowmotorweakness.

Investigations

• Investigationsarethesameasforadultssee pp.148–151.

• AgeneralanaestheticiscommonlyrequiredforanMRIinyoungchildren.

Pelvic,groin,andthighpaininadults

Anatomy

Anatomyofthepelvisandhipregion

• The bony pelvis consists of two innominate bones (ilium above the

acetabulumandischiumbelowit)thatarticulatewitheachotherattheanterior

symphysispubisandposteriorlywiththesacrumattheSIjoints(SIJs).

• SIJs are initially synovial but become fibrous with age. A few degrees of

rotationcanbedemonstratedinchildrenandyoungadults.

• Strongligamentsstabilizetheposteriorpelvisthroughsacroinominate,lumbo

(L5)–sacral,andlumbo(L5)–iliacattachments.

• Thesymphysispubisisacartilaginousjointandnormallydoesnotmove.

• When standing, weight is transferred through the head of the femur. The

femoral head is stabilized in the acetabulum by the acetabular labrum and

strongpericapsularligaments.

• The ligamentum teres crosses the hip joint and carries blood vessels to the

headofthe femur inchildrenand young adults.Inold age, bloodsupply is

largelyviavesselsthatenterthefemoralneck.

• Twobursaearefoundattheinsertionofthegluteusmaximus:oneseparatesit

fromthegreatertrochanter,theotherseparatesitfromthevastuslateralis.

• The ischial bursa separates gluteus maximusfromtheischial tuberosity and

canbecomeinflamedfromoveruse.

Anatomyofpelvicmusculature

• Threegroupsofmusclesmovethehipjoint:thegluteals,theflexormuscles,

andtheadductorgroup.

• Themajorglutealgroupmusclesare:

• gluteusmaximus(L5,S1/2):arisesmainlyfromiliumandsacrum,projects

down posteriolaterally and inserts into the posterior femur and the lateral

tensorfasciaelatae.Itextendsandexternallyrotatesthehip(thehamstrings

alsoextendthehip).

• gluteus medius (L4/5, S1): lies deeper and more lateral. It inserts into the

lateralgreatertrochanterandabductsandinternallyrotatesthehip.

• piriformis,obturatorinternus,andquadratusfemorisarisedeepinthepelvis

andinsertintotheposteriorgreatertrochanter.Allexternallyrotatethehip.

• Themajorhipflexor,psoasmajor(L2/3),isamassivemusclethatarisesfrom

thelateralpartofthevertebraeandintervertebraldiscs(T12–L5)andlateral

processesofthelumbarvertebrae.Itrunsanteriorlyovertheiliacrim,across

thepelvis,undertheinguinalligament,andinsertsintothelessertrochanter.

Theiliacus(L2–L4)arisesfromthe‘inside’oftheiliacblade,passesunderthe

inguinal ligament medially to the lesser trochanter. Both flex, but the psoas

alsointernallyrotatesthehip.

• Thepsoasisenvelopedinafascialsheath.Retroperitonealorspinalinfections

thattrackalongsofttissueplanessometimesinvolvesthepsoassheathandcan

causeinflammationinthepsoasbursa,which separatesthemusclefromthe

hipjoint.

• Alladductormusclesarisefromthepubisorischiopubicrami.Theadductor

longus and gracilis are the most superficial; they arise from the pubis and

insertintothefemoralshaftandpesanserinus(‘goose’sfoot’)belowtheknee,

respectively. The adductor magnus (L4/5) is the largest of the deeper

adductors;itinsertsintothemedialfemoralshaft.

• Adductors stabilize movement around the hip towards the end of the stance

phaseofthegait.Bodyweightistransferredontoonelegduringthisaction

and,therefore,adductorsneedtobestrong,especiallyforrunning.

Functionalanatomyofthehip

• Withaflexedknee,thelimitofhipflexionisabout135°.

• Hipextension(at30°),internalrotation(at30–35°),andexternalrotation(at

45–55°)islimitedbystrong,pericapsularligaments.

• Abductionislimitedto45–50°bycontactbetweenthegreatertrochanterand

acetabularlabrumrim.Adductionislimitedto20–30°withafixedpelvis(see

Plate15).Theseareadultranges.

• Greater femoral neck anteversion (angle of the neck compared to the distal

femur) allows greater internal rotation of the hip (and reduced external

rotation).Tibialtorsioncancompensatebutthisandhipanteversionresultsin

atoe-ingait.Femoralneckretroversion(iftheangleisposteriortothefemoral

intercondylar plane) allows greater external rotation of the hip, usually

resultinginatoe-outgait.

• Normallyinfantshavemoreanteversionthanolderchildrenoradults(30–40°

atage2yearscomparedwith8–15°atage>18years).

Neuroanatomy

• The femoral nerve is formed from L2–L4 nerve roots and supplies mainly

musclesofthequadricepsgroupandsomedeeperhipadductors.

• WithcontributionsfromL4–S3roots,nervesfromtheplexusconvergeatthe

inferiorborderofthepiriformistoformthesciaticnerve.Thisisataforamen

formed by the ilium (above and lateral), sacrum (medial), sacrospinous

ligament(below),andsacrotuberousligament(posteromedial).

• Inabout10%ofpeoplethesciaticnervedividesbeforeexitingthepelvis.In

some a branch exits above the piriformis muscle. Nerve entrapment and

traumaatthissitemaygiverisetopiriformissyndrome,andmaybenefitfrom

physicaltherapy.

Takingahistory

Age

Ageisariskfactorforsomeconditions:

• Unless there has been previous hip disease (e.g. osteonecrosis, synovitis),

trauma, or a long-standing biomechanical abnormality (e.g. epiphyseal

dysplasia)hiposteoarthritis(OA)isuncommoninadults<55yearsold.

• Paget’s disease of bone is rare in adults <50 years old except in familial

disease.

Distributionandtypeofboneandsofttissuepain

• Allmechanicallesionsofthelumbarspinecanresultinreferredpainaround

the pelvis and thighs. It is often bilateral, localizes poorly, and is aching in

nature.

• Lateral pelvic pain is often referred from the lumbosacral spine. If pain

localizes (i.e. the patient points) to the greater trochanter, it may be due to

trochanteric bursitis, enthesitis, or meralgia paraesthetica (lateral femoral

cutaneousnervesyndrome,seeTable3.18).

• Hip joint pain is felt in the groin, but it can be located deep in the buttock

whenischialbursitisandsacroiliacpainshouldalsobeconsidered.Itmaybe

referreddistallytotheanteromedialthighandknee.

• Groin pain on weight-bearing suggests hip pathology such as synovitis,

osteonecrosisorOA,butitisnotspecific.Tendonitisoftheadductorlongus,

osteitispubis,afemoralneckstressfracture,osteoidosteoma,orpsoasbursitis

cangivesimilarsymptoms.

• Bonepathologytypicallygivesunremittingpain.Sleepisoftendisturbed.

• PainfromdeepMSKpelvicstructuresistypicallypoorlylocalized,although

can be severe. If the pain appears to be ‘catastrophic’ consider pelvic bone

disease (tumours, infection, Paget’s disease, osteomalacia, osteoporotic

fracture)(see Chapter16)oranunstablepelvis(chronicosteitispubiswith

diastasis/laxityofthesymphysispubisandsacroiliacjoints).

• EnthesitisoftheanteriorpelvisandosteitispubisassociatedwithSpAs(see

Chapter8)areprobablyunder-recognized.

• Achinginthebackofthelegsafterstandingisfoundwithspondylolisthesis

(i.e.anteriordisplacementofavertebra).

• Sacroiliacpainandstiffnessradiatestothebuttocksandposteriorthighs.

Table3.18Patternsofpainaroundtheproximallegandtheirmajorcausesinadults

Patternof

pain

Causes

Painin

buttockand

posterior

thighs

Referredpainfrom:lumbarspine,e.g.facet,OA,

spondylolisthesis;SIjointinflammation;lowerlumbarnerve

rootirritation;sciaticnerveentrapment(piriformissyndrome)

Localizedpain:ischialbursitis/enthesitisorfracture;

coccidynia

Diffusemuscularpain/stiffness:myositisorPMR

Paget’sorotherbonelesionofsacrum

Lateral

pelvicpain

Referredfromlumbosacralspine

Trochantericbursitis/enthesitis

Gluteusmediustear

Lateralhipjointpain,e.g.osteophyte

Groinpain Hipdisease,e.g.OA,osteonecrosis,synovitis,

femoroacetabularimpingement

Psoasbursitis

Adductortendonitis,osteitispubis,pubisfracture

Pelvicenthesitis

Paget’sdisease(pelvisorfemur)

Femoralneckorpubicramusfracture

Hernia

thigh

Referredfrom:lumbarspine,e.g.facetOA,spondylolisthesis;

upperlumbarnerveroot;hipjoint,femoralneck

Myositis,PMR

Meralgiaparaesthetica(anterolateral)

Adductortendonitis,osteitispubis

Ischaemia(claudication)

Lymphnodes

Paininamusculardistribution

• DiffusepaininthebuttocksandthighsoccursinPMR.Itisoftensuddenor

subacuteinonset,associatedwithstiffness,andmaygivesimilarsymptomsto

thosecausedbysacroiliitisbutinvariablyoccursforthefirsttimeinamuch

olderagegroup.

• Pain is not invariably present for all types of autoimmune myositis (see

Chapter 14). When it does occur, it is unlikely to be confined to pelvic

musculature or to be unilateral, but should be considered where acute or

subacuteonsetdiffusepelvicgirdle/thighpainaccompaniesweakness.

• Multipleentheseallesions—particularlyofstructuresatthegreatertrochanter

—canpresentwithquitediffusepain—interpretedbypatientsas‘muscular’.

Qualityanddistributionofnervepain

• Nerverootpainisoftenclearlydefinedandsharp.Itmaybeburninginquality

and is often accompanied by numbness or paraesthesias. L5 or S1 lesions

generallycausepainbelowtheknee,butcanalsocauseposteriorthighpain.

L1–L3rootlesionscancausepainintheanteromedialthigh.

• Pain with paraesthesia on the anterolateral part of the thigh may be due to

entrapmentofthelateralcutaneousnerveofthethighunderthelateralpartof

theinguinalligament(i.e.meralgiaparaesthetica).Symptomsmaybereferred

to this area with L2 or L3 nerve root lesions, since this is where the nerve

originates.

• Diabetics with uncontrolled hyperglycaemia are at risk of diabetic

amyotrophy. Acute unilateral or bilateral thigh pain with muscle wasting

occurs.ItshouldnotbemisdiagnosedasPMR(inwhichweaknessorwasting

donotoccur)orinflammatorymyopathy.

• Footballersareatriskofadductortendonitis(often anadductor apophysitis)

and osteitis pubis owing to substantial mechanical forces placed on pelvic

structuresduringrunningandkicking.

• Althoughhipfracturesareusuallyobvious,theycanalsopresentsubacutelyin

a patient who continues to walk; this is particularly common among the

elderly,whomaydevelopstressfracturesofthehip.

Previoustrauma,lowback,andMSKproblems

• Previoustraumaordiseasecausingpermanentdeformityofanylumbosacral

orhipjointstructurecanbeconsideredariskfactorforasymmetry,poorcore

stabilityandMSKpains(Table3.19).

• Multiparity is a risk factor for osteitis pubis, sacroiliac, and pelvic pain,

particularlywherethereishypermobility.

• Trochanteric pain syndrome owing to enthesitis, bursitis or insertional

tendonitis/tendontearmaycoexistwithreferredbackpain.

• Enthesitis of the gluteus medius can occur at its greater trochanterinsertion

andgivesimilarsymptomstothosecausedbybursitis.

• Historically, tailors were at risk of ischial bursitis because of sitting on the

floorcontinuallycrossinganduncrossingtheirlegs,causingfrictionirritation

ofsofttissuesoverlyingtheischialtuberosity.

Fig.3.12Theapproximateareaswithinwhichsensorychangesmaybefoundinlesionsofthelateral

cutaneousnerveofthethigh(hatchedarea)andhighlumbarradiculopathy(brokenline).Shadedarea—

sensorysymptomsdistributionfrommeralgiaparaesthetica.

Table3.19Riskfactorsforpainfulpelvicorhiplesions

Riskfactor Pelvic/hippathology

Lowbacklesions(e.g.lumbarfacetdiseaseor

intervertebraldegenerativediscdisease)

Referrednon-dermatomal

pain

Sciaticpain

Hipjointstructurallesion(e.g.Perthes’disease,

slippedepiphysis,epiphysealdysplasia)

Hipdysplasia,avascular

necrosisorOA

Glucocorticoiduse Osteoporoticfracture

Osteonecrosisofthe

femoralhead(see Plate

17)

Autoimmuneandautoinflammatoryrheumatic

jointdisease(e.g.RA,JIA,axSpA,AS)

Synovitiship

SecondaryOAofthehip

Pyogenicarthritisofthe

hip

Periarticularenthesitis

CKD3b–5 CPPD/pseudogoutofthe

hipjoint

Multiplepregnancies Osteitispubis(±pelvic

instability)

Sports Adductor

tendonitis/apophysitis

Osteitispubis

Examinationofadultswithhipandpelvicpain

Thereaderisreferredtothesequenceofexaminationforthelowback,including

thesacroiliacandlowerlimbneurologicexaminationelsewhereinthischapter

(see  ‘Examination of an adult with low back pain’, pp. 144–147). Always

consider lower spinal, muscle, or neurological pathology when assessing

weaknessandpainaroundthepelvis.

Observationandpalpation

Forobservationandpalpation,thepatientshouldbesupineonacouch:

• Look for leg length discrepancy (hip disease, scoliosis) and a leg resting in

externalrotation(hipfracture).

• Psoriasismaybeassociatedwithpelvicenthesitis/sacroiliitis.

• Swellinginthegroinmaybeahernia(reducible,moveswithcough),lipoma

(soft/non-tender/diffuse), a saphenous varix, or lymphadenopathy

(hard/rubberyandinvariablymobile).Ahipjointeffusioncannotbefelt.

• Tendernessoverthehipjointinthegroinisnotspecificforjointpathology:

thejointisdeep—musclesandpsoasbursaoverlieit.

• Ifthegroinisverytenderwithslighttouch,considerhipfractureorinfection.

Hyperpathia(andallodynia)isconsistentwithCRPS(see Chapter22).

• Numbness over the anterolateral thigh suggests meralgia paraesthetica (Fig.

3.12).

• The adductor longus tendon can be palpated at its insertion at the pubic

tubercleanddistallyalongtheuppermedialthigh.Thepubictubercleisfound

bypalpating slowlyand lightlydownwards fromumbilicusoverthebladder

untilboneisreached.

• Pain from osteitis pubis or adductor apophysitis is often significant, with

abdominal rectus contraction (ask the patient to slowly lift their head and

shouldersoffthecouchkeepingyourfingeronthepubictubercle).

Hipexamination

The patient is supine. Tests generally help to discriminate articular and extra-

articulardisease,butnotthecausesofarticulardisease:

• Measure and determine actual or apparent leg length discrepancy: measure

fromtheanteriorsuperioriliacspinetothemedialtibialmalleolus;byflexing

hipsandknees,thesiteofshorteningshouldbecomeapparent.

• A fixedloss of extensionisa signofintra-articular hipdisease.The patient

flexesthehipandkneeononesideuntilnormallumbarlordosisflattensout

(confirmedbyfeelingpressureonyourhandplacedundertheirlumbarspine

duringthemanoeuvre).Iftheotherhipflexessimultaneously,itsuggestship

extensionlossonthatside(Thomas’test).

• Usingthepatellaortibialtubercleaspointers,testtherotationalhiprangein

extensionbyrotatingthestraightenedlegsbyholdingtheheels.

• Rotationalmovementsarealsotestedbyliftingtheleg,flexed90°attheknee,

and swinging the foot out (internal rotation) or in (external rotation). Hip

flexioncanbe tested inthis position too(see Plate15a). Patients without

intra-articularpathologyshouldhaveapain-freerangeofmovement.

• Rotational ranges in hip flexion and extension may differ between left and

rightinanindividual.Also,variationsinfemoralneckanteversioncontribute

tovariationsinrotationrange.

• Totesthipabduction/adduction,fixthepelvistoavoidpelvictiltbyplacing

onehandfirmlyovertheiliaccrest(see Plate15b).Occasionally,painatthe

end of abduction or internal rotation occurs with a bony block (solid ‘end-

feel’).Inanolderpatientthismightsuggestimpingementofamarginaljoint

osteophyte.

• Barlow’s manoeuvre checks for congenitaldislocationof the hips in babies.

Flexandadductthehipsexertinganaxialforceintotheposterior‘acetabulum’

todemonstrateposteriordislocation.

• Greaterretroversion(allowingexcessivehipexternalrotation)usuallyoccurs

in cases of slippedfemoralepiphysis.External rotation is accentuated when

the hip is flexed. The slip (usually inferoposterior) is thought to occur in

associationwithaperiodofrapidgrowth.

Muscleactivationtests

Specific muscle activation against resistance can be used to elicit pain, but

resultsneedtobeinterpretedcautiouslyinthecontextofknownhipdisease:

• Hip adductionagainstresistance(slidingtheir leginwards towardsthe other

against your hand) reproducing pain is a sensitive test for adductor longus

tendonitis, but may be positive in osteitis pubis, hip joint lesions, and other

softtissuelesionsintheadductormuscles.

• Testpsoasbyresistedhipflexioninslightinternalrotation.Psoasbursitisor

infection tracking along the psoas sheath is likely to give intense pain with

minimalresistance.

• Hipabduction(slidingthelegoutwardsagainstyourhand)maybeparticularly

painful in cases of gluteus medius tears, but also in trochanteric bursitis or

intra-articularpathology.

Palpateposterolateralstructures

Askthepatienttolieontheirsideandpalpatetheposterolateralstructures(Fig.

3.13):

• Tenderness over the greater trochanter is usually well-localized, although it

maybeanteriororposterolateraltothetrochanterandrefersasmallwaydown

theleg.

• Theischialtuberosityanditsoverlyingbursalieattheapexofthebuttock.

• Thesofttissuesoverlyingthepointwherethesciaticnerveexitsthepelvisis

foundmidwaybetweentheischialspineandthegreatertrochanter.Theremay

betendernessasaresultofsofttissuelesionsortraumacausingsciaticnerve

entrapment(piriformissyndrome),whichcanleadtofootdrop.

• Atendercoccyx(coccidynia)canbepalpatedinthisposition.Itcanalsobe

palpated(andthesacrococcygealjointmoved)fromabi-digitalexamination,

thoughthisrequirestheindexfingertobeplacedinsidetherectum,thethumb

outside,thetwodigitsthenholdingthejoint.

Fig.3.13Bonyanatomyoftheposteriorhipandpelvis,showingthepositioninwhichlesionsaroundthe

greatertrochanterandischialbursacanbepalpated.

Investigationofanadultwithhipandpelvispain

Radiographs

AnAPradiographofthepelvisisagoodinitialscreeningtestinpatientswith

pelvic,hip,orthighpain.APandlaterallumbarspinefilmsmaybewarranted:

• The pelvis is a common site of involvement in myeloma, metastatic

malignancy,andPaget’sdiseaseofbone(see Chapter16).

• Established, but often not early, sacroiliitis can be ruled out. The main

differentialdiagnosesofthecausesofsacroiliitisareAS,psoriaticorreactive

arthritis, enteric arthropathy, brucellosis and other infections,

hyperparathyroidismandosteitiscondensansilii (sclerosisofthe SIjoint on

theloweriliacside.)

• Wideningofthesymphysisinchildrenmaybeasignofcongenitaldisorders

of development (e.g. epispadias, achondrogenesis, chondrodysplasias,

hypophosphatasia),traumaandhyperparathyroidism(see Chapter16).

• Wideningofthesymphysispubis,osteitispubis(boneresorptionandsclerosis)

and osteitis condensans ilii are signs associated with chronic pelvic pain in

multiparouswomen.

• General osteopenia is a risk factor for general low bone mass measured by

densitometry; however, it is not a sensitive or specific indicator of

osteoporosis(i.e.maybeosteomalaciaorrickets).

• Regional osteoporosis confined to the femur is non-specific: hip synovitis,

infection,ortransientosteoporosisofthehiparepossible.

• Earlysynovitisandinfectionmaybedemonstratedthroughsubtleradiological

signssuchasjointspacewideningandchangeinsofttissuefatplanes.

• A‘frogleg’(lateral)viewofthehipshowstheanteriorandposteriorfemoral

head more clearly than an AP view (useful in early osteonecrosis/Perthes’

disease,slippedepiphysis).

• Theacetabulaearebestvisualizedon45°obliqueviews(acetabularfractures

canbemissedonaconventionalAPview).

• ‘Stork’ views of the symphysis pubis (standing on one leg) are useful for

confirmingdiastasisofthejoint.

Diagnosticultrasound

USisasensitiveandsimplewayofconfirmingahipjointeffusion.UsingUS,

fluid can be aspirated for culture and an assessment of the extent of synovial

thickeningcanbemade.

• TendondamageinthegroinareashouldbeidentifiablewithUSalone(guided

steroidinjectioncanthenbedoneifnecessary)butMRImaybeneededeither

tocharacterizepathologyfurtherorruleoutjointpathology.

Bonescintigraphy

Characteristic, though non-specific, patterns of bone scan abnormality are

recognizedinthehip/pelvicarea.

• The following conditions can be recognized: sacroiliitis, bone malignancy,

myeloma, Paget’s disease, hip fracture, femoral head osteonecrosis (see

Plate17),osteoidosteoma,OA,bursitis/enthesitisatthegreatertrochanterand

synovitisofthehip.

• Visualizing osteitis pubis/adductor apophysitis requires special seated ‘ring’

view.

CTandMRI

• MRIofthehighlumbarregionshouldbeconsideredtoconfirmanerveroot

lesioncausinggroinorthighpain.

• SpecificpatternsofX-rayattenuationorsignalchangearoundtheSIJsoccur

insacroiliitiswithCT/MRI,althoughactiveandpreviousinflammationcannot

easilybedistinguishedunlessbothmodalitiesofimagingarearranged.

• A suspicion of bony malignancy from radiographs of the pelvis requires

furthercharacterization.CTisthetechniqueofchoiceforcharacterizingbone

lesionsaroundthehip,suchasfemoralneckstressfracture,osteoidosteoma,

orotherbonetumours.CTmaygivemoreinformationaboutthelesion(andis

valuablefor‘guidedbiopsy’),butMRIisusefulincheckingforpelvicvisceral

lesions.

• MRIisthetechniqueofchoiceifhipinfectionorosteonecrosisissuspected.In

adults,patternsofsignalchangehavebeencorrelatedwithprognosis.

• During a single examination, the pattern of hip synovitis (vascularity and

thickness),cartilageloss,andsubchondralboneerosioncanbedocumented.

Laboratoryinvestigations

• ESRandCRPmaybenormalininflammatorySIJs,lumbarvertebraldisc,and

pelvicenthesisdisorders.

• PMRisinvariablyassociatedwithanacute-phaseresponse.

• MyelomaisunlikelyiftheESRisnormal.

• A high alkaline phosphatase is typically associated with an acute-phase

response,althoughintheelderly,itmightsuggestPaget’sdisease.

• ANAandRFareunlikelytohelpdiagnostically.

• Majormetabolicbonedisease,suchasosteomalaciaandhyperparathyroidism

isusuallyexcludedbyanormalserumcalciumandphosphate.

Treatmentofpelvicconditionsinadults

Treatmentofspinalandneuropathicpainiscoveredintheearliersectionon

‘Lowbackpaininadults’,pp.140–152andin Chapter21.

• NSAIDs may be required for a number of the conditions described earlier,

particularlyOA,hipsynovitis,andtendoninflammation.

• Physicaltherapyandrehabilitationplayavitalandearlypartinmanagement,

maintaining mobility, preventing tissue contracture, and re-

strengthening/stabilizingthelowerback,pelvis,andhip.

• Eitherphysicaltherapistsorpodiatristsmayhelpinaccuratelyevaluatingback

and lower limb biomechanics. Asymmetry and muscular imbalance may be

modifiablerelativelysimplywithfootorthotics,forexample.

• Steroidinjectionsmaybeimportantinthefollowingconditions:

• meralgiaparaesthetica.

• osteitispubis.

• trochantericbursitis/enthesitis.

• ischialbursitis/enthesitis.

• adductortendonitis.

• coccidynia.

• hipsynovitis(underimagingguidance).

• sacroiliitis—inintractablepainandunderX-rayorUSguidance.

• Injectiontechniquesarecoveredin Chapter24.

Surgery

• When the hip has been damaged by an inflammatory arthritis or OA the

principal surgical intervention is joint replacement. Osteotomy has been

mainlysupersededbymorereliablereplacement.

• Surgicalsynovectomyofthehipisadifficultprocedureandopeningthehip

carriesariskofavascularnecrosis.Thisprocedureisveryrarelydone.

• Excision arthroplasty is only really necessary where infection or poor bone

stockmakereconstructionunwise.Powerisoftengreatlyreducedandeventhe

previouslyfityoungpatientwillnotbeabletoambulatewithoutcrutches.

Pelvic,groin,andthighpaininchildrenand

adolescents

Generalconsiderations

Hipandpelvicproblemsinyoungchildrenusuallypresentwithalimpnoticed

bya parent.In anolderchildoradolescentpainmay bereported initially—in

groin,aroundbuttocksorgreatertrochanterareas.

• Thecommonestcausesof pelvic,hipandupperthighconditionsin children

are either due to developmental disorders, inflammatory lesions or

trauma/overuse(seeTable3.20).

• If stress fracture of the femoral neck is suspected in a teenage girl then

consider:amenorrhea,eatingdisorderandathleticover-training(‘femaletriad

syndrome’).

Table3.20Commoncausesofhipjointandpelvisareapainsinchildrenandadolescents

Typeofcondition Diagnosis Incidence(per10,000)

Developmental Perthes’disease 0.6

Slippedupperfemoral

epiphysis(SUFE)

0.1–1

Inflammatoryor

infection

Septicjoint,osteomyelitis

orpyomyositis

1(notknownfor

pyomyositis)

JIA 0.3

Irritablehip(transient

tenosynovitis)

Idiopathicchondrolysisof <0.1

thehip

Biomechanicaland

overuseinjury

Snappinghip ≈1

Tendinopathy/muscle

strain

Common

Enthesitis(apophysitis) Uncommon(numberdue

toSpAunknown)

Stressfracture(“female

triadsyndrome”)

Uncommon

Tumours Osteoidosteoma 0.1

Ewingsarcoma(femur) <0.1

Leukaemia/neuroblastoma <0.1

Other Intra-abdominalpathology

Examination

Examinationbeginswithgaitevaluation.Accountforthedevelopmentalstage.

Examinesquatting,single-leghopping,lunging,zig-zagrunningandabdominal

curls/sit-ups(todiscloseanysymphysealpain).

• Hip rangeof movementinchildrenissimilartoadults exceptthe degreeof

femoralanteversionisgreaterintoddlers(30–40°at2years)reducingto8–

15°by18yearsofage.

• Reduced range of movement and irritability at end of range is typical of

intraarticularpathology.Jointpainradiatesintothegroin.

• Palpate for tenderness over ASISs, iliac crests, iliac tubercles, greater

trochanters,SIJregionandpubictubercleswiththepatientstandingandlying

onthesidewithhipflexed(whenincludeposteriorsuperioriliacspinestoo).

• Includejointsaboveandbelow(lumbarspine,SIJ,knee)andtrytoreproduce

thehippainthroughpalpationandmanipulation.

• Also,examinegroinnodesandmassesandabdomen.

Leglengthdiscrepancy

Slightdifferencesarenormalandnotassociatedwithhiporkneerestriction.

• Broadly,leglengthdiscrepancycanbeascertainedbyassessmentofpelvictilt

andkneecreasesymmetrywhenstanding.

• Evaluationisthendonewiththepatientlyingpronemeasuringfromanterior

superior iliac spine to the medial malleolus and umbilicus to the medial

malleolus.Thelattermayneedtoaccountforpelvictilt,musclecontractureor

spasm.

• Unless leg length discrepancy is idiopathic, the shorter leg is usually the

abnormaloneandusuallyduetoeithershorteningofsofttissues,growthplate

trauma, Perthes disease, SUFE, tumours, or infection and secondary

degenerativechanges.

• Radiographicevaluationassesses skeletal,jointandepiphysealcausesofleg

lengthdiscrepancy.

Specificexaminationtests

Some tests in children and adolescents are similar to those in adults though

should beconsidereda guide to further tests/investigationsas none are highly

specificforpathology(Table3.21).

Table3.21Specialtests:pelvis/hipsinchildrenandadolescents

Test Manoeuvre Interpretation

Trendelenburg

(patient

standing)

Standingononelegortheother. Thenon-weight-

bearingsideofthe

pelvisdropswith

adjacenthipabductor

orpelvicstabilizer

deficiency(duetopain

inhibitionortrue

weakness)

Thomastest

(patient

supine)

Liftandflexonelegatthehip Aspelvistiltsthe

contralateralhipflexes:

fromatightpsoas,loss

ofhipjointextensionor

hipjointflexion

contracture

Obertest

(patient lying

onside)

Withtheaffectedleguppermost,

thelegisabductedandkneeflexed

to90°.Holdingthehipjointin

neutralwithslightextensionand

externalrotation,thelegis

released

Failureofthekneeto

adduct(fall)isa

positivetestindicating

contractionortightness

oftheiliotibialband

Faber/Patrick

test

(patientsupine)

Atthehipbringonelegpassively

intoflexion,abductionandexternal

rotationwiththefootrestingon

oppositeknee.Pressdowngently

butfirmlyontheflexedkneeand

thecontralateralanteriorsuperior

iliaccrest

Groinpainontheflexed

hipsidemayindicate

intraarticularhip

pathologybutalso

contralateralbuttock

painmayindicateanSI

lesiononthatside.

Kneepaininadults

Anatomyoftheknee

• Thekneeextends,flexes,androtates.

• The main extensor quadriceps consists of four muscle segments—rectus

femoris,vastuslateralis,medialis,andintermedius,whichconvergetoforma

tendon containing the patella that then inserts into the tibia. Rectus femoris

arisesfromthepelvisandvastusmusclesfromtheupperfemur.

• Thehamstringmuscles(bicepsfemoris,semitendinosus,semi-membranosus)

all arise from the ischial tuberosity and flex the knee. The biceps femoris

insertsaroundthefibularhead.Theothertwomusclesinsertintothetibiaon

themedialsideandcanexternallyrotatethefemur.

• Intheknee,thefemoralcondylesarticulatewithinsemicircularfibrocartilage

meniscionthetibialcondyles(Fig.3.14).Onlytheperipheral10–30%ofthe

menisciisvascularandinnervatedandcanpotentiallyrepairitself.

• Asthekneeapproachesfullextension,thefemurinternallyrotatesonthetibia

(bicepsfemorisaction)tighteningeachpairofligamentsrelativetoeachother.

Thisconfigurationconfersmaximumstability.

• Asflexionisinitiated,asmallamountoffemoralexternalrotationonthetibia

occurs.This‘unlocking’isdonebythepopliteus—amusclethatarisesfrom

theposteriorsurfaceofthetibiabelow.Itpassesupobliquelyacrosstheback

ofthekneeandinserts,viaacord-liketendon,intothelateralfemoralcondyle.

Thetendonpartlylieswithinthekneejointcapsule.

• Groovesonthefemoralcondylearticularsurfacesallowtightcongruitywith

theanteriorhornsofthemenisciwhenthekneeisextended.Iffullextension—

and this optimal articulation configuration—is lost, then articular cartilage

degenerationinvariablyfollows.Thisisparticularlyimportantininflammatory

arthritis.

• Thecruciateligamentsaretheprincipaljointstabilizers.Theanteriorcruciate

attachesabovetothe inside ofthelateral femoral condyle andbelowto the

tibiainfrontofthetibialspinesthoughaslipattachestotheanteriorhornof

thelateralmeniscus.Itsmainroleistocontrolandcontaintheamountofknee

rotationwhenthejointisflexed.

• The posterior cruciate attaches above to the inside of the medial femoral

condyle. At the other end, it attaches in a (posterior) groove between tibial

condyles. Its main role is to stabilize the joint by preventing forward

displacementofthefemurrelativetothetibiawhenthekneeisflexed.

• The cruciates are extra-articular and are covered by a layer of vascular

synovium.Bleedingusuallyaccompaniesdisruption.

• Thetibialormedialcollateralligament(MCL)hassuperficialanddeeplayers

(Fig.3.15).Itstabilizesthekneeagainstvalgusstresses,mostlyduringflexion.

• The superficial MCL overlies, and moves relative to, the deep part and is

separatedfromitbyabursa.ThelowerpartofthesuperficialMCLiscovered

bythelongadductors,gracilis,semitendinosus,andsartoriusmuscles,asthey

mergeintothepesanserinusbeforeinsertingintothetibia.

• TheMCLandpesanserinusareseparatedbytheanserinebursa.DeeperMCL

fibresattachto,andstabilize,themedialmeniscus.

Fig.3.14Axialsectionoftherightkneejoint(lookingdownonthetibialplateau,wherethefootisfixedon

thefloor).Thefemoralcondylesarticulatewithinthemenisci.Asthekneeextendsthecruciateligaments

tightenandpullthefemoralcondylesactingtointernallyrotatethefemurthroughthelastfewdegreesof

extension.Thekneetherefore‘locks’andisstablewhenthelegisstraight.

Fig.3.15Anteriorkneestructures.

• The fibular or lateral collateral ligament (LCL) joins the lateral femoral

condyletothefibularheadandisseparatedfromitbyabursa.Itstabilizesthe

kneeonitslateralside.Ithasnomeniscalattachment.Asmallbursaseparates

itfromtheoverlappingtendoninsertionofbicepsfemoris.

• Thepatellaisa seamedbonethatarticulatesinthe femoralcondylargroove

and makes quadriceps action more efficient. Patella articular facet

configuration can vary; congenital bi/tripartite patellae are associated with

anteriorkneepain.

• The strongest force on the patella is from vastus lateralis (Fig. 3.16).

Mechanical factors that increase the ratio of lateral to medial forces during

patellatrackingsuchasawidepelvis,amorelateraloriginofvastuslateralis,

femoralneckanteversion,externaltibialtorsion,andaweakvastusmedialis

areriskfactorsforpatellatrackingproblemsandanteriorkneepain.

• Therearebursaebetweenthequadricepstendonandthefemur(suprapatellar),

the patellartendon and tibial tubercle(deep infrapatellar), andoverlyingthe

patella (prepatellar) and patellar tendon insertion (superficial infrapatellar).

The suprapatellar bursa communicates with the knee joint and large joint

effusionsinvariablyfillit.

• Posteriorly, bursaeseparateeach ofthe headsofgastrocnemius (whicharise

fromfemoralcondyles)fromthejointcapsule.Thebursaecommunicatewith

thekneejointandcanfillfromjointeffusions.

Fig.3.16(a)Theiliotibialband.(b)ThepatellaQangle(normalvalues—men10°,women15°).

Takingahistoryofkneepain:adults

Askaboutthesiteofpain

Try to establish whether pain is from articular, soft tissue, or anterior knee

structures.Isitreferredpain?

• Bursa,tendon,andmostligamentlesionscausewell-localizedpain.

• Localizedtibiofemoraljointlinepainsuggestsmeniscalpathology.

• Localized medial knee pain has a number of possible causes: MCL tear or

chronic inflammation (calcification of MCL origin termed the Pellegrini–

Stiedaphenomenon),medialmeniscustear,meniscalcyst,anserinetendonitis,

bursitis,orenthesitis(semimembranosusinsertion).

• Enthesitis of structures at their insertion to the patella margins can result in

considerablepain.

• Overuseinrunnersandcyclistscancauselocalizedinflammationandpainof

the iliotibial band (ITB) or its underlying bursa over the lateral femoral

condyle(asthebandmovesacrosstheboneasthekneeflexes).

• Anterior pain in adults invariably suggests an underlying mechanical

abnormality. In older adults, the most common cause is patellofemoral OA

(Table3.22).

• AnteriorkneepainmaybereferredfromthehiporL3nerveroot.Hippainis

anachingpain;nerverootpainissharpoftenwithparaesthesia.

• Posterior kneepainassociated with‘alump’isoften due tosynovitis in the

posteriorkneecompartmentwithpoplitealcystformation(Baker’scyst).

Table3.22Causesofanteriorkneepaininadults

Common(non-

inflammatory)

PatellofemoralOA(lookformechanicalfactorsand

generalizedOA)

Referredhippain,e.g.hipOA

Referredpainfromlumbarspine,lateralpelvis,ITB,

orgreatertrochanterlesions

Tear/cystofanteriormeniscalhorn

Patellarligamentfat-padsyndrome

Common

(inflammatory)

Patellaligamententhesitis(enteropathicSpA,PsA,or

axSpA)

Crystal-inducedMSKinflammation

Synovitisofanteriorjointcompartment(e.g.RA,

PsA)

Uncommon(non-

inflammatory)

Osteochondritisatpatellarlowerpole—overuseinjury

injumpingsports

Patellarfracture

Enthesopathyatpatellarmargins(maybepartof

DISH)

Uncommon

(inflammatory)

Bursitis(prepatellar,superficial/deepinfrapatellar)

Sepsisofjointoranteriorjointstructures

Sinding–Larsen–Johanssondisease.

Askaboutinjury

Kneeinjuriesarecommon;themostsignificantisanteriorcruciateinjury.Ask

aboutinjuryandifthekneefeelsunstableor‘givesway’:

• Anteriorcruciateinjuriesareinvariablyassociatedwithahaemarthrosis,thusa

painful effusion will have occurred immediately. Meniscus tears can cause

immediatepain,butsynovitisandswellingaredelayedforabout6hours.

• Patients mayvolunteerthat the knee‘keepsgiving out onme’.This feeling

may be the pivot shift phenomenon caused by reduced anterior cruciate

stabilityagainstavalgusstressasthekneeisflexing.

• AnteriorcruciateandMCLinjuriesoftencoexist(sincetheyareattached).Ask

aboutmedialkneepainoriginallyandsubsequently.

Askaboutkneelocking

Knee locking is a mechanical effect of disruption of normal articulation by

‘loosebodies’:

• Suspectmeniscusdamageinthemiddleagedorifthepatientplayssports.A

meniscustearisthemostcommoncauseofthekneelocking.Inadolescents,

locking may be due to a tear in a discoid meniscus (>98% lateral).

Morphologicallyabnormaldiscsarepronetodegeneration.

• Synovialchondromatosisisararecause.

• Somepatientswithanteriorkneepaindescribethekneelockingorgivingway.

Thisisduetoreflexquadricepsinhibitionratherthantrueinstability.

Askabouttheinitialonsetofpain

• Acutepainisusualwithinjuriesofcruciatesandverticalmeniscaltears.

• Acuteonsetpainwithouttrauma(butalwayswithswelling)suggestsinfection,

crystalarthritis,orspontaneoushaemarthrosis.

• Intheveryelderly,traumaticlesionsmaybemissed,sincethepresentationis

notalwaysstriking,e.g.intra-articularfracturewithhaemarthrosis.

• An insidious onset of pain is usual in cleavage tears of menisci (horizontal

tears), which occur typically in adults where the disc is degenerate, in

adolescentswithdiscoidmenisci,andinearlyosteochondritisdissecans.

Askaboutthepatternandtypeofpain

• Painfromsynovitisisoftenassociatedwithstiffnessandisoftenworseaftera

periodofimmobility.Almostwithoutexceptionkneesynovitiscanoccurinall

formsofarthritis.

• Painfromsubchondraldamage(e.g.OA)isalmostalwaysworseonweight-

bearing,butthisassociationisnotspecific.

• Painonkneeling/squattingischaracteristicofanteriorkneepain.

• Burningpainmaybeneurogenic,e.g.L3nerverootorosteodystrophypainor

iffocalmaybeenthesitic.

Pastmedical,family,occupational,andleisurehistory

• Knee synovitis and patellar enthesitis occur in all forms of SpA. Ask about

previous uveitis, low back pain, urethral discharge, sexually transmitted

disease,IBD-typesymptoms,andpsoriasis.

• Gout(see Chapter7)isnotuncommonaroundtheknee.Askaboutgoutrisk

factorsandwhetherthepatienthaseverhadacutefirstMTPJpain.

• There may be a family history of OA, an hereditary disease of connective

tissue,orhypermobilityinyoungadultswithOA.

• Prepatellar bursitis classically occurred in housemaids, hence the nickname

‘housemaid’sknee’.Frictioncausedbyrepeatedkneelingcancauseit.

• Sportsinjuriesarecommon.Anteriorcruciateinjuryoccurscharacteristically

inskiing.Meniscalinjuriesarecommoninsoccer.Jumpingevents(e.g.high

jump,basketball)canleadtopatellartendonapophysitis.Cyclingisassociated

withanteriorkneepain.MCLandmeniscalinjuriesarecommoninskiingand

weight-bearingactivitieswhererotationandchangeofdirectionarefrequent.

CyclingandrunningareassociatedwithITB/bursapainandinflammation.

Examinationofanadultwithkneepain

Fromfrontandbehind,observethepatientstanding

• Lookformechanicalabnormalitiesthatmightbeassociatedwithkneelesions:

patellaasymmetry,prominenttibialtuberclesfrompreviousOsgood–Schlatter

disease(anteriorkneepain),flat feet,andhypermobility(patelladislocation,

hyperextensionof>10°).

• Checkformechanicalabnormalitieswhichmightsuggestspecificpathology:

genu varum (bowed leg, typical appearance with primarily medial

compartment OA), obvious suprapatellarkneeswelling(synovitis), psoriasis

(associatedsynovitisorenthesitis),andgenuvalgum(knock-kneed).

Examinationofthesittingpatient

Ask the patienttositon the examination table with legs hanging, kneesbent.

Patellar tracking and pain from medial meniscus damage can be assessed. An

alternative approach is with the patient supine. Observe any muscle wasting.

Palpateanterior,medial,andlateralstructures:

• Inpatientswithanteriorkneepain,lookforsymmetricpatellaralignment.

• Observe active knee extension. Patellar movement should be smooth, pain

free,andsymmetric.

• Passivelyexternallyrotateeachlowerlegtoitsextreme.Thisisareasonably

sensitive test for conditions of the medial knee compartment (e.g. meniscus

tear)andmedialkneestructures.Discomfortwillbefelt.IftheMCListotally

deficient,anabnormallyincreasedrangeofexternalrotationmayoccur.

• Quadricepswasting(accentuateddepressioninmusclejustabovethepatella)

occurswithdisuseafterinjuriesandchronicarthritis.

• Sitesofbursae,patellartendon,andligamentinsertionsshouldbepalpatedin

patientswithlocalizedpain(Fig.3.17).

• Tibiofemoral joint line tenderness is likely to be due to either meniscus

pathologyormarginalosteophytes.Osteophytesgivebonyswelling.

• Anterior pain from patellofemoral joint disorders may be elicited by gentle

pressure down on the patella. Mobilizing the patella sideways will give an

impressionoftissuelaxity(possibleunderlyinghypermobility).

• Factors that predispose to patellofemoral pain syndrome include: high or

lateral patella, weak vastus medialis, excessive pronation, weak ankle

dorsiflexors,tighthamstrings,reducedmovementattheankle,andawideQ-

angle.TheQ-angleisformedbetweenalinefrom theanteriorsuperioriliac

spinetothecentreofthepatella,andalineextendedupwardsfromthetibial

tuberclethroughthecentreofthepatella.Thelargertheanglethegreaterthe

lateraltensilepullonthepatella(Fig.3.17).

• Localized tenderness of the femoral condyle is often the only sign of

osteochondritis dissecans in adolescents. The most common site is on the

insideofthemedialfemoralcondyle(75%).

Examineforjointsynovitis(synovialinflammationgivingsynovialthickening

and/ortenderness)andaneffusion

• The joint may be warm. Chronic synovitis doesn’t always result in a warm

joint,butinfection,acutecrystalarthritis,andhaemarthrosisusuallydo.

• Gross synovitis can produce obvious effusions and/or synovial thickening

mosteasilyfeltaroundthepatellaredges.

• Effusionsmaybeconfirmedbythepatellartaptest(see Plate18).

• Small effusions can be detected by eliciting the ‘bulge sign’. Fluid in the

medialcompartmentissweptfirmlyupwardandlaterallyintothesuprapatellar

pouch.Firmpressureonthelateralsideofthejointmaythenpushfluidback

intothemedialcompartment,producingabulge.

• Thickenedsynoviumcanbedetectedbyexperiencedexaminersintheabsence

ofadetectableeffusion.Itisnotalwaystender.

• Posteriorcompartmentsynovialthickeningandpoplitealcystscanbefeltby

wrappingthefingersaroundunderthekneewhenitisslightlyflexed.

• Incontrasttoadults,poplitealcystsinchildrenarenotusuallyassociatedwith

intra-articularpathology.Investigationisnotalwaysnecessary.

Fig.3.17Positionofthekneeforpalpationofmostofitsstructures.Palpatingforenthesitisatthepatellar

tendoninsertion.(a)Palpationovertheinsertionofsemimembranosusandpesanserinusunderthetibial

plateau(b)Thesiteofthemajorityofosteochondritislesionsinthekneeisshownbythe‘X’.

Testthekneeforstability

Therearemanytestsforinstability:instabilitymaybestraightorrotationaland

canbegradedaccordingtoconsensuscriteria(consultorthopaedicstexts).

• TheLachmanntest(Fig.3.18)isarguablythemostsensitivetestforeliciting

anterior cruciate disruption: hold the knee flexed between 20–30°, grasped

aboveandbelowthejoint.Attempttomovethetibiaforwardsandbackwards

onthefemur.Askaboutpainandfeelforlaxityora‘clunk’.

• Theanteriordrawtestisnot assensitive astheLachmanntestfordetecting

partial anterior cruciate tears, but is easier to do. The patient lies flat, hip

flexed,thekneeflexedat90°,withthefootflatonthetable.Fixthefootby

gentlysittingonitandpullthetopofthelowerlegforwardsinthelineofthe

thigh.Askaboutpainandfeelforlaxity.

• Theposteriordrawtestidentifiesposteriorcruciatedisruption:withtheknee

flexedto90°,pressthetopofthelowerlegbackwardsinthelineofthethigh,

askaboutpainandfeelforlaxity.

• Test medial stability at 0° and 30° of flexion (MCL stabilizes maximally at

30°) by holding the upper leg still and applying a valgus force to the tibia.

Laxity associated with widening of the tibiofemoral joint (with or without

pain)isapositivetestandsuggestsMCLdeficiency.

• Lateral(LCLandITB)stabilityissimilarlytested,thoughusingavarusforce

onthelowerleg.

• MCL tears can accompany anterior cruciate injuries and deep lesions are

associated with simultaneous tears of the medial meniscus. Such complex

pathologycanmakespecificexaminationmanoeuversdifficulttointerpret.

Testformeniscusdamage

• McMurraytest(Fig.3.19).Flextheknee,internallyrotatethelowerleg,then

extend the joint. Repeat with the lower leg externally rotated. The fingers

(overthejointline)mayfeela‘clunk’asafemoralcondylepassesoveratorn

meniscus. It isoftenpositive(21–65% of cases)whensurgery subsequently

revealsnotear.

• Askthepatienttoturnover.Whenprone,lookandpalpateforswellinginthe

poplitealfossaandproximalcalfthatmayindicatealowlyingpoplitealcyst.

• Inflammation ofthe bursaunderlying theITB mayresultintendernessover

thelateralfemoralcondyle.TheITBmaybetight.Thisisdemonstratedusing

theObertest.Withthepatientlyingontheirsideandaffectedleguppermost,

the leg is abducted and knee flexed to 90°. Holding the hip joint in neutral

withslightextensionandexternalrotation,thelegisreleased.Failureofthe

knee to adduct/fall is a positive test—leg length inequality and foot over-

pronationmaybecausativefactors.

• Detectingspecificstructuresintheposteriorfossaisoftendifficultbecauseof

the lack of bony landmarks and overlapping soft tissue structures. Synovial

cysts may form under pressure and are often hard and tender. Diffuse

thickeningsuggestsjointsynovitis.

RelevantproximalMSKexamination

As always examine the immediate proximal structures at the end of the

examinationsequence—hereexaminethehipandgait.

• Gaitexamination—considerthelowerlimbasfunctionallyinter-relatedfrom

lowerspinetotoes.

• Hip examination can help determine ante/retroversion at the hip—and the

configurationofsuchcanhaveabearingonlowerlegpronation,in-toeingand

painsatbothkneeandinfeet(seeFig.3.20).

Fig.3.18Dynamictestsofanteriorcruciatefunction.Patientsshouldberelaxedlyingsupineonacouch.

Excessivelaxityisthemostimportantsign.

Fig.3.19Dynamictestdesignedtoelicitsignsofmeniscusdamage.‘Clunks’,intra-articularpain,and

coarsecrepitusmayindicatedamage.Thetestisnotspecificandisopentomisinterpretation.

Fig.3.20Femoralanteversion,retroversion,andtibialtorsion.(a)Wherethefemoralneckangulates

excessivelyforwardrelativetoanimaginaryaxisthroughthefemoralcondyles,thehipisanteverted.(b)

Femoralneckanteversioncanleadtoagreaterthanusualrangeofhipinternalrotationandatoe-ingait.(c)

and(d)Retroversion,wherethefemoralneckangulatesposteriorlyrelativetoafemoralcondyleaxis,can

causeatoe-outgait.(e)In-toeingcanalsobecausedbyexcessivemedialtibialtorsion.Normallytheankle

mortisefaces15°externallyrelativetoasagittalplaneaxisthroughthetibialtubercle(arrow)butinmedial

torsionitfacesforwardorinternally.

Investigationsofadultswithkneepain

Radiographs

AP and lateral weight-bearing radiographs are suitable screening views if the

diagnosisisunclearafterclinicalassessment:

• Early synovitis may only be evident from the presence of an effusion,

periarticular osteopenia, or soft tissue swelling. Patterns of bone damage in

chronicarthropathiesmayberecognized.

• Signsofjointinfection,whichmaynotnecessarilypresentacutely,arepatchy

boneosteolysisandirregularlossofbonecortex.

• Osteonecrosisisuncommoninthekneealthoughitisseeninfemoralcondylar

bone,oftenwithoutsymptoms,insicklecellanaemia.

• Loss of joint space, angulation deformity, osteophytes, subchondral bone

sclerosis,andbonecystsarehallmarkfeaturesofOA.

• Linear or vague intra-articular calcification suggests chondrocalcinosis

(associatedwithcalciumpyrophosphatedihydrate(CPPD)arthritis).

• Gross‘thumbprint’calcificationistypicalofsynovialchondromatosis.

Specializedradiographicviews:tomographicviews;‘skyline’(axialwithknee

bent)view;orlateralviewtakenwithatleast30°offlexion

• Tomographyisusefulforclarifyingnon-peripheralosteochondraldefects.

• Skyline views demonstrate anomalous patellar facet configuration and can

reveal patellofemoral incongruity though multiple views may be needed.

Subchondralpatellarpathologyisseenmoreclearlythanonlateralviews.

• Patellaaltaismostreliablyseenonalateralviewwith30°flexion.

Furtherimaging

Further imaging depends on differential diagnosis and a discussion with your

radiologist:

• PeriarticularsofttissuelesionscanbecharacterizedwithMRI,althoughwith

superficiallesionsadequateinformationneededforfurthermanagementmay

beobtainablewithUSalone.

• Patterns of meniscus damage are recognized on MRI, give an indication of

prognosis,andaidthesurgeon’sdecisiontoproceedtoarthroscopy.

• MRIisessentialifthereislikelytobeacombinationoflesions,e.g.anterior

cruciate,MCL,andmedialmeniscuslesions.

• Inanteriorkneecompartmentsymptomsalone,USisareasonablefirstoption

forimagingbecauseinflammatorylesionscanbeinjectedwithglucocorticoid

ifneededusingimagingguidance.

• MRIismoresensitivethanradiographsorUSatidentifyingjointerosionsin

RA(‘pre-erosions’).

• The place of CT or MRI in investigating radiographically detected bone

tumoursdependsonthenatureofthelesion.

Aspirationofjointandperiarticularfluidcollections

• Earlyaspirationisessentialifinfectionissuspected(see Plate19).

• Thekneeisacommonsiteofmonoarthritisformsofsystemicdiseases(e.g.

PsA,CPPDdisease).

• Sendjointfluidforcellcount,polarizedlightmicroscopy,andculture.

• Inadults,theusualdifferentialdiagnosisofsepsisofkneestructuresisgout,

sofluidshouldbeexaminedbypolarizedlightmicroscopyforuratecrystals.

• Blood-stainedfluideithersuggestsatraumatictaporchondrocalcinosis.Frank

blood suggests haemarthrosis, the major causes of which are cruciate tear,

bleedingdiathesis,intra-articularfracture,andPVNS.

• Bursa fluid may be more successfully detected and aspirated using US

guidance.

Laboratoryinvestigations

Theseshouldbedirectedtowardssuspectedunderlyingdisease:

• FBC,acute-phasemeasures(ESR,CRP).

• Bloodurea,electrolytes,creatinine,andurate.

• Bloodcalcium,phosphate,albumin,alkalinephosphatase,25-OHvitaminD,

andPTHtoscreenformetabolicbonedisease.

• Autoantibodies: rheumatoid factor (RF), ACPA, antinuclear (ANA), and

extractablenuclearantibodies(ENAs)tocharacterizeanautoimmuneprocess

wheresynovitisischronic.

• Serumangiotensinconvertingenzyme(ACE)forsarcoidosis.

• IgM Borrelia burgdorferi serology for acute arthropathy in Lyme disease,

streptococcal antibodies for reactive streptococcal arthritis and parvovirus

serology.

Treatmentofadultswithkneepainconditions

• Ingeneral,mostsofttissuelesionswillsettlewithrestandNSAIDs.

• Anterior knee pain may respond well to isometric exercises, adjustments to

foot alignment, e.g. with sensible shoes, orthotics (support insoles), and

hamstringstretchingexercises.

• The acute swollen knee requires aspiration, rest for 24 hours and gentle

mobilization.

• If infection is considered, broad-spectrum antibiotics against staphylococcal

andstreptococcalagentsshouldbestartedimmediatelywhileawaitingculture

data. In infection, intra-articular antibiotics and steroids should be avoided.

Thepatientshouldnotbearweightonanacutelyinfectedjoint(see Chapter

17).

• Acute and chronic inflammation can leadtojointdestruction and instability

thisisrelevantforRA—earlytreatmentmaypreventlong-termmorbidity.

• Physicaltherapyandsplintingplayanimportantroleinmaintainingfunction

andpreventingcontractures,etc.

Addressbiomechanicalfactors

Input from aphysicaltherapistmay be helpful in cases of anterior kneepain.

SuccessfromMcConnell(patellar)tapingismorelikelyinnon-patellofemoral

OA-relatedanteriorkneepain.

• Quadriceps strengthening exercises can be reviewed and reinforced by

physicaltherapistsincasesofkneeOA.

• Kneepain,particularlyanteriorpain,maybelinkedtofootabnormalities(e.g.

over-pronation),andhipalignment(Q-angle,above).

• Specificmusclestrengtheningexercises,footorthotics,andkneebracesshould

beconsidered.

Localsteroidinjection

Chapter24hasmoredetailonlocalsteroidinjections.

Localsteroidinjectionscanbehelpfulinthefollowingsituations:

• Acuteflareofnon-infectiveinflammatorydisease:

• OA(especiallywhenininflammatoryphase)—mildOAmayalsorespondto

hyaluronaninjections.

• autoimmunearthritis,e.g.RA.

• intra-articulargoutorCPPD/pseudogout.

• SpAormorelikelyPsAeffusion/monoarthritis.

• Bursitis(maybegout):

• pre-andinfrapatella(superficialanddeep)bursa(thelattermayrequireUS

guidance).

• anserine.

• Baker’s cyst (note: the knee joint is injected at the site of the pathology

assumingthereisintra-articularcommunicationbetweenjointandcyst.Direct

poplitealcystinjectionshouldbeunderUSguidanceonlytoavoiddamageto

vascularandnervetissues).

• Enthesitis,e.g.semimembranosusinsertion.

• Trauma,e.g.painoverMCLinsertion.

• Othersofttissue:ITBsyndrome.

• In patients with large joint effusions, merely aspirating the effusion may

provide some level of symptomatic relief—this procedure may need to be

done alone initially without steroid injection pending results from fluid

microscopyandculture.

• Knee OA may respond transiently to an injectable steroid, such as

methylprednisolone. Saline irrigation and injections with hyaluronan

preparationsarealsoused,butresponseisvariable.

• Note: all intra-articular injection therapies are more effectivewhenpatient’s

kneeisimmobilizedfor24hoursfollowingtheprocedure.

Drugs

• NSAIDs will invariably be helpful in cases of inflammatory and septic

arthritis.

• Colchicine 0.5 mg two to three times daily for 5 days is often useful in

relievingpainfromcrystalarthritisinpatientsintolerantofNSAIDs.

• Paracetamol/acetaminophenmaybeaseffectiveasNSAIDsforsomepatients.

• TheeffectofglucosamineandchondroitinforOAisdebated.Althoughsome

studiesdemonstrateimprovedpaincontrolandfunction,otherstudiesindicate

thatthesearenobetterthanplacebo.

Surgery

• Arthroscopy is often used as a diagnostic tool in cases of undiagnosed

monoarthritisandtoconfirmandtrimcartilagetears.Synoviumandsynovial

lesions (e.g. PVNS, synovial chondromatosis) can be biopsied or excised

(synovectomy)andthejointcanbeirrigated.

• Inappropriatecases,jointreplacementcanberemarkablysuccessfulandisan

importantoptiontoconsiderinOAandinflammatoryarthritis,wherepainis

severeandpresentatrest,andwhenmobilityissubstantiallyrestricted.

• Unicondylar osteotomycanaidrealignment of thetibiofemoral joint, e.g.in

metabolicbonedisease,suchasPaget’sdisease.

Other

• InOA,capsaicincreamappliedthreeorfourtimesdailytopainfulsuperficial

structures,e.g.patellarmarginsormarginal tibiofemoraljointpain,canease

symptoms.Responseiscumulativeandmaynotoccurfor6–8weeks.

• Yttrium-90radiationsynovectomyhasalonghistoryofuseforisolatedknee

synovitisoccurringasaresultofanumberofconditions.Y-90injectioncanbe

arrangedtofollowarthroscopicsynovectomyaimingtomaximizetheeffectof

bothprocedures.

• Topicallidocainepatchesmayalsobeusefulforcontrolofpainlimitedtoone

joint.

Kneepainandlowerlimbdevelopmentin

childrenandadolescents

Generalconsiderations

Inyoungerchildren,especially,knee,foot,andankleproblemsneedassessment

in light of developmental stage and with reference to any developmental

abnormalities.

History

• Growingpainsarecommonandoccurtypicallyinchildren<6years.Thereis

a nighttime predominance, hence the term ‘benign nocturnal pain of

childhood’.Kneeisoftenidentifiedasakeysitebutalsothigh,shins,andfeet.

• Osteochondrosesofkneestructuresarecommoninthegrowingskeleton(see

Table16.11).

• Osteochondritis can affect the articular cartilage (e.g. medial/proximal tibia

(Blount’s))oranenthesisoranepiphysealplate.

• The osteochondritis lesion becomes more severe if the cartilage becomes

separatedasafragment(‘dissecans’lesion).

• Cause of osteochondritis at an enthesis is assumed to be traction-trauma in

aetiologythoughthenumberofchildrenwiththeselesions,whomighthave

ERA,PsA,orJSpAisnotknown.

• Anteriorkneepainatallagesisrelativelycommon(theterm‘chondromalacia

patella’isasurgicalfindingwhichmayormaynotbeassociatedwithpain).

• The commonest cause of anterior knee pain in adolescents—termed

patellofemoral syndrome (PFS)—is attributable to abnormal loading of the

patellofemoral joint and patella mal-tracking. There is often underlying

biomechanical imbalance including muscle tightness and vastus medialis

obliqus(VMO)weakness.

• Anterior kneepain can besecondary topatellainstability. Thisis avariable

lesion which ranges from mild dynamic imbalance with lateral patellar

compressiontorecurrentpatelladislocationandchronicdislocation.

• Othercausesofanteriorkneepaininactivechildrenincludespatellaligament

originorinsertionalenthesitis(inERA,JSpAorJPsA),localbursitisorfatpad

syndrome.

• Impingement of the infrapatellar fat pad—which is richly innervated—

between patella and femoral condyle is amplified by mal-tracking of the

patella,kneeextension,prolongedstandingandkneeling.

• Thekneeisacommonpresentingsiteforinflammatorydiseaseparticularlyin

IBD-relatedarthritisandJPsA.

• A swollen knee can be a presenting sign of JIA, PVNS, tuberculous/septic

arthritis,andhaemarthrosis(trauma).

• Painisthemainpresentingfeaturesoftumours,whichcanoccuraroundthe

knee (e.g. osteoid osteoma, chondroblastoma, Ewing sarcoma, leukaemia,

neuroblastoma).

• Mechanical symptoms on movement (catching, knee giving way, painful

clunks, etc.) may occur with patellofemoral instability or with an internal

structurallesion—suchascruciateligamentdeficiencyorsynovialplica.

• Synovial plicae are embryonic remnants, with a septated structure, which

becometenderandinflamedwhentrappedbetweenpatellaandmedialfemoral

condyle. Snapping and catching during flexion differentiate it from other

biomechanicallesions.

• Finallyaskabouthip/groinpainsgivenreferredpainfromthehipjointmaybe

presentandcandenotePerthesdiseaseorSUFE.

Examination

A general overview of relative MSK stiffness, hypermobility, functional

movementability,andmuscletoneishelpfulbeforearegionalexaminationtakes

place.

• Functionalbiomechanicsareassessedbyevaluationofgait,andmanoeuvres

such asjumping,hopping, and squatting. This isfollowedby assessment of

musclegroupstrengthandstretch.

• Assessforthe‘J’signofpatellartracking.Thisismedialshiftofthepatellain

earlyflexion asit entersthe trochlea,suggestive ofVMO weaknessor tight

lateralpatellaretinaculum.

• Fixed loss of extension or loss of full flexion is indicative of intraarticular

pathology.

• Ajointeffusionisshownbysweep(orbulge)sign(seeearlier).

• Othertestsincludepatellarcompression(Clarketest),Lachmantest;anterior

and posterior draw tests; McMurray and Trendelenburg tests—see  ‘Knee

paininadults’,pp.170–183.

Lowerlimbdevelopmentalfactorsandvariations

Developmentalfactors

• Developmentalcharacteristicsoftenimplythatdifferentagegroupsareprone

toadifferentspectrumofconditions.

• Duetoligamentouslaxity,whenbabiesbegintowalk,themidfootisflattothe

floor.Alongitudinalarchusuallydevelopsby5years.

• During growth, tendon insertions (apophyses) are often weaker than the

tendons themselves. Traction strain on tendons can lead to apophysitis

(osteochondritis).Thisisacommonpatternofinjuryinthefootinactiveolder

children.

Femoralanteversion

• Thiscausesinternalfemoraltorsionleadingtoamediallyrotatedpatellaand

in-toeing.

• SeeFig.3.20.

• Femoral anteversion is present at birth in 40% but decreases with age and

disappearsby10yearsofage.

• Mildpersistencewithin-toeingdoesnotusuallyresultinfunctionaldisability.

• Itmaypersistwithpatternsofsittingsuchasthe‘W’position.Sittingcrossed

leggedmayencourageexternalrotationatthehipsinstead.

Internaltibialtorsion

• Thisresultsinin-toeingandisnormalintoddlers,resolvingat2–4years.

• SeeFig.3.20.

• Thigh-foot axis angle of more than about −10° confirms the diagnosis,

althoughtreatmentisonlyconsideredwhengreaterthan−45°.

• Bycontrast,externaltibialtorsionisacommoncauseofanout-toegaitand

mayleadtoPFS.

• Osteotomy may be recommended for a thigh-foot axis angle of more than

+40°.

Genuvarum(bowlegs)

• Bow legs are normal in toddlers and normal beyond 4 years if mild and

symmetrical.

• Bowlegsappearmorepronouncedinanoverweightchildandassociatedin-

toeingmaygiveappearanceofaclumsygait,butdoesnotrequireintervention.

• Asymmetricorexaggeratedbowing andreportsofpainrequiresafull MSK

assessmentincludingmetrology(ofintercondylardistanceandlateralthrustat

theknee)andgaitassessment.

• Radiographs may disclose Blount’s disease (osteochondritis of the medial

aspectoftheproximaltibialphysis).

• Bowingcanoccurinrickets(checkvitaminDlevels).

• A full leg AP radiograph assesses hip, knee, and ankle contribution and

measuresjoint-to-diaphysisanglestoidentifywhichphysisiscontributingto

thedeformity.

• MRI,CT,andDXAarerarelyuseful.

Genuvalgum(knockknees)

• Knock knees is physiological between 2 and 6 years of age and does not

progressafter7years.Interventionwithbracesororthosesisunwarrantedand

meddlesome.

• Adolescentidiopathicgenuvalgummaybeassociatedwithcircumductedgait,

anterior knee pain and patellofemoral instability. Often hereditary, it may

progressintoadulthoodtoprematureOAofthepatellofemoraljointandlateral

compartmentoftheknee.

• Anangleof12°ofvalgusorintermalleolardistanceof>8cmshouldprompt

orthopaedicassessmentforadolescentgenuvalgum.

• Othercausesofgenuvalgumincludelocalpathologyfromtraumaorinfection

(usually unilateral), skeletal dysplasias, neurofibromatosis and vitamin D-

resistantrickets.

• Genuvalgumisbestassessedusingafull-lengthstandingAPradiograph.The

mechanical axis or centre of gravity (drawn from the centre of the femoral

head to the centre of the ankle) should bisect the knee and lie within the

intercondylarcentralareaoftheknee.

Lowerlegandfootdisordersinadults

Anatomy

Anatomyofbonesandjoints

• The leg absorbs six times the body weight during weight-bearing. Strong

ligaments secure the ankle (formed by tibia above/medially and fibular

malleolus laterally) and talocalcaneal (subtalar) joints and bones of the

midfoot(Fig.3.21).

• Anomalousossiclesinthefootarecommon.Someareassociatedwithspecific

pathology. There are many potential sites, though the sesamoids in flexor

hallucisbrevis(FHB)areinvariable.

• The foot is an optimal mechanical device to support body weight when

walking or running over flat, inclined and uneven types of terrain. The

configuration of bones at synovial articulations allows dorsal flexion (foot

pulledup),plantarflexion(towalkontoes),inversion(foottipsin),eversion

(foot tips out) and small degrees of adduction and abduction. Midfoot

movementsallowpronationandsupination.

• Thenormalanklejointrangeisabout25°ofdorsalflexionand50°ofplantar

flexionfromneutral(foot90°toleg).Therangeofsubtalarinversion–eversion

isnormally10–15°.

Anatomyofthelongmusclesandtendons

• In the lower leg, a strong fascia connects the tibia and fibula. Lower leg

muscles primarily move the foot. They are separated into compartments by

fasciaandarepronetopressureeffects.

• The foot dorsal flexors—tibialis anterior, extensor digitorum longus (EDL),

extensor hallucis longus (EHL), and peroneus tertius—lie adjacent to the

anteromedial side of the tibia. Their tendons pass in front of the ankle in

synovial sheaths held down by strong retinaculae (Fig. 3.22). The tibialis

anterior, the bulkiest flexor, inserts into the medial midfoot (medial

cuneiform).

• Intheposteriorlowerleg,thegastrocnemius(andplantaris),whicharisefrom

thefemur,plantarflexesthefootbypullingthebackofthecalcaneum.The

soleus,whicharisesinthelowerleg,mergeswiththemintheAchillestendon.

Thistendonhasadeepandsuperficialbursaatitsinsertionsite.

• Plantarflexionisassistedweaklybylongmuscles,whichariseinthelower

leg, pass behind the medial malleolus in synovial sheaths (Fig. 3.22), and

insertintothesole.Theymostlyinvertthefoot.Tibialisposterior,thebulkiest

plantarflexor,insertsintotheplantarsurfaceofthenavicular.

• Theperoneuslongusandbrevisarisefromthefibularsideofthelegandpass

around the lateral malleolus in a common synovial sheath held by a

retinaculum.Longuspassesintothesoleandinsertsintothemedialcuneiform.

Brevisinsertsintothefifthmetatarsalbase.Bothevertthefoot.

• Thetibialnerveandarteryfollowthecourseofthemedialtendonsunderthe

flexorretinaculum(Fig.3.22).

Fig.3.21Thebonesofthefoot.

Anatomyofintrinsicfootstructure

• Intrinsic foot structures have been greatly modified during evolution to

combine provision of a flexible platform for support and a rigid lever for

thrustingbodyweightforwardwhenwalking.

• Inthesoleofthefoot,musclesarealignedlongitudinallyinfourlayers.The

deepestlayersincludephalangealinterosseiintheforefeet, tibialisposterior,

peroneus longus, adductor hallucis, and FHB, which has two insertions into

theproximalgreattoephalanx,eachcontainingasesamoid.

• The superficial layers include flexor digitorum longus (FDL), which inserts

into the lateral four distal phalanges, the phalangeal lumbricals, flexor

digitorumbrevis,andabductorhallucis.Thelattertwomusclesarisefromthe

plantarsurfaceofthecalcaneumdeeptotheplantarfascia.

• Flexor tendons merge with the deeper part of the plantar fascia, a swath of

tissuethatextendsfromoscalcistothemetatarsalarea.

• Longitudinal muscles, ligaments, and fascia contribute to stabilize the foot

with a longitudinal arch—its apex at the talus, but also with some effect

laterally.Thefootarchestransversely—itsapexatmedialcuneiformlevel.

Neuroanatomy

• The sciatic nerve splits into tibial and common peroneal nerves above the

knee. The common peroneal is prone to pressure neuropathy as it runs

superficiallyaroundthefibularhead.Thenervethendivides.Adeepbranch

runsdistallywithEDLundertheextensorretinaculumtothefoot.Itsupplies

tibialis anterior, EHL and EDL. A superficial branch supplies the peroneal

musclesandmostoftheskinoverthedorsumofthefoot.

• The tibial nerve runs in the posterior lower leg compartment supplying

gastrocnemiusandsoleus.Itthenpassesunderthemedialflexorretinaculum

dividing into medial and lateral plantar nerves, which supply the intrinsic

plantarmusclesofthefootandskinofthesole.

Functionalanatomy

• Inanormalgaitpattern,thefootisdorsiflexedandinvertors/evertorsstabilize

thehindfootforheelstrike.Asweightistransferredforward,thefootplantar

flexes and pronates, the great toe extends (optimally between 65° and 75°),

andpushoffoccursthroughthemedialsideoftheforefoot.

• Allmetatarsalsbearweightandcansufferweight-bearinginjury.

• Ligamentousattachmentsaroundthehindfootarestrong.Afallonapronated

invertedfootwithoutdirecttraumacanresultinafractureofthedistalfibula.

This is probably a consequence of the relative strength of the talofibular

ligamentscomparedwithbone.

Conditionsofthelowerleg

• Patientswithlowerlegconditionspresentwithpainordeformity.

• Painsinthecalfmaybeduetolocalsofttissueormuscleconditions,andare

commonlyduetoreferredlumbosacralpain.Thesepainsareoftendescribed

by patients as ‘cramps’—suggesting a muscle problem at first. A detailed

historymaysuggestnerverootpathology.

• Imbalanceofmusclesinthefootcanleadtoincreasedtensionattendonand

fascialinsertionsinthecalfandshin,resultingin‘shinsplints’.Shinsplints

usuallypresentafteractivityandarerelievedbyrest.Conditionstoconsider

include:

• stressfracturesofthetibiaorfibula.

• tibialisposteriorfasciitis—oftenwithaflat,pronatedfoot.

• compartmentsyndrome(softtissueandvascularswelling).

• poplitealarterystenosis.

• referrednervepain(spinalclaudication).

• peripheralvasculardisease(intermittentclaudication).

Fig.3.22Tendons,retinaculae,andbursaeofthehindfoot.

Takingahistoryfromanadultwithlowerlegorfootpain

Askaboutsiteandqualityofpaininthelowerleg

• Localizedanteriorpainoccursinbonylesionsoftheanteriortibia,e.g.stress

fractures,periostitis.

• Burning pain suggests a neurogenic cause. Diffuse burning pain may be

caused by peripheral neuropathy, CRPS (see  Chapter 22), or (rarely)

erythromelalgia.

• Mostcommonlyoccurringintheelderly,bilaterallegpainwith‘heaviness’or

‘stiffness’limitingwalkingdistanceistypicalofspinalstenosis.Analternative

would be vascular claudication where often pain is more overt, and critical

ischaemiacangivenightpaineasedbyhangingthelegsoverthesideofthe

bed(gravityeffects).

• Simultaneouskneeproblemsmayberelevant.Escapeofsynovialfluidfrom

the knee into the soft tissues of the calf can present with acute pain and

swelling and be misdiagnosed as a deep vein thrombosis

(pseudothrombophlebitis).Often ahistory ofprecedingjointeffusioncanbe

elicited.

• Low-lyingsynovialcystsconnectingwiththekneecancausecalfpain(withor

withoutswelling).Thisinvariablyoccursonlywithchronicsynovitis.

Establishpossiblecausesofhindfootpain

(SeeTable3.23.)

• Establishing the cause of hindfoot pain from the history alone is difficult.

Thereareimportantclues,mainlyfrompatternsofinjuryoroveruse.

• Posterior heelpain has afew causes.Oftenclinically indistinguishablefrom

Achilles tendonitis or retrocalcaneal bursitis, enthesitis is usually associated

with axSpA (see  Chapter 8). An os trigonum may become damaged

especiallyinsoccerplayersandballerinas(seelaterinsection).

• Theoriginofplantarheelpainisvaried.Mechanicalplantarfasciitisisthought

tooccurmorefrequentlyinpeoplewhoareontheirfeetforlongperiodsof

time, those who are obese, have thin heel fat pads, or poor footwear.

Symptomsofarthritisandenthesopathyelsewhere,lowbackpain(sacroiliitis),

eye inflammation (iritis), psoriasis, or previous gut or ‘urethral’ infection,

mightsuggestSpA.

• Lesscommoncausesofplantarheelpainincludefracturethroughacalcaneal

spur and lateral plantar nerve entrapment between the fascia of abductor

hallucis and quadratus plantae muscles (causing pain/paraesthesias on the

lateralsideofthesole).

• In the elderly and postmenopausal women, calcaneal stress fractures are a

recognizedfeatureofosteoporosisandcanpresentwithheelpain.

• Ankle and talocalcaneal synovitis, OA, ankle osteochondritis dissecans, and

tendonitisaroundthehindfootmaybedifficulttodistinguishfromthehistory

alone.SynovitisoraneffusionoftenaccompaniesOAofthesejoints.

EstablishpossiblecausesofmidfootandfirstMTPJpain

• Gout (see  Chapter 6), OA (see  Chapter 6), enthesitis, and referred L5

nerverootpainarethemostlikelydiagnosesofmidfootandfirstMTPJpain.

• Gout should alwaysbe considered a possiblecause of painfullesionsin the

footinpeopleatrisk.Goutisnotalwaysintra-articular,intra-bursalorintra-

tendon. Local or diffuse soft tissue inflammation is common and often

misdiagnosedascellulitis.

• The first toe and midfoot are common sites for PsA; check radiograph for

typicalPsAperiostealnewboneformation.

• L5painisreferredtothedorsumandS1paintothesole,ofthefoot.

• InolderadultsOAofmidfootjointsiscommon.Mildsynovitiscanoccurwith

itandmaybecausedbyCPPDdisease(see Chapter7).

Table3.23Conditionscausinglocalizedfootpaininadults

Siteofpain Commonlesions

Ankle

region

Ankleortalocalcanealjoint:synovitis(e.g.gout),OA.L4/L5

rootpain

Posterior

heel

Achillestendonitis.Retrocalcanealbursitis.Achillesenthesitis.

Osteonecrosisofostrigonum

Medialside

ofheel

Asforankleregion.Calcanealfracture.Tibialisposterior

tendonitis.Plantarfasciitis

Lateralside

ofheel

Asforankleregion.Calcanealfracture.Peronealtendonitis.

Fifthmetatarsalbasefracture

Underneath

heel

Plantarfasciitis.Calcanealfracture.Infra-calcanealbursitis.

Lateralplantarnerveentrapment

Topoffoot Midfootjointsynovitis(e.g.gout),OA.Navicular

osteochondritis.Enthesitis.L5rootpain

Soleoffoot S1rootpain.Plantarfasciitis.Metatarsalstressfracture.

Tibial/plantarnerveentrapment

Toes MTPsynovitis(e.g.RA,gout).MTPOA.Morton’s

metatarsalgia.Bursitis.Enthesitis/dactylitis

Robert–Jonesfracturefromaninversion–pronationinjury.

Establishpossiblecausesofforefootpain

• In those with forefoot pain, typically referred to as metatarsalgia, establish

whethertheconditionisfocalorduetoarthropathy.

• Painundertheballofthefootwhilewalkingisnon-specificbutmightsuggest

any MTPJ abnormality, distal metatarsal stress fracture, Freiberg’s disease,

plantarnerveneuroma,orbursitis.

• Patients with RA often describe pain under the MTPJs and a feeling of

‘walkingonpebbles’(duetojointswellingand/orsubluxation).Synovitisof

theMTPjointsisacommonfeatureofearlyRA.

• Acutepainundertheforefootspreadingintooneormore(adjacent)toesand

worseonwalkingsuggestsaplantarnerveneuroma(Morton’smetatarsalgia)

orintermetatarsalbursitis.

• Pain associated with paraesthesias or numbnessundertheforefootmight be

due to S1 root irritation (common) or entrapment of the tibial nerve in the

hindfoot(rare).Askaboutbackpainandotherhindfootproblems.

• Non-traumatic toe painassociatedwith swelling of theentiretoe suggests a

dactylitis (associated with axSpA). Although many toes may be affected,

dactylitismaybeunilateralandaffectjustonetoe.

• The development of hallux valgus is associated with tight footwear. The

deformityisassociatedwithalteredweight-bearingandasecondtoe(hammer)

deformity.

• Big toe pain might be due to hallux rigidus. It is usually due to OA and

importanttorecognizeasitmaypreventtoedorsiflexionsufficientlytoleadto

acompromisedgaitpattern.

• Painspecificallyunderthehalluxmaybeduetodamagetothesesamoidsin

theflexorhallucisbrevistendonandbemisdiagnosedasajointproblem.

Askforadescriptionofthepain

• Asinthehand,neurogenicpainiscommonandtypical.

• Severe or unremitting pain when at rest suggests intrinsic bone pathology.

Considerosteonecrosis,infection,fracture,andtumours,e.g.osteoidosteoma.

• Neurogenicpainmaybesharpandwelldefined(e.g.inacuteL5orS1root

pain),deep,achy,andlesswelldefined(e.g.chronicnerverootsymptomsas

in spinal or foramenal stenosis), or burning in quality. Paraesthesias and

numbnessmayaccompanyboth.

• If swelling accompanies neurogenic pain, consider a complex regional pain

syndrome.Therearenumeroustriggers,e.g.traumaandsurgery.Patientsmay

beunwillingtowalkandapparentdisabilitymayappearprofound.

Weakness

Iftrueweaknessisthemajorproblemratherthanpain,thediagnosisisusually

between a myopathic process, but more likely is a spinal or peripheral nerve

lesion(see ‘Examination’,p.194).

Examinationofanadultwithlowerlegorfootpain

Observation

Observe the lower legs and feet from front and back, while the patient is

standing.Noteanyswelling,deformities,orrashes:

• Lowerlegdeformitiestonote:tibiavarum(orbowlegs)inanolderadultmay

be due to Paget’s disease of the tibia. Muscle wasting might suggest disuse

atrophy, old polio, or spinal stenosis (bilateral and subtle usually in older

adults).

• Oedema or soft tissue swelling may be relevant to an underlying condition

causing ankle synovitis. Although it may cause discomfort, oedema from

cardiacfailure,venouscongestion,hypoproteinaemia,orlymphoedemaisnot

painfulunlessthereareulcersorthrombophlebitis.

• Gout can cause swelling anywhere; gouty tenosynovitis can mimic the

appearanceofacellulitisintheregionofajoint.

• Calfswellingmaybeduetoveinthrombosisorrupturedpoplitealcyst.

Commonpatternsoffootdeformityare:flatfeet(pesplanus),high-archedfeet

(pescavus)withhighmedialarch,halluxvalgusandrigidus,over-ridingtoes,

hammertoes,orclawtoes.

• Skinconditionsfromvenousabnormalitiesarecommonintheelderly.Other

skin lesions which may be relevant include purpura, panniculitis—which is

oftensubtleandovertheshins—andpyodermagangrenosum.

Askthepatienttowalkinbarefeet

Gaitpatternsshouldbenoted:

• Anantalgic(‘limp/wince’)gaitisanon-specificindicatorofpain.

• A wide-based gait (>10 cm wider than normal) suggests instability: joint

instability,muscleweakness,orneurologicallesionsmaybethecause.

• A foot that slaps down or a high stepping gait suggests tibialis anterior

weakness(L4nerverootorcommonperonealnervelesion).

• Significant weakness of gluteus medius and gluteus maximus in L5 and S1

rootlesions,respectively,canresultinlurchingduringgait.Intheformer,as

weight is taken on the affected side, gluteus medius may be weak in

controlling the small 2–3 cm lateral displacement in the weight-bearing hip

thatnormallyoccurs.Thiscanbecompensatedforifthebodycentreofgravity

isbroughtoverthehipbylurchingtheupperbodyovertheaffectedside.With

gluteus maximus lesions (S1) extension of the hip, which helps mediate

motionthroughthestancephasepriortotoeing-off,maybeweak.Thrusting

thethorax forwardwithanarchedback (forwardlurch)compensatesforthe

weaknessandhelpstomaintainhipextension.

• A flat-footed gait withlittleor weak toe-offmaysuggestanS1 root lesion;

however,‘flat-foot’(lossofthemedialarch)withassociatedhindfooteversion

andheelpain(plantarfasciitis)isextremelycommon.Oftenthearchweakness

correctswhenthepatientisaskedtowalk.

Examinethelowerleg

Withthepatientsupineonthecouch,examinethelowerleg:

• Afterarupturedpopliteal(Baker’s)cyst,calftissuesareoftendiffuselytender

and swollen. Calf circumferencescanbecompared(e.g.10cmbelowtibial

tubercle). There may also be mild skin erythema. Findings are not specific.

Goutandinfectionarethemainalternativesifthereismarkedtenderness.

• Checkforbruising,swelling,andtendernessaroundthefibulaheadinpatients

withfootdrop(possibleperonealnervepalsy).Neurologicalexaminationmay

bedoneatthispoint.

• Localized anterior tibial tenderness is often found in patients with stress

fracturesorwithpseudo-fractures.

• Tibialdeformityinadultsmaybeassociatedwithdiffusebonytendernessand

heat(arteriovenousshunting)inPaget’sdisease.

Examinetheankleandhindfoot

At the ankle and hindfoot, examine for joint and tendon synovitis, palpate

specificstructuresandtestpassivehindfootjointmobility:

• Synovitis of hindfoot joints is not always easily detected. With ankle joint

synovitis, thickened tissue may be felt anteriorly in the ankle crease (where

theremaybea‘springyfullness’)orlaterallyaroundthemalleoli.

• Posteriortibialandperonealtendonitisareassociatedwithsofttissueswelling

of the medial and lateral hindfoot, respectively. Synovial thickening from

ankleandtalocalcanealjointsmayalsobefelthereandsynovitisofstructures

maycoexistinRAorSpA.Painfromresistedmovementoftendonsmaynot

bespecific.

• Pathology of medial hindfoot structures may be associated with tibial nerve

entrapmentresultinginsensorysymptomsonthesoleofthefoot.Theremay

beapositiveTinel’ssign.

• Posterior heel pain may be due to Achilles tendonitis, enthesitis and

mechanicaldamagetothetendon,andretrocalcanealbursitis.Deeptenderness

maysuggestanostrigonumlesion.

• Thelossofpassivehindfootmovementsisnotspecificandcanbeassociated

withanycauseofankleorsubtalararthritis(20–30°ofdorsiflexionand45–

55°ofplantarflexionisaveragefortheankleanda10–20°inversion–eversion

range is average for the subtalar joint). Subtalar joint movement can be

difficulttotestaccurately.

• Thepainofplantarfasciitismay beelicitedbyfirmpalpationofthe medial

underside of the calcaneum. A negative test does not rule out pathology, as

oftenthehistoryismoresensitive.FullMSKexaminationisrequiredtocheck

forfeaturesofSpA,suchasarthritis/enthesitiselsewhereandsacroiliitis.

Examineformidfootlesions

Identifying specific midfoot lesions is difficult, though bony landmarks and

discretetenderareascanbenoted:

• Twisting the midfoot may elicit pain but locating the source in the midfoot

may be difficult. Common lesions include PsA, OA, gout, and enthesitis or

synovitisfromSpAorRArespectively.

• Bonytendernessalonewithoutsofttissueswellingdoesnotruleoutsynovitis

ofanadjacentjoint.

• Themidfootisatypicalsiteforneuroarthropathyindiabetes.

• Bonyexostosesthatmayhaveformedatsitesofpressurearecommoninthe

foot(e.g.medialordorsalaspectofthefirstMTPJ,baseorheadofthefifth

metatarsal,distaltalus,oroverthemidfoot).

• Bothgoutandinfectionresultinswelling,skinerythemaandlocaltenderness.

Gout of the first MTPJ occurs at any one time in 70% of patients with the

condition.Itcanoccuranywhereinthefoot.

Examinetheforefoot

Checkforbonyorotherswelling,digitseparation,andexaminethesoleofthe

foot.SqueezingthewholeforefootatthelineoftheMTPJsisanon-specific,but

usefulscreeningtestforpainfulforefootlesions:

• Tenderswellingofthewholetoe(dactylitis)occursinSpA,sarcoidosis(see

Chapter8),andHIVinfection.Swellingissoftnotbony.Tenderbonyswelling

suggestsabunionandiscommononthedorsalaspectofthetoesandthefirst

andfifthMTPJs.

• Forefoot splaying and interdigital separation suggests MTP synovitis or

interdigital bursitis. MTPJs may be individually tender (simultaneously

palpatedwiththumbbelowandfingerabove).

• Tenderness between metatarsal heads is typical in Morton’s metatarsalgia.

There may be a sensory deficit in the interdigital cleft. The differential

diagnosis (in adolescents) may be osteochondritis of the second and third

metatarsalhead.

• Check for hallux rigidus. Passive hallux dorsiflexion should be >50°.

Extendingthehalluxcanrevealanabilitytoformamediallongitudinalarchin

patientswithflatfeet(Jack’stest).

• Discretebonytendernesswithoutswellingoccurswithstressfractures.

• Uneven callus distribution under the forefoot may suggest an abnormally

focusedareaofweight-bearingandanunderlyingmechanicalabnormality.

• Rashes on the sole of the foot are uncommon but important to consider are

pompholyx, pustular psoriasis, and keratoderma blennorrhagica (‘reactive

arthritis’,see Chapter8).

• Loss of sensation under the forefoot may be due to an S1 root lesion,

peripheral neuropathy (e.g. diabetes), mononeuritis (e.g. vasculitis; see

Chapter15),Sjögren’ssyndrome(see Chapter12),otherAICTDsor,rarely,

tibialnerveentrapment(examinehindfoot).

Neurologicalexamination

Neurological examination of the feet is essential in cases where pain is

neurogenicandlikelytobereferredornerverootinoriginorthereisweakness,

numbness,orparaesthesias(Table3.24).

RelevantproximalMSKexamination

Asalwaysexamineproximally—here,theknee.

• Gaitexaminationisimportant—considerthelowerlimbasfunctionallyinter-

relatedfromlowerspinetotoes.

• Hip examination can help determine ante/retroversion at the hip—and the

configurationofsuchcanhaveabearingonlowerlegpronation,in-toeingand

painsatbothkneeandinfeet(seeFig.3.20).

Investigationsofanadultwithlowerlegorfootpain

Imagingofthelowerleg

• Suspectedtibialabnormalitiessuchasstressfracturesandpseudofracturesin

osteomalaciaandPaget’sdiseasehavecharacteristicradiologicalappearances.

• Periosteal changes occur intrauma,psoriatic arthritis (above ankle), HPOA,

andpachydermalperiostitis.

• Inathleteswithexercise-relatedpain,three-phasebonescintigraphyispartof

thework-upforanteriorshinpain.

• Insuspected(butradiograph-negative)casesofbonydisease,suchascortical

stressfracture,periostitis,orcorticalhyperostosis,bonescintigraphymaybe

usefultoidentifysubtlepathology.

• MRIisneededin suspectedcasesofmyopathy thoughimagingmaybdone

moreusefullyoftheupperleg.

Table3.24Patternsofcommonabnormalexaminationfindings(primarilyinthefeet)inlowerlumbar

nerverootlesions

Nerve

root

Abnormalfinding

L4 Weaknessofankledorsiflexion(tibialisanterior)

Patientfindswalkingontheirheelsdifficult(strongankle

dorsiflexonneeded)

Reducedkneereflex(L3andL4)

L5 Weaknessofbigtoedorsiflexion(extensorhallucislongus)

Weaknessoffooteversion(peronealmuscles,alsoS1)

Sensorydeficitoverdorsumoffoot

Reducedanklereflex(L5andS1)

S1 Weaknessofankleplantarflexion(gastrocnemiusandsoleus)

Patientfindswalkingon,orrepeatedlyrisingonto,tiptoedifficult

Sensorydeficitoversoleoffoot

Reducedanklereflex

Manoeuvresmaybeaffectedbypain,makinginterpretationdifficult.

Imagingofthefoot

Informationavailableonradiographsofthehindfootincludes:

• Increased soft tissue attenuation around the tendon insertion in cases of

Achillestendonitisorretrocalcanealbursitis.

• ErosionsorperiostitisattheAchillestendoninsertioninenthesitisassociated

withSpA.

• ErosionsingoutandRA-associatedretrocalcanealbursitis.

• Axial radiographs of the hindfoot are useful in showing talocalcaneal joint

abnormalities,e.g.inRA.

• If radiographs arenormal in patientswithposterior heel pain,UScan show

patternsoftendonandbursalinflammation.MRIcanfurthercharacterizeany

discretepatternoftendoninjury.

• Osteonecrosisofanostrigonumorposteriortalarprocessortarsalnavicular

maybeidentifiedbyradiographs.Itisinvariablylocatedbybonescintigraphy

andcanbecharacterizedfurther,usuallywithsofttissueswelling,byMRI.

• Aplantarspurmaydenoterecurrentplantarfasciitis.

• Plantarheelpainmaybeduetoafractureinaspur.Erosionsjustabovethe

spurmaybeseen.ThethicknessofheelfatpadcanbegaugedfromitsX-ray

attenuation(thin=riskforplantarfasciitis).Afatpad>23mmthickinmen

and>21.5mmthickinwomenisassociatedwithacromegaly.

• Calcaneal fractures or an osteoid osteoma can be seen in some cases with

radiographsalone.Bonescintigraphy/CTaremoresensitive.

• Patternsofjoint,enthesis,andtendoninflammationcanbedocumentedusing

MRIorbonescintigraphy.Thisisusefulinformationwhencharacterizingan

arthropathy.

• Bony abnormalities in the mid and forefoot are generally revealed by

radiographsalone,thoughmetatarsalstressfracturesmaybemissed.MRIcan

discriminateaplantarneuromafrominterdigitalbursitisandMTPJsynovitis.

TheformerareprobablybestinitiallydemonstratedbyUS.

Otherinvestigations

• Neurophysiology (NCS) is a useful adjunct to clinical examination in

diagnosis of lower limb neuropathies, and can help discriminate between

peripheral(commonperonealorsciatic)ornerverootcausesoffootdrop,and

alsoS1rootortibialnerveentrapmentcausesofparaesthesiasofthesoleof

thefoot.

• Joint/bursa fluid aspiration is mandatory in suspected cases of sepsis and

shouldbesentforculture(remembertoconsidergonococcusinyoungadults

andTBinpatientsfromendemicorinner-cityareas).Fluidshouldbesentfor

polarizedmicroscopyifacrystal-induceddiseaseissuspected.

• Laboratory tests requested should reflect suspicion of specific infective,

inflammatory,metabolic,ormalignantpathology.

Treatmentoflowerlegandfootconditions:adults

Lowerlegdisorders

• Anterior shin pain should be treated according to cause. If there is also a

problemoffootalignment,thenorthosesthatsupportboththehindfootand

midarchmaybeveryuseful.Patientsmayvolunteerthatgoodwalkingshoes

or‘trainers’(‘sneakers’)help(asisthecasewithplantarfasciitis).

• Exercise-induced lower leg pain has a number of causes and includes shin

splints and compartment syndrome. The latter may require further

investigationwithpressurereadingsorexercisescintigraphy(

99m

Tc-MIBI).In

cases resistant to rest, analgesia, and modification of triggering factors,

decompressivesurgerymayberequired.

• Patients with Paget’s disease of the tibia may require treatment with IV

zoledronateandwillneedabiomechanicalassessment.

Ankleandhindfootdisorders

• Tendonitis around the ankle should respond to treatment of its underlying

cause. Chronic posterior tibial tendonitis left untreated will eventually

acceleratethedevelopmentofhindfootvalgus.Considerheelandarchsupport

orthoticsearly.

• Steroid injection of inflamed ankle, subtalar and (both posterior tibial and

peroneal) tendons can be done easily (though with subtalar injection, image

guidanceisadvisable).See Chapter24.

• Plantarfasciitismayrespondtoanumberofmeasures:

• Hindandmidfootorthoticsand/orsupportiveshoes.

• NSAIDs.

• Modificationofweight-bearingactivity.

• Achillestendonstretching.

• Hindfootstrapping.

• Restingnightsplint(preventingankleplantarflexion).

• Steroidinjectionaroundthemedialcalcanealtubercle.

• surgery.

• Disease modifying anti-rheumatic drugs/immunosuppressants (e.g.

sulfasalazineormethotrexate)ifpartofPsAorSpA.

• Externalbeamradiotherapy.

Forefootdisorders

• Localizedforefootpain(e.g.metatarsalgia)mayrespondtosupportpadsanda

change to a wider, more supportive, low-heel shoe. A podiatry/chiropody

opinionshouldbesoughtasrequired.

• Forefoot stress fractures and metatarsal head osteochondritis require rest,

supportivefootwearandtimetoheal.

• Patientswithchronicforefootpainmaybenefitfromapodiatricassessment.

‘Stress offloading’ foot orthoses for metatarsalgia and other biomechanical

abnormalities (e.g. hallux rigidus) can be individually moulded using

thermoplasticmaterials.

Steroidinjections

Steroidinjectionsmaybeofvalueinthefollowing:

• Anklejointinflammation(e.g.RA,PSA, OA,acuteCPPDandgout)(see

Plate20a).

• Subtalarjointinflammation(imagingguidanceneeded).

• Tarsaltunnelsyndrome.

• Achilles peritendinitis (steroid injections for Achilles nodules should be

avoided as the risk of rupture is high. The same concern, though probably

lesserrisk,appliestoAchillesperitendinitis).

• Calcanealapophysitis(Sever’sdisease—Achillestendoninsertion).

• Retrocalcanealbursitis.

• Plantarfasciitis.

• Gout/OA/enthesitisatfirstMTPJ.

• InitialtreatmentofaMorton’sneuroma.

Surgery

• Minor surgical techniques can be curative in tarsal tunnel syndrome and in

excisinganinterdigital(Morton’s)neuroma.

• Consider excision of painful exostoses and troublesome rheumatoid nodules

andamputationofdeformedorover-ridingtoes.

• Majorsurgicalprocedureswithgoodoutcomesinappropriatepatientsinclude

fusion of hindfoot joints and forefoot arthroplasty in chronic inflammatory

arthritides.

• Osteotomyrealignmentofahalluxvalgusdeformitycanbesuccessfulinthe

longterm.

Lowerlegandfootdisordersinchildrenand

adolescents

Generalconsiderations

Footandankleproblemsarecommoninchildrenandadolescentsandmostare

attributabletominortraumaorrepetitivestress.Concernscanarisefromover-

interpretationofcommondevelopmentalvariationorcongenitalanomalies(see

Table2.1)andfailureofconditioningorrehabilitationafteracuteinjury.

Takingahistoryinchildrenandadolescents

• Overuse and acute trauma is common: tendinopathy, stress fractures,

osteochondritis and apophysitis. Taking an accurate history of trauma is

important.

• If stress fracture is suspected (e.g. second, third, or fifth metatarsals or

navicularorcalcaneal)inateenagegirlthenamenorrhea,eatingdisorderand

overtraining(inanathlete)needstobeconsidered(‘femaletriadsyndrome’).

• A history of initial trauma then chronic symptomology is recognized with

some lesions—particularly lateral tibiofibular ligament injury, ‘turf-toe’ and

tarso-metatarsaljointinjury.

• Pescavusorplanus,tarsalcoalitions(stiffnessandsometimespaininthehind-

midfoot),andmetatarsusadductuspresentinginyoungchildrenareprimarily

developmental/congenital in origin. Symptoms may have been present since

thechildstartedwalkingthoughnotalwaysandahistoryofdiscomfortmay

haveevolvedoveralongperiodoftime.

• Painundertheheelorareluctancetoheelstrikecandiscloseplantarfasciitis

(e.g.tractionapophysitis).

• Tendonitis may not be an isolated lesion. For example, posterior tibial

tendonitiscanoftenaccompanyanaccessorynavicularandperonealtendonitis

isassociatedwithexcessivepronation.

• Osteochondritisofdifferentstructurespresent acrosssomewhatdifferingbut

broad age ranges: fifth metatarsal base enthesis (9–15 years), Achilles

insertionalapophysitis(6–17years),naviculararticularchondritis(3–7years

old).

• A dissecans osteochondritis lesion of the dome of the talus presents with

hindfootpain±catching/lockingofthehindfoot.Severelesionscandevelop

osteonecrosis.

• JIAandpainamplificationsyndromescanpresentwithfootsymptomsthough

it is wise to rule out all trauma and developmental lesions initially. Dual

pathologyofcoursemayexist.

Examination

Examinationshouldbeginwithfunctionalassessmentofgait,jumping,hopping,

toewalking,walkingonheelsandininversion,andfigure-of-8running.Major

problemswillbecomeapparent.

• Observewhenstandingandlookforpelvictilt,hindfootvalgus,subtalarand

forefootposition,mediallongitudinalfootarch,clawtoesandaMorton’sfoot

(firstrayshorterthansecond).

• Palpateandmovethefoottoreproducepainandassessrangeofmovement.

• Beawarethatifthesubtalarisonlyexaminedoffloaded,abnormalitiesofthe

jointmaynotbeapparent.

• Testheelrisetoassessrigidorflexiblepesplanus.

• Check thigh–foot angle to screen for tibial torsion (see  ‘Internal tibial

torsion’,p.180).

• Other examination: is there correctable forefoot adduction? Is there pain on

hindfoot external rotation suggesting a deficiency to the anterior talofibular

ligament?.

• Checkstrength(activemovementagainstresistance)ofankledorsiflexionand

plantar flexion, subtalar inversion (tibialis posterior), subtalar eversion

(peronealtendons),firstMTPJdorsiflexion(EHL)andplantarflexion(FHL).

• Finallyexaminetheknee(see p.185).

Commonfootconditionsinchildrenandadolescents

Metatarsusadductus(MTA)

This is a common exaggerated turning in of the forefoot typically identified

whenthechildstartstowalk.

• MTAmaybedetectedatbirth,whenattributedtoaninuterofootposition.

• Most MTA configurations are flexible and asymptomatic and require no

intervention.

• Stretching may help the foot move into a straighter position and may be

supportedbytheuseofaboot,althoughevidenceforthisislimited.Casting

andsurgeryarerarelyrequired—onlyinseverecases.

Calcaneovalgus

This excess dorsiflexion and valgus of the hindfoot, detected in neonates, is

typicallyidentifiedwhenthechildstartstowalk.

• Thepositionofthefootisusuallycorrectablebytheexaminer.

• Thereisnodislocationorbonydeformity.

• Muscleimbalanceduetoneurologicaldisturbancemayresultinweaknessof

theplantarflexorsandunopposedactionoftibialisanteriorandfootextensors.

• Radiographs typically show posteromedial bowing of the tibia and the first

metatarsalliningupwithaverticallyheldtalus.

• The condition differs from rocker bottom feet which are not correctable—

whenthetalusisplantartothefirstmetatarsal.

• Prognosis is good with spontaneous resolution. Passive stretching exercises

mayexpediteresolution.

Pesplanus

Pesplanus(flatfeet)isanormalvariantinyoungchildrenunlessthefootisrigid

fromaneurologicaldeficit(diplegia)orbonychanges.

• Associationsofpesplanusincludehindfootvalgus,tighteningoftheAchilles

tendon,andinwardrotationoftheforefoottobalancetheheelposition(orthe

footmaybegintoslantoutwardsfromthemiddleofthefoot).

• Hypermobilepesplanuscorrectsifthechildrisesontip-toe.

Radiographs need only be done for rigid flat feet or if pain suggests a tarsal

coalition,congenitalverticaltalus,oraccessorynavicular.

• Usuallynotreatmentisneededandthepatientshouldbeencouragedtowalk

barefootasmuchaspossible.

• Thevalueofarchsupportsisdebatedas thisdoes notimprovethedynamic

support of the foot and may make things worse, although can provide pain

relief.

Pescavus

A high medial longitudinal arch that does not flatten when weight-bearing is

termedpescavus.Itispresentin10%ofthepopulation.

• Afullneurologicalhistory(includingofmotormilestones)andexaminationis

wise.

• Pes cavus may rarely indicate neuromuscular disease (hereditary motor

sensoryneuropathy,Friedrich’sataxia,musculardystrophy,orcerebralpalsy).

• Ifpescavusisunilateralorrapidlyprogressive,thenconsidertheremaybea

spinaltumour.

• Associated clawing of the toes, contracture of the plantar fascia, and

dorsiflexedgreattoemaycausemidfootpain.

• Mayalsoaffectfootwear.

• Physiotherapy, foot orthoses, and foot wear modifications for pain or

instabilityshouldbeconsidered.

• Surgical treatment is reserved for cases where conservative measures have

failed.Surgeryincludestendontransfers,softtissuemanipulation,osteotomy

andarthrodesis

Talipesequinovarus(clubfoot)

• The flexible variant is a common congenital deformity and requires

physiotherapyguidancealone.

• Therigidform,whichisofgeneticaetiology,typicallyrespondstothePonseti

methodofmanipulationwithoutinvasivesurgery.

Tarsalcoalition

A tarsal coalitionis a congenitalanomalywhere there isanabnormal fibrous,

cartilaginousorosseousconnectionbetweenhindfootbones.

• Coalitionsareusuallyasymptomatic.

• Painoccurswhenthereisdecompensationofsupportingmusculature,arigid

flatfoot,hindfootvalgus,orperonealspasticity.

• The commonest coalitions are calcaneonavicular (presenting at 8–12 years

old)andtalocalcaneal(presentingin12–15-year-olds).

• RadiographsconfirmthelesionsbutMRIishelpfulincharacterizingfibrous

variantsandassessmentofbonestress(boneoedema).

• Managementincludes‘determined’physiotherapyworkingongaitandmuscle

supportofthefoot,which,ifsuccessfulavoidssurgery.

• Overallsurgeryisrarelyrequiredandnotdesired.

In-toeing

Clumsinessorregulartrippingafter2yearsofage iscommon.Mildin-toeing

maybeanormalvariant.However,assessmentrequiresathoroughexamination

ofpotentialcontributingfactorswhichmightbemodifiablewithphysiotherapy

and/orfootorthoses(e.g.femoralanteversion,MTA,oranyconditionresulting

inmuscleweakness).

Toeanomalies

• Congenitalcurlytoesresultfromshorteningofflexortendonsaschildstartsto

walk. Surgical tendon release can be considered in cases where there are

painfulblistersorrubbing.

• A hammer toe is a tendon contracture with progressive PIPJ flexion and

compensatoryextensionattheMTPJsandDIPJs.Management,includingfor

pain,isusuallyconservative.

• AmallettoeisacontractureoftheDIPJs.

• A claw toe is formedfromdorsaltoe subluxation at the MTPJs and flexion

deformitiesatthePIPJsandDIPJs.

• Toeinstability(dorsalsubluxationoftheproximalphalanxoverthemetatarsal

head)israreinyoungpeople.Oftenthereisahistoryofrepeattearing(pain)

andswellingoftheplantarplatewithlocaltendernessandswelling.

• Polydactyly occurs 1 in 500 live births with radial, ulnar, or central extra

digits.Thereisahighlikelihoodofsyndromicgeneticanomalyandchanceof

multiplegeneticdefects.Areferraltoageneticistisrecommended.

• Syndactylyisanembryonicfailureofapoptosisofthedigitwebbingatabout

16weeks’gestation.Mostlesionsareisolateddefectsbuttheremayalsobean

associationwithgeneticdefects.

Chapter4
Thespectrumofdisordersassociatedwithadult
rheumaticandmusculoskeletaldiseases
Skindisordersandrheumaticdisease
Skinvasculitisinadults
Cardiacconditions
Pulmonaryconditions
Renalconditions
Endocrineconditions
Gutandhepatobiliaryconditions
Malignancy
Neurologicalconditions
Ophthalmicconditions
Skindisordersandrheumaticdisease
Theimportanceofexaminingtheskin
• Theskinisthemostaccessibleorgantoexamine.
• Pattern recognition of skin symptoms and lesions is valuable in aiding
diagnosis(e.g.acuteorchronicsarcoid)andprognosisofrheumaticdiseases
(e.g.nodulesandvasculitisinRA).
• MSK abnormalities may be mirrored by skin abnormalities (e.g. joint
hypermobilityandskinlaxitywithbruising,scarring,andstriae).
• Someantirheumaticdrugsproducespecificandpotentiallyseriouscutaneous
reactionsthatrequirepromptmanagement.
• SomerareautoinflammatoryconditionsassociatedwithMSKsymptomscan
manifestprimarilywithskinpathology(see Chapter18).
Regionalabnormalities
Thescalp

Scalpsymptomsandlesionsmaybesubtle.
• ScalptendernessisasignofGCA.
• C2root/occipitalneuropathy(e.g.inC1–C3facetjointOAorcrowned dens
syndrome/CPPDdisease)orshinglesmaybeassociatedwithdysaesthesiaover
thescalpandoccipitalneuralgia.
• Alopeciamaybelocalized(areata)ordiffuse(e.g.inSLEorirondeficiency).
Scarringalopeciaistypicalofdiscoidlupus.
• Scalppsoriasismaybepatchyanddiscrete,andoftenaffectsthehairline.
Faceandears
Face and ears are in sun-exposed areas. Consider ultraviolet (UV) skin
sensitivity.
• AvarietyofpatternsofSLE-associated,UV-sensitiverashesmayoccur.The
rashisoftendiffuse.Shadedareas(e.g.nasolabialfolds)maynotbeaffected
(see Chapter13).
• AsinSLE,rosaceacanpresentwithanerythematousfacialrash.Distinctionis
sometimesdifficultwithoutbiopsy.
• Periorbitaloedemaoccursindermatomyositis,angio-oedema(whichmaybea
presentingfeatureofSLE),andinnephroticsyndrome.
• Heliotrope rash refers to violaceous oedema/erythema of the eyelids in
dermatomyositis(see Chapter14).
• Thecutaneousinfiltrationofchronicsarcoid(lupuspernio)(see Chapter18)
acrossthenoseandcheeksmaybeovert(papular)butalsomaybequitesubtle
(see Plate21).
• Saddle nose deformity/nasal cartilage destruction has a number of causes:
PR3-positiveANCA-associatedvasculitis(AAV;see Chapter15),relapsing
polychondritis (  Chapter 18), hereditary connective tissue disease (e.g.
Stickler’ssyndrome;see Chapter19),andlethalmidlinegranuloma.Nasal
septalperforationcanoccurfromcocaineuse.
• Oralaphthousulcersarecommon.Oralulcerationmayfollowdiseaseactivity
(e.g.inSLE).Ulcersinreactivearthritisaretypicallypainless.Oralaphthous
ulcersarefrequentlyidiopathic,andnotassociatedwithsystemicdisease.
• Large punched-out and numerous tongue and buccal ulcers that scar are a
hallmarkofBehçet’sdisease(see Chapter18).Theymayremainforseveral
weeks.
• Strawberryerythemaofthetongueandlipsshouldnotbemissedinchildren.It
may denote self-limiting streptococcal infections but may also herald the
desquamatingpalmar(andsole)rashofKawasakidisease(KD;see Chapter
15).

• Lacywhitestreaksonthebuccalmucosasuggestlichenplanus.

• The pinna is a common site for gouty tophi and discoid lupus. Relapsing

polychondritis typically causes softening and distortion of cartilage (but is

lobe-sparing).

• Lipidskindepositsaroundtheeyeoccurinhyperlipidaemiaandmulticentric

reticulohistiocytosis.

Handsandnails

Handsandnailsshouldbeexaminedclosely.

• Aphotosensitiveeruptionsparesthefingerwebsandpalms.

• Erythema on the back of the fingers may help distinguish dermatomyositis

fromSLE.

• InpatientswithRaynaud’sdisease(RD),fingerulceration,fingerpulpatrophy

(withsmoothtaperingofthefingertips),induration,andtetheringoftheskin

indicatescleroderma(see Chapter13).

• Unlikenormalskin,theskinofsclerodermadoesnotformfinewrinkleswhen

pinched.

• Onycholysis, nail-pitting, salmon patches, and subungual hyperkeratosis are

typicalofpsoriasis(see Chapter8).

• Subungual splinter haemorrhages may be associated with trauma, infective

endocarditis,vasculitis,orthromboangiitisobliterans.

• Nailfold capillariescan beexaminedwith anophthalmoscope at40dioptres

after applying a drop of oil (or surgical lubricant) to the cuticle. Enlarged

(dilated) capillary loops and capillary ‘dropout’ suggests an underlying

autoimmune connective tissue disease (AICTD), particularly systemic

sclerosis(SScl).

• Nailfold vasculopathy is non-specific, and can occur with vasculitis,

dermatomyositisandinfectiveendocarditis.

Typesoferuption

Macularrashes

Macularrashesareflat(non-palpable)areasofalteredskincolour.Papulesare

lumps<1cmindiameter.

• Maculopapularrashesaretypicalofviralinfections.

• Ashort-lived,pinkish,maculopapulareruptionoccursonthetrunkandlimbs

insystemic-onsetJIA(soJIA;see Chapter9)andadult-onsetStill’sdisease

(see Chapter18).Itisoftenprominentinthelateafternoon,andcoincides

with temperature spikes. If scratched, the rash may blanch (Koebner

phenomenon).

• Erythema that enlarges to form erythematous patches with pale centres

suggestsrheumaticfever(‘erythemamarginatum’).

• A ‘bulls-eye’ erythematous lesion around a tick bite may be the erythema

migransofLymedisease.

• Maculopapular eruptions can occur from NSAIDs, gold, sulfasalazine,

azathioprinehypersensitivity,andleflunomide(see Chapter23).

Pustulesandblisters

Blistersmaybevesicles(<0.5cm)orbullae(>0.5cm).

• Themostcommonpustularrashisduetofolliculitis.

• PustulesconfinedtothehandsandfeetsuggestreactivearthritisorSAPHO,

althoughlocalformsofpsoriasismaybeindistinguishable.Psoriasiscanalso

occuras‘raindrop’erythematouslesions,alsoknownasguttatelesions.

• Generalized pustular rashes can occur in vasculitis, the neutrophilic

dermatoses, intestinal bypass syndromes, Behçet’s disease, and gonococcal

bacteraemia.

• Bullous eruptions may be due to SLE and drug reactions, pemphigus, and

pemphigoid.

Plaques

Plaquesareslightlyraised,circumscribedareas—oftendiscshaped.

• Plaquesarethehallmarkofpsoriasis.Skinmaybescalyandflakeoffeasily.

Lesionsareoftenred.

• Psoriaticplaquescanoccuranywhereontheskin,buttypicalsitesareoverthe

extensorsurfacesofthejoints,intheinterglutealcleft,atsitesofskinfriction

(e.g.underwaistbandsoftrousersorunderwear)andtheumbilicus.

• Scaling may be a feature of discoid lupus; scaling tends to occur at the

peripheryofthelesion.

Vascularlesions

Bleedingintotheskinthatdoesnotblanchiscalledpurpura.Itmaysometimes

be palpable. Telangiectases are dilated small vascular lesions that blanch on

pressure.

• Non-palpablepurpuramaybeduetothrombocytopenia,plateletdysfunction,

trauma (± capillary/skin fragility, e.g. chronic steroid use), haemophilia,

anticoagulation, and hereditary connective tissue diseases (e.g. EDS; see

Chapter19).

• Palpable purpura suggests vasculitis, including drug-induced disease (see

Chapter15).

• Widespread telangiectasia occurs in limited cutaneous scleroderma (lcSScl;

see  Chapter 13), hereditary haemorrhagic telangiectasia, and

dermatomyositis.

• Livedoid rashes can be subtle, occur mainly over the legs, can occur in

smokers but are also associated with SLE and antiphospholipid syndrome

(APS).

• Lumpy erythema on thelowerlegsespecially, which can be tender, may be

panniculitis (e.g. erythema nodosum), and related to systemic disease (e.g.

sarcoid,Crohn’s)

Ulcersandulceratingrashes

Ulcers are defined as a loss or defect of dermis and epidermis produced by

sloughingofnecrotictissue.

• Cutaneousulcerationmayhavemorethanonecauseinautoimmunediseases.

Forexample,vasculitis,venousstasisinanimmobilepatient,andulceration

overnodulesorpressurepointsmayallcontributetothesamesetoflesions.

Trauma may be an important cause of cutaneous ulcers in a patient who is

alreadypredisposedtowardsformingtheselesions.

• Anindurated,expanding,plum-colouredplaqueoracneiformpustulethatthen

ulcerates suggests pyoderma gangrenosum. The ulcer has irregular, bluish

margins.

• Neurotropiculcersareclassicsequelaeofdiabetes,buttheycanalsooccurin

associationwithmononeuritismultiplex(fromvasculitis)andotherrheumatic

diseases.

• Vasculitic ulcers in the context of livedo reticularis and antibodies to

phospholipids(e.g.cardiolipin)maydenoteAPS(see Chapter11).

Texturalabnormalities

Abnormalitiesofthetextureoftheskinmaybedifficulttodiscern.Atrophyand

thinning,laxity,thickening,andindurationmayallbeassociatedwithdisease.

• Generalizedskinatrophyandthinningisanage-relatedprocess,butthiscan

beacceleratedbychronicsteroiduse;hereditarydiseasesofconnectivetissue

shouldalsobeconsidered.

• Skinlaxitycanbestbedemonstratedoverelbowandkneeextensorsurfaces.

Generalized laxity of connective tissue may result in varicose veins and

internalorganprolapse.

• True acral and digital puffiness in a patient with Raynaud’s disease is

suggestiveofSScl.Skinthickeninghasa varietyof causes(seelaterinthis

topicand Chapter13).

• Sclerodermaandscleroderma-likeskinmaybelocalized,limited,ordiffuse—

thisdistinctionisimportant(Table4.1).

Diagnosticissuesinpatientswithskinthickening

• Raynaud’s disease (RD) invariably precedes the onset of SScl, but is not a

characteristicofmorpheaorlinearscleroderma.

• In patients with RD, abnormal nailfold capillaries on capillaroscopy may

indicateSScl(see Plate9).

• The specificities of autoantibodies are often predictive of SScl subtype. In

patientswithRD,ANAhaspredictivevalueforidentifyingpatientswhomay

progresstoSScl; anticentromereantibodycan predictprogressionto limited

cutaneous SScl; anti-topoisomerase I (SCL-70) and anti-RNA polymerase

antibodiesarelinkedwithprogressiontodiffusecutaneousSScl(dcSScl).

• PatientswithdcSSclhaveapreponderanceofvisceral organ involvementin

the first 5 years of disease; screening investigations are usually useful, and

shouldincludecardiovascularscreeningtests(referto Chapter13).

• Eosinophilic fasciitis (see  Chapter 18) may occur as a paraneoplastic

syndrome,andisassociatedwithhaematologicalmalignancies.

• Linearsclerodermainchildrencanproducelifelongdeformitiesbecauselimbs

failtodevelopcorrectlengthandbulk.

Table4.1Patternrecognitioninpatientswithskinthickening

Classification Skinfeatures

Morphea

maybe

localized

(guttate)or

generalized

Earlysmallskinareasaffected(itchy).Progressionto

hideboundskin,typicallyontrunk(areolaspared)andlegs.

Lesionsbecomewaxyandhypo/hyper-pigmentedguttate

(small<10mm)papulesusuallyonneckandanteriorchest

Linear

scleroderma

Linearband-likepatternoftenindermatomaldistribution.

Atrophyofmusclesiscommon.Fixedjointdeformitiesand

growthabnormalitiescanoccur

‘Coupde

sabre’

Linearsclerodermaontheface/scalpcanbedepressed;ivory

inappearance.Hemi-atrophycanoccur

SScl(early) Earlymorning‘puffiness’inhandsandfeet,facial‘tightness’.

Non-pittingoedemaofintactdermalandepidermal

appendages.Highdegreeofsuspicionneeded

SScl(classic) Firm,taut,hideboundskinproximaltoMCPjoints.Skinmay

becoarse,pigmented,anddry.Epidermalthinning,lossof

hair,andsweatingcanoccur.Telangiectasiaandskin

calcinosisbecomeobvious.Skincreasesdisappear.Such

changeproximaltoelbowsorkneesinthelimbsorbelowthe

clavicles(inthosewithfaceandneckinvolvement)classifies

diseaseasdiffuseasopposedtolimitedsystemicsclerosis

SScl(late) 2–15yearsafteronsetofclassicalphase,skinsoftens,but

pigmentationchangesremain.Skinbecomesatrophicandcan

ulcerate

Eosinophilic

fasciitis

Phases:early—pittingoedema;progressive—peaud’orange;

late—induration(‘woodyfeel’)withvenousgutteringwhen

limbelevated.Armsandlegsmostcommonlyaffected,but

fingersmainlyspared.Synovitisandlow-grademyositismay

occur.Eosinophiliaisusuallystriking,butnotalwayspresent

Lipodermato-

sclerosis

Hyperpigmentationandindurationoflowerlegsassociated

withvenousstasis(‘champagne-bottlelegs’)

Diabetes Waxythickeningofextremities.Insidiousprogression.Joints

ofthehandsbecomestiff,thetendonscanthicken.Skin

changesproximaltowristandonthefaceveryunlikely,but

stiffeningofelbowandshoulderjointsnotuncommon

Dependent

lymphoedema

Feet/ankles/lowerlegs.Oftenpitting.Chronicpresencemay

givehyperkeratosis.Maincauses:R-orL-sidedheartfailure,

renalfailure,nephroticsyndrome,andlow-proteinstates

Skinvasculitisinadults

Background

Thereareavarietyofwaysinwhichsystemicvasculitismaypresent,including

fever of unknown origin, organ infarction, gastrointestinal (GI) bleeding, and

highacutephaseinagenerallyunwellpatient.Avasculiticskinrashisoneof

themostcommonpresentingfeaturesofsystemicvasculitis,andisanimportant

diagnosticclue(see Chapter15).

Whentoconsideradiagnosisofvasculitis

• Primarysystemicvasculitisisrare.

• Cutaneous vasculitis, however, is not rare; it can follow viral or bacterial

illness,canbetriggeredbydrugs,andisassociatedwithmalignancy.Biopsy

generally demonstrates degranulation of neutrophils (‘leucocytoclasis’) and

evidenceofvesseldestruction.

• Thelistofcausesislong(Table4.2);however,inabout50%ofcasesnocause

maybefound.

• Cutaneousvasculitismayalsooccurinassociationwithanotherautoimmune

disease not normally characterized by vasculitis, such as SLE, RA, and

Sjögren’ssyndrome.

Importantconsiderations

The following important points of clinical assessment should be followed in

patientswithpossiblevasculiticrashes.

• Determinewhetherthepatienthasbeentakinganewdrug.Manyantibiotics,

including penicillins, sulfonamides, and cephalosporins, cause cutaneous

vasculitis.Biologicsmaytoo,notablyanti-TNFα.

• Evaluatethepatientforevidenceofchronicinfection:hepatitisB,hepatitisC,

andHIVareworthconsidering.Endocarditisshouldalsobeconsidered(e.g.

theelderly,orpatientswhouseIVdrugs).

• Lookforevidenceofaprimaryautoimmunedisorderthatmaybeassociated

with cutaneous vasculitis. IBD, for example, can occasionally cause a

leucocytoclastic vasculitis in addition to oral ulcerations and pyoderma

gangrenosum.BecauseSLEiscommon,checkANAandserumcomplement

C3/C4.

• Lookforevidenceofcryoglobulinaemicvasculitis.Serumcryoglobulinstests

areoftenmishandled,leadingtofalse-negativeresults,primarilybecausethe

sampleneedstobekeptwarm(usuallybysimplyholdingintheclosedpalm

ofthehand)andshouldbetakenstraighttothelaboratory.

• RFisdetectedin80%ofpatientswithmixedessentialcryoglobulinaemia,and

maybeabetterscreeningtestthanthelatter.

• Age-appropriate screening for malignancy should be done. Serum and urine

electrophoresiswithimmunofixationmaybeofvalue.

• Urinalysis may demonstrate ‘active sediment’; evidence of haematuria,

proteinuria,or redbloodcell castsmay bethe firstcluethat apatient hasa

systemicvasculitis.

Systemicvasculitis

• Untreated primary systemic vasculitis is generally characterized by general

inflammation; many patients will complain of B-type symptoms, including

fevers,weightloss,andnightsweats.Patientswithcutaneousvasculitisalone,

ontheotherhand,oftenfeelquitewell.

• The extracutaneous signs and symptoms may provide clues to the correct

diagnosis:

• Henoch–Schönleinpurpura(HSP):colickyabdominalpain.

• Eosinophilic granulomatosis with polyangiitis: adult-onset asthma,

eosinophilia.

• PR3-positiveAAV:chronicsinusitis,pneumonitis.

• Microscopicpolyangiitis:haemoptysis,redbloodcellcasts.

• Mononeuritis multiplex, which presents as a ‘wrist drop’ or ‘foot drop’, is

suggestiveofsystemicvasculitisinanon-diabeticpatient.

Table4.2Precipitantsandassociationsofleucocytoclasticsmallvesselvasculitis

Drugs Sulphonamides,forexample(therearemany).Some

drugsmaycausealymphocyticvasculitiswithout

leucocytoclasis

Infections HepatitisB,hepatitisC,HIV

β-haemolyticStreptococcus

Foreignprotein E.g.serumsickness

Autoimmune

disease

Rheumatoidarthritis

Sjögren’ssyndrome(anti-Ropositive)

SLE(thoughlivedoidvasculitismayoccurinassociation

withsecondaryAPS,andthismaybelymphocytic

withoutleucocytoclasis)

Inflammatory

diseases

Sarcoid

Crohn’sdisease,ulcerativecolitis,chronicactive

hepatitis

Malignancy Myelo-andlymphoproliferativedisorders

Solidtumours

Cryoglobulinaemia

Investigations

Skinbiopsy

• Discussthecasewithahistopathologist.

• Punchbiopsyissimple,andmaybesufficienttoyieldadiagnosis.Elliptical

biopsyprovidesmoretissue,andmayincreaseyield.

• Useaneedletolifttheskinsample.Avoidforceps-induceddamage.

• Biopsy should extend to the subcutaneous fat, which generally includes the

arterioles and venules affected by primary systemic vasculitis. Idiopathic

leucocytoclastic vasculitis affects the capillaries but generally spares the

arteriolesandvenules.

• Biopsy should be sent for routine histology and for direct

immunofluorescence, which may yield important clues regarding the

underlyingcause:

• IgA:HSP.

• IgM,C3:cryoglobulinaemicvasculitis.

• IgG,IgM,IgA,C3:SLE.

• Lowimmunoreactantstaining:AAV.

• SamplesforimmunofluorescenceshouldbesnapfrozeninliquidN

ordryice

ortransported immediatelytothelaboratory.Immunofluorescence cannotbe

doneonsamplestreatedwithformalin.

• SeeTable4.3foralistoflaboratoryinvestigationstobecarriedoutinpatients

withsuspectedvasculitis.

Table4.3Laboratorytestsinpatientswithsuspectedvasculitis

Haematology FBC,ESR,lupusanticoagulant

Biochemistry Electrolytes,urea,creatinine,LFTs,ACE,CRP,serumand

urineproteinelectrophoresis

Microbiology Urinemicroscopyforredcellcasts,bloodculture,HepBand

Cserology,considerHIV,streptococcalantibodies.Also,save

10mLofclottedbloodforviralserologyandrepeatin2–3

weeksforpairedtitreanalysis

Immunology Immunoglobulins(includeIgGsubsetsifIgG4diseasebeing

considered),cryoglobulins,ANA,ENAs,RF,anti-cardiolipin

antibodies,ANCA,Complement(C3,C4,CH50/CH100,anti-

C1qantibodiesifconsideringurticarialvasculitis))

Cardiacconditions

SubclinicalcardiacinvolvementisfoundinmanyrheumaticMSKdiseases,and

itisnotuncommonforacardiacabnormalitytobediscoveredincidentally.As

our ability to treat the underlying rheumatic diseases improves, our ability to

identify and to treat the cardiac complications of these diseases becomes

increasinglyimportant.

Pericardium

• Pericardial effusion has been reportedinassociation with a large number of

rheumaticdiseases,includingSScl,Sjögren’ssyndrome,polymyositis,mixed

connectivetissuedisease(MCTD),RA,SpAs,andsystemicvasculitides.

• Inthemajorityofcases,effusionsarediscoveredincidentally,areoftensmall,

clinicallyasymptomatic,andrequirenospecifictherapy.

• Pericardial effusions can also occur in the setting of non-rheumatic illness.

Whenapatientwithaknownrheumaticdiseasepresentswithasymptomatic

effusion, it is important to consider other possible explanations, such as

infection(e.g.TB,viral),malignancy,andotherunrelatedconditions(uraemia,

hypothyroidism).

• Pericardial effusions are common in SLE and are due to immune complex

depositionintothe pericardium.Effusions canbe serous, serosanguinous,or

haemorrhagic. Analysis of the pericardial fluid generally demonstrates

evidenceofcomplement,immunecomplexes,andleucocytes,consistentwith

anactiveinflammatorystate.

• Although pericardial effusions are common with SLE, they are generally

trivial. Cardiac tamponade is found in <1% of patients with SLE.Sincethe

effusion tends to reflect the overall disease, generally treatment of the

underlying disease is adequate to resolve the effusion. Rarely, therapeutic

pericardiocentesismayberequired.

• Pericardial effusions are found in up to 30% of patients with RA, although

onlyasmallnumberofthesepatientswillpresentwithpericarditisorevidence

oftamponade.

• PericardialeffusionsaremorecommoninRF-positivepatientswithahistory

ofrheumatoidnodules.Chronicpericardialeffusionscanbecomeinfected,and

inrarecasesleadtoconstrictivepericarditis.

• Forbothgroupsofpatients,thepresenceofasymptomaticpericardialeffusion

isassociatedwithincreasedmortality.InonestudyofpatientswithSLEwho

presentedwithcardiactamponade,the5-yearsurvivalwasonly46%.

Myocardium

• Myocarditis isan uncommonfeature ofrheumatic diseases.Myocarditis can

befoundamongpatientswithactiveSLEandRA,althoughitgenerallydoes

notleadtoclinicallysignificantdysfunction.

• CardiomyopathyamongpatientswithRAandSLEismorelikelytobedueto

prematurecoronaryarterydisease,followedbythedevelopmentofischaemic

heartdisease.

• Although uncommon, the possibility of hydroxychloroquine-induced

cardiomyopathy should be considered in patients who develop congestive

heartfailureintheabsenceofcoronaryarterydisease. Thediagnosiscanbe

confirmed with myocardial biopsy, and the condition responds to drug

cessation.

• Eosinophilicgranulomatosiswithpolyangiitis(EGPA;formerlyChurg–Strauss

vasculitis) can lead to an acute eosinophilic myocarditis that can be life-

threateningifnottreatedpromptly.

• One-third of patients with AAV may have cardiac dysfunction as a

consequenceoftheunderlyingvasculitis.Themajorityofthesepatientswill

have wall motion abnormalities on echocardiography, but valvulitis and

ventricular aneurysm havealsobeenreported.The majority of these lesions

will be asymptomatic, but the 5-year survival rate for patients with cardiac

lesionsattributabletoAAVis57%.

Valvulardisease

• Aortic regurgitation is an important potential consequence of aortitis, which

can occur with any of the large-vessel vasculitides (including Takayasu

arteritis,GCA,andBehçet’sdisease).Theaortitisleadstoaneurysms,which

createvalvularincompetence.

• Aortic regurgitation can also occur as a consequence of AS. Unlike the

vasculitides, in AS there is inflammation at the aortic root leading to dense

scarringoftheaorticvalves.Althoughthemechanismisuniquetothisdisease,

itshouldbemonitoredandtreatedlikeanyformofaorticinsufficiency.

• Mitralregurgitationandmitralvalveprolapsearecommonmanifestationsof

SLE.

• MitralvalveprolapsemayalsobeafeatureofEhlers–Danlossyndrome.

• A more serious valvulitiscanoccurin association with SLE or APS. In the

processofhealing,thevalvesbecomescarredandcalcified,aprocessthatcan

eventuallyleadtoclinicallysignificantvalvulardisease.

• Libman–SacksendocarditisisaclassicmanifestationofSLE.Inthisdisease,

vegetations form from immune complexes, mononuclear cells, and fibrin,

which attach to the valves. Although not infectious, these vegetations can

embolize.

• Haemodynamically insignificant valve lesions have also been reported in

associationwithRA,MCTD,SScl,andSjögren’ssyndrome.

Coronaryarterydisease

• Surprisingly, the primary vasculitides rarely lead to coronary artery

inflammation, although coronary artery vasculitis has been reported in

associationwithPANandAAVs.

• APS is associatedwitha substantial increasedriskof myocardial infarction,

evenintheabsenceoftruecoronaryarterydisease.

• BothRAandSLEarestronglyassociatedwithcoronaryarterydisease.This

may be the result of systemic inflammation or a response to chronic

immunosuppression.Regardless,patientswiththesediagnosesshouldundergo

earlycardiacevaluationtoaddressmodifiableriskfactorsforcoronaryartery

disease.

• Accelerated atherosclerosis may be an important consequence of

glucocorticoidexposure. Evenchroniclow-doseprednisonemay placesome

patientsatincreasedriskofcardiovasculardisease.

Conductionabnormalities

• Clinically insignificant dysrhythmias and conduction defects are common

among patients with inflammatory myopathies (dermatomyositis,

polymyositis)andscleroderma.

• Clinically significant abnormalities (including heart block) can be seen in

patients with SpAs as a result of the same scaring process that leads to the

valvularabnormalitiesnotedearlier.

Pulmonaryconditions

Pleura

• An exudative pleural effusion is found in up to 50% of patients with SLE.

These effusions can be unilateral or bilateral, and frequently are found in

associationwithapericardialeffusion.

• Pleural disease is a common manifestation of RA, which is associated with

pleural effusions and pleural thickening. Effusions are generally

asymptomatic,andarefoundinthesettingofactivedisease.

• Asymptomaticpleuraleffusionscanalsobefoundin10–30%ofpatientswith

AAV.

• Pleural effusions are classified as transudates, typically arising as a

consequence of left ventricular, renal and hepatic failure, and SLE; or

exudates,usuallyduetoinfection,malignancyorpulmonaryembolism.

• Bythe‘Light’criteria(witha75–80%sensitivity)atransudateis:

• clear.

• specificgravity<1.012.

• fluidprotein<2g/dL.

• fluid:serumproteinratio<0.5.

• fluid:serumLDHratio<2/3.

• cholesterol<45g/dL.

• Inthesamecriteria,anexudateisdefinedas:

• cloudy.

• specificgravity>1.020.

• fluidprotein>2.9g/dL.

• fluid:serumproteinratio>0.5.

• fluid:serumLDHratio>2/3.

• cholesterol>45g/dL.

• Ifanexudateisidentifiedfluidshouldbeexaminedfor:

• amylase:inoesophagealrupture,pancreatitis.

• glucose:decreasedininfection,malignancyandRA.

• pH:lowinempyema.

• Gramstain.

• polymerasechainreaction(PCR)fortuberculosis.

Pulmonarynodules/masses

• BothPR3-positiveAAVandsarcoidosisareoftendiagnosedincidentally,after

the discovery of lung masses. Sarcoidosis is associated with hilar

lymphadenopathy, while PR3-positiveAAV generally presents with multiple

peripheralpulmonarynodulesthatcanbemistakenforlungcancer.

• Inapatientwithaknownrheumaticdiseasewhopresentswithalungmass,it

isalwaysimportanttoconsiderthepossibilityofmalignancy.Lungcancerrisk

isincreasedamongpatientswithRAandSScl,andmanyrheumaticdiseases

areassociatedwithanincreasedriskoflymphoma.

• PR3-positive AAV (and less commonly, AS and RA) can lead to cavitating

apicallesionsthatcanbemistakenforTB.

Interstitiallungdisease(ILD)

• ILD and pulmonary fibrosis (with a predilection for the lung bases and

periphery) is a common feature of both dcSScl and the inflammatory

myopathies.

• Pulmonary fibrosis is found in 20–65% of patients with SScl.

Radiographically, the lesions take on the appearance of ground glass ILD

infiltratesthatgraduallyleadtohoneycombingandfibrosis.

• ILD may be the initial manifestation of an inflammatory myopathy, and

pulmonarysymptomsmayprecedeclinicalevidenceofmuscleinvolvement.

• RAisalsoassociatedwithILD.

• Apicalfibrosiscanbefoundin1%ofpatientswithAS.Apicalfibrosisisalso

anuncommonfeatureofrheumatoidlung.

• Pulmonary fibrosis can also occur as the long-term sequelae of pulmonary

capillaritis,whichmayoccurinpatientswithAAV.

• ILDinprimarySjögren’ssyndromecanbesubtleandevolveinsidiously.The

usualpatternisnon-specific(NSIP).

• Bronchiolitis obliterans organizing pneumonia (BOOP) has been associated

withautoimmunerheumaticandconnectivetissuediseasesbuttheassociation

isnotfrequent.

Vasculature

• Haemoptysiscanbetheresultofpulmonarycapillaritis,whichcanbefoundin

association with the so-called pulmonary renal syndromes: SLE, AAV

(predominantly microscopic polyangiitis), and anti-glomerular basement

membrane syndrome. Acute or severe pulmonary vasculitis may require

promptplasmapheresis.

• Cryoglobulinaemicvasculitiscanalsocausepulmonarycapillaritis,although

thisisnotoneofitsmorecommonmanifestations.

• Pulmonary artery hypertension (PAH) is most commonly associated with

lcSScl. Isolated PAH can also be seen with dcSScl, although it generally

appearsasaconsequenceofpulmonaryfibrosis.

• SScl causes PAH by narrowing of the small arteries and arterioles that

graduallyleadstoobliterationofthepulmonaryvascularbed.

• RA,SLE,inflammatorymyopathy,MCTD,andSjögren’ssyndromecanalso

be associated with PAH, but it is considered an uncommon feature of these

diseases.

Airways

• RAcanleadtolaryngealobstructionwhenitaffectsthecricoarytenoidjoints.

Itusuallypresentswithhoarsenessorodynophagia.

• SubglotticstenosisisacommonfeatureofPR3-positiveAAV,whichcanlead

tosignificantstridor.

• Uncontrolled relapsing polychondritis can cause tracheomalacia, which is a

significantcauseofmorbidityforthisdisease.

• Any part of the airway can become symptomatic in primary Sjögren’s

syndrome:xerotrachea,xerostomia,sinussymptoms.

Renalconditions

Evaluationofrenalfailure:overview

Thekidneysareanessentialcomponentintheevaluationandmanagementofthe

rheumaticMSKdiseases.

• Intermsoftimecourse,renalfailuremaybesecondarytoacutekidneyinjury

(AKI)orchronickidneydisease(CKD).AKIcanoccurinpatientswithstable

CKD.

• AKI(grade1)isdefinedwhenoneofthefollowingcriteriaismet:

• Serumcreatininerisesby≥26µmol/Lwithin48hours.

• Serumcreatininerises≥1.5×fromthereferencevalue,which isknownor

presumedtohaveoccurredwithin1week.

• Urineoutputis<0.5mL/kg/hourfor>6consecutivehours.

• Theabove-listedindicesaretheminimumrequiredfordefinition(grade2and

3 AKI have definitions: http://www.renal.org/guidelines/modules/acute-

kidney-injury).

• UrgenturinalysisandrenalultrasoundshouldbeobtainedinallAKIpatients.

• Glomerularfiltrationratevalue(mL/min/1.73m

)classifiesrenal functionas

WHOstage:normal(grade1;>90),mild(grade2;60–89),moderate(grade3;

30–59),severe(grade4;15–29),severefailure(grade5;<15).

• The presenceofred bloodcells andprotein,or redbloodcell casts(i.e. ‘an

activesediment’)impliesglomerulonephritis,whichcanoccurwithvasculitis

andSLE.

Pre-renalazotaemia

• Hypovolaemia is an important cause of pre-renal AKI. Dehydration and

anaemiacanbothleadtopre-renalazotaemia(e.g.theelderlyRApatient).

• Renal hypoperfusion can also be caused by diminished blood flow to the

kidneys.Diseases involvingtherenalartery(such asrenalarterystenosisor

thrombosisorPANaffectingtherenalartery)maycausepre-renalazotaemia.

ThismaybeacuteleadingtoAKIorslowlyevolvingcausingCKD.

• Conditions associated with low cardiac output (including shock, congestive

heart failure, myocarditis, tamponade, and pulmonary arterial hypertension)

mayallpredisposethepatienttopre-renalAKI.

• Hyperviscosity,whichisseenwithtypeI(monoclonal)cryoglobulinaemia,is

averyrarecauseofpre-renalazotaemia.

• All of these conditions may be exacerbated by drugs that decrease renal

perfusion,includingNSAIDsandACEinhibitors.

• Withpre-renalazotaemia,thefractionalexcretionofsodium[FENa=(UNa×

PCr)/(PNa × UCr)] is <1.0; this test is not reliable in patients treated with

diuretics.

Post-renalazotaemia

• Nephrolithiasisisnotacommoncauseofpost-renalazotaemia,butshouldbe

consideredinapatientwithgout:5–10%ofrenalcalculiintheUnitedStates

arecausedbyuricacid;thisisparticularlycommonamongpatientswithgout

whohavebeentreatedwithuricosuricagents(e.g.probenecid).

• Sarcoidosis can cause hypercalcaemia and hypercalciuria, which in turn can

lead to nephrolithiasis and nephrocalcinosis, both of which can rarely cause

post-renalazotaemia.

• Methotrexate and trimethoprim/sulfamethoxazole can cause crystalluria and

renalobstruction.

• Ultrasoundisausefulmodalitytoevaluatebothforthepresenceofobstruction

leadingtohydronephrosisandrenalcalculi.

Intrinsicrenalfailure:‘activesediment’

• Intrinsicrenaldiseasefromarheumatologicalconditionscanpresentacutely

(AKI)orinsidiouslyasevolvingCKD.

• The nephritic syndromes are an important cause of moderate/severe AKI

amongpatientswithrheumaticdiseases,particularlyvasculitisandSLE.

• The presence of haematuria, proteinuria, and red blood cell casts strongly

suggeststhepresenceofglomerulonephritis.

• A renal biopsy is crucial to determining the underlying diagnosis and the

severity/chronicityofthedisease.

• Nephritic syndromes can be divided into ‘focal proliferative’ and ‘diffuse

proliferative’basedonhistology.

• CausesoffocalproliferativeglomerulonephritisincludeSLE,HSP,andother

formsofsmallvesselvasculitis.

• Diffuseproliferativeglomerulonephritisiscausedbycryoglobulinaemia,SLE,

anti-glomerular basement membrane disease (Goodpasture’s syndrome), and

small-vesselvasculitis(includingAAVandrenal-limitedvasculitis).

• Direct immunofluorescence can also provide valuable information regarding

the correct diagnosis: SLE biopsy demonstrates multiple immunoreactants

(‘fullhouse’stainingpattern);IgAdepositionimpliesHSP;cryoglobulinaemic

vasculitisleadstoIgG andC3deposition; sparseorabsentimmunoreactants

onbiopsyissometimescalled‘pauci-immune’,andimpliesanAAV.

Intrinsicrenalfailure:‘blandsediment’

• Ablandsedimentreferstoaurinesamplethatisacellular;transparenthyaline

castsmaybeseen.

• Ablandsedimentisalsoseeninpre-renalandpost-renalazotaemia.

• Acutetubularnecrosis(ATN)reflectsacute,intrinsicrenalfailureassociated

withaurinesedimentthathasmuddybrowncastsandtubularepithelialcells.

• NephrotoxictubularinjuryfromdrugsisacommoncauseofATNinpatients

withrheumaticdisease.

• Prolonged pre-renal azotaemia can lead to permanent kidney damage;

therefore,diseasesoftherenalartery(includingpolyarteritisnodosaandrenal

arterythrombosisfromAPS)shouldbeconsidered.

• Interstitial nephritis is most commonly seen as a drug reaction (e.g. gold,

penicillamine).

• Interstitialnephritiscanalsobeseenasamanifestationofseveralrheumatic

diseases,includingSjögren’s,SLE,sarcoidosis,andEGPA.

• NSAIDscauserenalvasoconstrictionandinterstitialnephritis,bothofwhich

caneventuallyleadtoachronicanalgesicnephropathy.

• UnliketheotherformsofAAV,themechanismofrenalfailureamongpatients

withtheEGPAisaninterstitialnephritis;glomerulonephritisisrelativelyrare

withthisdiagnosis.

• The most common causes of secondary renal amyloidosis are AS, RA and

FMF. Glomerular deposits of amyloid lead to proteinuria (which can be

nephroticrange)andprogressiverenalfailure.

SSclrenalcrisis

• SScl renal crisis is a rheumatologic emergency characterized by AKI and

malignanthypertension(see Chapter25,p.720).

• PatientswithdcSSclareatgreatestrisk.

• SSclrenalcrisisgenerallyoccurswithinthefirst4yearsafterdiagnosis,butit

canoccuratanytime.Patientswhoaretreatedwithhigh-doseglucocorticoids

andareanti-RNPpositiveareathighestrisk.

• Urinalysis generally demonstrates a bland sediment. Kidney biopsy

demonstrates evidence of a thrombotic microangiopathy that histologically

cannot be distinguished from malignant hypertensive nephrosclerosis,

haemolytic–uraemicsyndrome,SLE,orAPS.

• ThecornerstoneoftherapyisescalatingdosesofACEinhibitors,followedby

angiotensin II receptor blockers (ARBs) and calcium channel blockers if

adequatebloodpressurecontrolisnotachieved.

Renaltubularacidosis

• Renaltubularacidosis(RTA)isanon-aniongapmetabolicacidosiscausedby

afailureoftherenaltubulestomaintainacid–basestatus.

• Type I RTA, caused by an inability to excrete acid, is found with Sjögren’s

syndromeandSLE.

• Type IV RTA is most commonly caused by hyporeninaemic

hypoaldosteronism, can occur as a result of treatment with NSAIDs, ACE-

inhibitors,andARBs.Thisiscommonlyassociatedwithhyperkalaemia.

Endocrineconditions

Well-characterized MSK conditions occur in many endocrine disorders. Some

arespecificforcertaindisorders;othersarenon-specific,butoccurwithgreater

frequencyamongpatientswithendocrinedisease.MSKfeaturesoccureitheras

a result of metabolic disturbances or are influenced by a common link in

autoimmunepathophysiology.

Diabetes

• Dupuytren’s contracture, trigger finger, carpal tunnel syndrome, diffuse

idiopathicskeletalhyperostosis(DISH),andadhesivecapsulitisalloccurwith

greaterfrequencyamongpatientswithdiabetes.

• Someformoftissueorjointhypomobility/stiffnessiscommonamongpatients

with diabetes (Table 4.4); in some cases, this can appear similar to

scleroderma.Thesescleroderma-likeskinchangesaremoreprevalentamong

patientswithtypeIdiabetes.

• Handweaknessmaybeduetodiabeticneuropathyandmaybemistakenfor

carpal tunnel syndrome. Neurophysiology tests help discriminate between

thesetwodiagnoses.

• Calcificationofsofttissuesaroundtheshoulderoccursinapproximately20%

ofdiabetics,andisassociatedwithvariablesymptomsanddisability.

• Diabetic amyotrophyisuncommon. Itpresentsacutely with pain,weakness,

and wasting of the proximal lower limb muscles. It may be unilateral.

Differential diagnosis includes myositis (see  Chapter 14) and PMR. It is

associatedwithuncontrolledhyperglycaemia.Theaetiologyisunknown,butit

isprobablyaneuromyopathy.

• Though rare (1:500 diabetics), neuropathic arthritis can occur in advanced

disease.Mostpatientsareaged40–60yearsandhavepoorglycaemiccontrol.

Tarsal and metatarsal joints are most frequently affected (60%). The usual

presentationisofswellingofthefootwithnoorlittlepain.Traumamayhave

occurred.EarlyradiographicchangescanresembleOA.

• Asymptomatic osteolysis can occur at the distal metatarsals and proximal

phalangeswithrelativejointsparing:aetiologyunknown.

• Osteomyelitisisnotuncommonandneedstobediscriminatedfromcellulitis

andneuropathicarthritis(Charcot’sjoint).Atriple-phasebonescanshouldbe

helpful. Osteomyelitis is usually disclosed by prominent blood flow in the

dynamic(first)phaseandincreaseduptakeoftracerbysofttissueandbonein

laterstages.Cellulitisisassociatedwithminimaluptakeoftracerin bonein

the delayed (third) phase. Neuropathic joints display minimal first-phase

abnormalitiesbutprominenttraceruptakeinthethirdphase.

• Diabeticmuscleinfarctioncanpresentasapainfulmusclemassandisaresult

of arterial narrowing. Often mistaken for thrombophlebitis, myositis or

vasculitis, this is a late complication of diabetes. Biopsy may be needed to

confirmthisdiagnosis.

• Diabetes may be associated with a ‘metabolic syndrome’ (diabetes +

hypertension,hyperuricaemia,obesity).

Table 4.4 Patterns of joint and tissue hypomobility/stiffness in diabetes by reported series. Tissue

changes are thought to occur from changes in hydration properties/kinetics of glycosaminoglycans

(consequenceofanexcesslocalproductionofsugaralcohols)

Patientseries Majorabnormalities Associations

Diabetics

overall

Inabout30–40%mainlyinlong-

standingdisease:slowdecreaseinhand

mobility;waxyskinthickening

(‘scleroderma-like’)

Occasionallung

fibrosis.

Microvascular

diabetic

complications

Adults 55–76%prevalenceofjoint

hypomobilityintype1/type2diabetes,

respectively

Notassociated

withdiabetic

complications

Mature-onset

diabetes(mean

61years)

Stiffeningofconnectivetissue(assessed

inhands)

Diabetic

nephropathy

Childrenwith

type1diabetes

31%havelimitedjointmobility Nonewith

glycaemic

control,

retinopathy,or

proteinuria

Juvenileand

youngadult

onset(age1–24

years)diabetes

34%hadskinthickening.Changesrarely

proximaltoMCPsandneverproximalto

wrists.Jointcontracturesin>50%,often

thirdorfourthfingers

Noflexortendon

rubs(asseenin

scleroderma)

Hypothyroidism

• Over 25% of patients with hypothyroidism have an arthropathy—cross-

sectional data. The likeliest explanation is coincidental arthritis disease:

generalized OA, CPPD-related (see next bullet point) or an autoimmune

arthritis (e.g. RA). Whether a specific arthritis occurs directly as a result of

thyroidabnormality,isdebatable.

• Radiographically-defined chondrocalcinosis is only marginally increased

comparedwithcontrols(17%vs10%).About1/10patientswithacuteCPPD

arehypothyroid.

• ThyroiddiseasemayalsobeautoimmuneandtheserumANApositive,again

oftenmistakenforassumingthepresenceofaprimaryrheumaticcondition.

• Carpaltunnelsyndromeiscommon(7%).Upto10%ofpatientswithcarpal

tunnelsyndromemayhavehypothyroidism.

• Hyperuricaemiaiscommon,butgoutattacksarerare.However,screeningfor

hypothyroidism in patients with gout is recommended. Treated

hypothyroidism then requires review of the need for uric acid-lowering

therapy.

• Myopathy isrelativelycommon. About1in 20 casesof acquired myopathy

are due to hypothyroidism. The presentation can mimic polymyositis with

elevation of muscle enzymes, but muscle biopsy typically shows no

inflammatory cell infiltrate. Improvement with thyroxine replacement is

sometimescomplicatedbymusclecramps,buttheseshouldresolveinafew

weeks.

• Thecombinationof weakness,muscularstiffness,andan increaseinmuscle

mass in an adult with myxoedema is termed Hoffman’s syndrome. Muscle

massincreaseissometimesstrikingandcantakemanymonthstoresolveon

treatment.

• Lymphocytic thyroiditis (Hashimoto’s) is an autoimmune condition

characterized by hypothyroidism and autoantibodies to thyroglobulin and

thyroid microsomes. These antibodies are found in 40% of patients with

primary Sjögren’s syndrome, but only about 10% are or have been overtly

hypothyroid.

Thyrotoxicosis

• Hyperthyroidismcancauseaproximalmyopathy(70%),shoulderperiarthritis

(7%),acropachy(thickeningofextremities),andosteoporosis.

• Graves’diseaseisfrequentlyassociatedwithfatigueandmuscularweakness.

Itisassociatedwithautoimmunerheumaticandconnectivetissuediseases.

Thyroidacropachy

This is rare (<2% of patients with thyrotoxicosis) and most often occurs in

treatedpatientswhoarehypo/euthyroid.

• Thereisclubbing,andpainfulsofttissueswellingofhandsandfeet.

• Periosteal new bone occurs on the radial aspect of the second and third

metacarpals.

• Acropachyoccursmostfrequentlyinpatientswhohavetheophthalmopathyor

dermopathyassociatedwithautoimmunethyroiddisease.

Hyperparathyroidism

See Chapter16.

Thefollowingpointsrefertobothprimaryandsecondarydisease:

• MSK symptoms are the initial manifestation in up to 16% of patients with

primaryhyperparathyroidism.

• Hyperparathyroidism,chondrocalcinosis,andCPPDfrequentlycoexist.Acute

CPPDcanbetriggeredbyparathyroidectomy.

• ChronicCPPDarthropathycanmimicRA.UnlikeRA,synovialproliferation

isabsent.Radiographically,erosionshaveapredilectionforthecarpus,mid-

feetandsecond/thirdMCPJs.Pericapsularcalcificationisoftenpresent.

• An erosive polyarthritis favouring the large joints can occur with renal

osteodystrophyinpatientswithchronicrenalfailureondialysis.Itmayrelate

to a number of different, or combination of, crystal induced inflammatory-

basedmechanisms(hydroxyapatite,basiccalciumphosphate,pyrophosphate,

urate).

• Hyperparathyroidism is associated with a specific shoulder arthropathy

characterizedbyintra/periarticularerosionsofthehumeralhead.Thismaybe

sub-clinical.

• Subjective muscle weakness and fatigability are common complaints.

Typically,muscleenzymesarenormalandbiopsyshowstypeIIfibreatrophy;

thefeaturesofaninflammatorymyopathyaregenerallyabsent.

• The hallmark of radiographic changes is bone resorption: sub-periosteal

(typically on the radial side of second and third phalanges), intracortical,

subchondral, trabecular, sub-ligamentous, and localized (Brown’s tumours)

resorptionpatternsareseen.Bonesclerosis,periostitis,andchondrocalcinosis

alsooccur.

• Fragility fracture is common and often precedes a diagnosis of primary

hyperparathyroidism. Although significant and fast accretion of bone occurs

aftersurgery,bonemassoftenremainslowlongterm.

Acromegaly

• Over-stimulation of bone and connective tissue cells from excessive growth

hormone can result in several features: bursal and cartilage hyperplasia,

synovial and bony proliferation, an OA-like picture, backache, and

hypermobility.

• Joint complaints usually manifest about 10 years after the onset of clinical

acromegaly.Kneesarefrequentlyaffected.

• Jointsymptomsarenottypicalofaninflammatoryarthritis.Morningstiffness

isnotprominentandjointswellingispresentin<50%.

• Carpaltunnelsyndromeaffects>50%andisfrequentlybilateral.

• Backandneckpainandradicularsymptomsfromnerverootcompressionor

spinalstenosisarenotuncommonandarerelatedtoaxialbonyproliferation.

• Apainlessproximalmyopathyoccursinfrequently.

• Radiographs characteristically show widened joint spaces (e.g. >2.5 mm in

adult MCPJs) and a thickened heel pad (>23 mm in men and >21.5 mm in

women).

• Diagnosis relies on demonstration of a failure of growth hormone to be

suppressedbyaglucosetolerancetest,butalateralskullradiographisagood

screeningtestas90%haveenlargementofthepituitaryfossa.

Gutandhepatobiliaryconditions

MSK features frequently occur in patients with gut or hepatobiliary disease

(Table4.5).

• Dataonthefrequencyofrheumatologicalfeaturesarelargelybasedonstudies

ofhospitalpatientswithclinicallyovertgutorbiliarydisease—leadingtoan

underestimateofthefrequencyofassociation.

• Well-establishedassociationsinclude:

• toxiceffectsofmedications(e.g.NSAIDs;see Chapter3).

• irritablebowelsyndromeandfibromyalgia.

• functionalGImotilitydisorders(e.g.SScl,EDS).

• sacroiliitis,arthritis,andenthesitisinpatientswithSpAandIBD.

• degenerativearthritisinhaemochromatosisandWilson’sdisease.

• The frequency of enthesitis in patients with IBD may be underestimated.

Enthesitismaybedetectedatthemedial/lateralhumeralepicondyles,Achilles’

tendon insertion, calcaneal plantar fascia origin and insertion, greater

trochanters, and the patellar tendon origin and its insertion at the tibial

tubercle.

• Radiology studies in patients with IBD suggest that sacroiliitis is under-

recognizedbyclinicians.

Severityofrheumatologicmanifestations

• Optimal surveillancestrategiesfor the MSKmanifestationsof gut or biliary

diseasearenotknowninmanyinstances.

• Faecalcalprotectinisasensitivemeasure forIBDscreeninginpatientswith

SpA,butmodestelevationscanoccurinanumberofscenarios.

• Life-threateningvasculitismayoccurfromchronicviralinfection.HepatitisB

is associated with polyarteritis nodosa, and hepatitis C may lead to

cryoglobulinaemicvasculitis.

• In mostpatients whodevelopjoint inflammationor enthesitisafterbacterial

dysentery,theconditionisself-limiting.Chronicityandseveritymaybelinked

toHLA-B27.Progressivespondylitisisrare.

Gutandhepatobiliaryconditionsinpatientswithrheumaticdiseases

(Tables4.6and4.7;alsosee Chapter15,‘Vasculitis’)

• Themostcommon problemamongpatientswithRAisdyspepsiaassociated

withgastroduodenalerosionsorulcersduetoNSAIDs.Pepticlesionsmaybe

clinicallysilentandmaypresentwithdroppinghaemoglobinlevelsoranacute

bleed.

• RAmaybethemostcommoncauseofAAamyloidosis.Biopsiesoftheupper

GI tract will demonstrate amyloid deposits in 13% of patients. There are

numerous GI manifestations of amyloidosis, including GI haemorrhage,

malabsorption,obstruction,andhepatosplenomegaly.

• InSLE,seriousgutandhepatobiliarymanifestationsarerelativelyuncommon

(5%),butnausea,anorexia,vomiting,anddiarrhoeaarequitefrequent.

• SSclhasnumerousGImanifestationsincludingrefractorygastro-oesophageal

reflux disease, gastric antral vascular ectasia (‘watermelon stomach’),

oesophagealdysmotility,bacterialover-growth,andfaecalincontinence.

• TherefluxassociatedwithSScloftenrequirestreatmentwithhigh-doseproton

pumpinhibitors.

• ‘Watermelonstomach’canleadtosignificantacuteandchronichaemorrhage.

• In SScl, bloating and abdominal distension caused by bacterial overgrowth

mayrespondtocycliccoursesofantibiotics.

• Mesentericvasculitisisclassicallycausedbypolyarteritisnodosa,butcanbe

seenwithavarietyofrheumaticillnesses,includingTakayasuarteritis,AAV,

and (rarely) with SLE. Although mesenteric angina is the symptom most

strongly associated with mesenteric vasculitis, the earliest sign of intestinal

ischaemiaisdiarrhoea.

• HSP is an IgA-mediated small vessel vasculitis that presents with colicky

abdominal pain and purpura (adults and children). Although generally mild

and self-limited in children, it can occasionally cause intussusception and

bowelnecrosis.

Table4.5Associationsbetweengastrointestinal(GI)andrheumaticdisorders

GIdisorder> Rheumatic

disorder

Association

Entericinfection Reactivearthritis:

self-limitinginmost

Arthritisin2%whogetShigella,

Salmonella,Yersinia,

Campylobacter,Clostridium

difficileoverallbutin20%of

infectedwhoareHLA-B27+

Crohn’sdisease Arthritis20%.AS

10%.Sacroiliitisin

26%

60%ofspondyloarthritispatients

havehistologicalevidenceof

bowelinflammation.Seealso

belowintable

Ulcerativecolitis Arthritis20%.AS

7%.Sacroiliitis

15%

Seealsoaboveintable.Severity

ofgutandjointinflammation

variesinitsassociationbutSI

joint/pineinflammationdoesnot

Whipple’sdisease Migratoryarthritis

in>60%

Tropherymawhippleiidentifiedin

smallbowel.Diarrhoeaoccursin

>75%ultimately

Intestinalbypass

surgery(blindloop

Polyarticular

symptoms50%in

Intestinalbacterialovergrowthin

smallbowel?Associatedwith

syndrome) scleroderma jointsymptoms

Coeliacdisease Arthritisisrare ?Increasedintestinalpermeability

Viralenteritis Rare(<0.5%) Mostcommon:Coxsackieorecho

HepatitisA Arthralgia15%.

Vasculitisrare

Causalassociation

HepatitisB Arthralgia10–25%.

PAN

Aetiological

HepatitisC Sialadenitisin

>50%.Vasculitis

(cryoglobulinaemic)

?AetiologicalinSjögren’s

syndrome.HepatitisCidentified

in27–96%ofpatientswith

cryoglobulinaemia

Primarybiliary

cirrhosis

Polyarthritis19%.

Scleroderma18%.

Sjögren’s50%

Autoimmune‘overlap’.Features

maybesubclinical

Chronicactive

hepatitis

Polyarthralgiaor

arthritisin25–50%

Autoimmunity

Haemochromatosis OA50% Ironstoragedisease

Wilson’sdisease OAin50%adults.

Chondrocalcinosis

Copperstoragedisease

Table4.6GutandhepatobiliarymanifestationsofrheumatologicaldiseasesI:general

Disease Abnormalities Presentationwith

Rheumatoidarthritis(see

Chapter5)

TMJarthritis.

Oesophageal

dysmotility

Impaired

mastication

Dysphagia,reflux

GIvasculitis(0.1%) Ulcers,pain,

infarction

Portalhypertension Splenomegaly

(Felty’s)

Liverinvolvement

(Felty’s)

Enzyme

abnormalities

Hepatosplenomegaly Palpableviscera

Systemiclupus(see Chapter

10)

Oesophageal

dysmotility

Dysphagia,reflux

GIvasculitis Ulcers,pain,

perforation

Protein-losing

enteropathy

Hypoalbuminaemia

Peritonitis Ascites(10%),

serositis

Hepatosplenomegaly

(30%)

Palpableviscera

Scleroderma(see Chapter13) Oesophageal

dysmotility

Heartburn/dysphagia

Delayedgastric

emptying

Aggravatedreflux

Intestinal

dysmotilityand

fibrosis(80%)

Malabsorption,

pseudo-obstruction

(<1%)

Pseudo-andwide-

mouthdiverticula

Haemorrhage,stasis,

bacterialovergrowth

Polymyositisand

dermatomyositis(see Chapter

14)

Muscleweakness Aspiration,

dysphagia

Disorderedmotility Dysphagia,

constipation

Vasculitis(rare) Ulcers,perforation

MCTD Hypomobility Dysphagia,reflux,

pseudo-obstruction

Sjögren’ssyndrome(see

Chapter12)

Membrane

desiccation

Xerostomia,

dysphagia

Oesophagealwebs

(10%)

Dysphagia(>60%)

Gastric

infiltrates/atrophy

Masses,dyspepsia

Pancreatitis Pain,amylasaemia

Hepaticdysfunction Hepatomegaly

(~25%)

Hepaticcirrhosis Primarybiliary

cirrhosis

Spondyloarthritis(see

Chapter8)

Ileocolonic

inflammation

Maybe

asymptomatic

Adult-onsetStill’sdisease Hepatitis,peritonitis,

hepatosplenomegaly

Painorabnormal

enzymes(~75%)

SystemicJIA

(see Chapter9)

Serositis Abdominalpain

Hepatomegaly Abnormalenzymes

Marfansyndrome,joint

hypermobilitysyndrome,

Ehlers–Danlossyndrome(see

Chapter19)

Defectivecollagen Hypomotility,

malabsorption,

visceral

rupture/laxity

Functional GI

disorders

Table4.7GutandhepatobiliarymanifestationsofrheumaticdiseasesII:vasculitis.Seealso Chapter

Disease FrequencyofGIvasculitisandfeatures

Polyarteritis

nodosa

80%(mesenteric).Buccalulcers,cholecystitis(15%),

bowelinfarction,perforation,appendicitis,pancreatitis,

strictures,chronicwastingsyndrome

Henoch–

Schönleinpurpura

44–68%.Abdominalpain,melena,haematemesis,

ulcers,intussusception,cholecystitis,infarction,

perforation,appendicitis

EGPA ~40%.Haemorrhage,ulceration,infarction,perforation

Behçet’sdisease Buccalandintestinalulcers,haemorrhage,perforation,

pyloricstenosis,rectalulcers

Systemiclupus

erythematosus

2%.Buccalulcers,ileocolitis,gastritis,ulceration,

perforation,intussusception,volvulus(1%),pneumatosis

Kawasakidisease Abdominalpain,intestinalobstruction,non-infective

diarrhoea

AAV <5%.Cholecystitis,appendicitis,ileocolitis,infarction

Juvenile

dermatomyositis

Wellrecognized.Perforation,pneumatosis

MCTD Rare.Ulceration,perforation,pancreatitis

RAandJIA 0.1%.Buccalulcers,abdominalpain,pepticulcers,

acalculus-cholecystitis,gutinfarction,andperforation

Polymyositisand

dermatomyositis

Veryrare.Mucosalulcers,perforation,andpneumatosis

Cryoglobulinaemia Rare.Ischaemiaandinfarction

Gutandhepatobiliarysideeffectsfromdrugsusedintreatingrheumatic

andbonediseases

(Seealso Chapter23.)

Themainrheumatologydrugscausingsideeffectsare:

• NSAIDs—whichareacommoncauseofGIdistress.COX-2inhibitorswere

developed to decrease the risk of peptic ulcer disease; most have been

withdrawn from the market due to concerns regarding increased risk of

cardiovascular events and those remaining may be no more effective than

takingaconventionalNSAIDwithaprotonpumpinhibitor.

• Glucocorticoidsmaycausegastritis,pepticulcerdisease,andGIhaemorrhage.

Althoughtheabsoluteincreaseineventsissmall,thecombinationofsteroids

andNSAIDsresultsinasynergisticincreaseintheriskofGIsequelae.

• Methotrexate (MTX) may cause stomatitis, which may respond to

supplemental folate. Nausea, emesis, and dysgeusia may respond to dose

reduction. MTX can cause a transaminitis; it is therefore recommended that

patientsminimizealcoholintake.

• Sulfasalazinegutandhepatobiliarysideeffectsarecommonandmayoccurin

up to 20% of patients. The most frequent are mild: indigestion, nausea,

vomiting,anorexia,andabdominalpain.Gutulceration,bloodydiarrhoeaand

seriousliverproblems arerare;in 65%ofpatients, sideeffects occurin the

first3monthsoftreatment.

• Azathioprine(AZA)cancausenausea(15%),vomiting(10%),andabdominal

pain(8%).Diarrhoeaisrare(5%).Liverenzymeabnormalitiesareoftenmild

andmayremitonloweringthedose.TheGIsideeffectscanoccurinpatients

withnormallevelsofthiopurinemethyltransferase.

• Penicillaminecausesalteredtaste(25%withinthefirst3–6months),nauseaor

vomiting (18%), and stomatitis/mouth ulcers (5%). Hepatotoxicity and

haemorrhagiccolitisarerare.

• Chloroquine and hydroxychloroquine, can cause non-specific GI intolerance

(10%).Theonsetisofteninsidious.

• Ciclosporin causes gingival hyperplasia, nausea, diarrhoea, and elevation in

hepaticenzymes.

• Effects of cyclophosphamide on the gut are frequent: nausea, vomiting,

diarrhoea,andstomatitis.Serioushepatotoxicityisrare.

• Leflunomidecancausenausea(8–13%),diarrhoea(upto25%),andabnormal

liverenzymes.Instudies,mostrisesintransaminaseshavebeenmild(<2-fold)

andarereversibleondrugwithdrawal.

• Oralbisphosphonates(suchasalendronicacidandrisedronate)andstrontium

ranelate cancausenausea, dyspepsia, and diarrhoea.Oesophagealulceration

has occasionally been noted with alendronate, although it is thought this

occurs only in people who do not follow the instructions for taking them.

Myalgiasandarthralgiascanalsooccurwithbisphosphonates.

• Calcitonin either given as subcutaneous injection or as nasal spray cangive

abdominalpainsanddiarrhoea.

Malignancy

Rheumatic MSK features may be clues to the existence of cancer. Symptoms

may arise directly from neoplastic tissue invasion or indirectly as a

paraneoplasticphenomenon.

Primaryandsecondaryneoplasticdiseasesofboneandjoints

• Synovialtumoursarerare.Sarcoma(synovioma)ismorecommoninmenthan

womenandunusualinthose>60years.Itusuallyoccursinthelegs(70%)and

can occur around tendon sheaths and bursa. At diagnosis, pulmonary

metastasesarecommon.

• Para-articular involvement by bone tumours may give a monoarticular

effusion.Invasionofsynoviummayoccurandmalignantcellscanbedetected

injointfluid.Breast,bronchogeniccarcinoma,GItumours,andmelanomacan

allmetastasizetojoints.

• Lymphomas and leukaemias may simulate various conditions especially in

childrenandcausesynovitisinasingleorinmultiplejoints.

• Arthritiscomplicatingthepresentation ofmyeloma oran acuteleukaemiais

mostlikelytobepolyarticularandasymmetric.

• Inadults,arthritiscomplicatingleukaemiaisrare(5%ofcases).

• Leukaemia is the most common cause of neoplastic skeletal symptoms in

childhoodandadolescence(15%ofleukaemiacases).

• Neuroblastomasarethemostfrequentcauseofasolidtumourmetastasizingto

theskeletoninchildren.

CluesthatmayleadtoasuspicionofmalignancydirectlycausingMSK

symptoms

• Constitutionalsymptomswithoutevidenceforvasculitis.

• Thecoexistenceofbonepainfrommetastases(see Plate16).Also,consider

metabolicbonediseases,sarcoid,SAPHOsyndrome,andtheSpAconditions.

• Haemorrhagic joint fluid (also consider trauma, PVNS,

chondrocalcinosis/pseudogout).

• Radiographsthatshowadjacentbonedestruction,perhapswithlossofcortex

(alsoconsiderinfection).

• Radiographiccalcificationinsofttissuemass(considersynovioma).

Paraneoplasticidiopathicinflammatorymyopathy(IIM)

• IIMsmaybeduetocarcinomatousneuromyopathy.

• Polymyositis, dermatomyositis, Eaton–Lambert myasthenic syndrome

(ELMS), and hypophosphataemic (oncogenic) osteomalacia are all found in

associationwithmalignancy(Table4.8).

• Carcinomatous neuromyopathy is characterized by symmetric muscle

weaknessandwastingandcanpre-datethemalignancy.

Table4.8Myopathyandlinkswithmalignancy

Condition Typical

patternof

weakness

Commoncancer

associations

Otherfeatures

Carcinomatous

neuromyopathy

Pelvicgirdle

—symmetric

Lung:15%men,

12%women.

Ovary:16%.

Stomach:7%men,

Wasting,EMG

abnormality,and

increaseinmuscle

enzymesarenot

13%women invariable

Dermatomyositis

(+?PM)

Proximal

limb.Truncal

Reflectsunderlying

cancerfrequencyin

localpopulation

Responsetosteroids

isusual

Myasthenia

gravis(MG)

Frequently

ocularand

bulbar

muscles

involved

Thymus.Any Musclestrength

fluctuates

(fatiguability).

Respondstoanti-

cholinesterases

Eaton–Lambert

myasthenic

syndrome

(ELMS)

Pelvicgirdle

muscles.

Alteredgait.

Ocular

musclesnot

affected

Smallcelllung.Can

occurupto2–3

yearsafterELMS

Autonomic

disturbances.EMG

+poorresponseto

anticholinesterase

distinguishfrom

Oncogenic

osteomalacia

Generalized.

Develops

insidiously

Small,discrete

mesenchymal

tumoursinbone,soft

tissues,andsinuses.

Neurofibromatosis

Bonepainand

osteomalacia.High

FGF23,

hypophosphataemia

andlow1,25(OH)

vit-D

Non-myopathyparaneoplasticsyndromes

• Thenon-myopathicparaneoplasticsyndromesarerare.

• Hypertrophic pulmonary osteoarthropathy consists of clubbing, periostitis of

diaphysisoflongbones,andanarthropathy(variesfromarthralgiastodiffuse

polyarthritis). Suspicion of HPOA should be investigated with bone

scintigraphy,whichtypicallyshowsincreasedradionuclideuptakeinaffected

bones.Radiographsoftenshowperiostealelevation.

• HPOA complicates 20% of primary lung tumours, but it is associated with

othermalignancies.

• Polyarthritis may be the presenting feature of cancer. Most cases occur >60

years old. The arthritis associated with malignancy tends to be asymmetric,

anddoesnotcauseerosions.

• Eosinophilic fasciitis, severe bilateral palmar fasciitis (often mistaken for

scleroderma), and fasciitis associated with panniculitis have been associated

withmalignancy.

• Casesof‘shoulder–hand’syndrome(aformofosteodystrophy;see Chapter

22)havebeenreportedinassociationwithmalignancy.

Rheumatologicaldiseasesassociatedwithanincreasedincidenceof

malignancy

AnumberofrheumaticMSKdiseasesareassociatedwithanincreasedincidence

ofmalignancycomparedwithhealthypopulations.

• Non-Hodgkin’slymphomaismoststronglyassociatedwithRA.Myelomaand

paraproteinaemiaarealsofoundinRApatients.

• TherelativeriskofcoloncanceramongRApatientsis0.77;thismaybedueto

theuseofchronicNSAIDsinthispatientpopulation,whichmaybeprotective.

• Non-Hodgkin’s lymphoma develops in a subset of patients with Sjögren’s

syndrome(4%).Itsonsetmaybeindicatedbyrapidenlargementofsalivary

glands, the appearance of a paraprotein, or decrease in circulating

immunoglobulinsorRFtitre.

• SSclhasbeenassociatedwithanincreasedriskofbothlungcancerandnon-

Hodgkin’slymphoma.

• Dermatomyositisisprobablyassociatedwithmalignancyinadults,thoughas

convincing evidence for an association of polymyositis with malignancy is

lacking.Gonadaltumoursarerelativelycommonamongsuchpatients.

• Eosinophilicfasciitismaybeassociatedwithmalignancy.

Rheumatologicaldrugsandmalignancy

(Seealso Chapter23.)

• Chronicazathioprineuseisassociatedwithanincreasedriskofskincancerso

patients taking azathioprine long term should be counselled regarding sun

protectionandmonitoringforskincancer.

• Use of cyclophosphamide is associated withanincreasedriskof lymphoma

andbladdercancer.

• Anti-TNFαdrugtherapyistheoreticallyassociatedwithariskofmalignancy.

However,patientdiseaseregistrieshavenotidentifiedanexcessincidencein

patientstreatedlong-termwiththetherapy.

• If malignancy develops while a patient is taking anti-TNFα then usually its

correcttostopthetherapy.

• Thereisincompletedataonwhetherstartinganti-TNFαincreasestheriskof

relapse of malignancy in patients previously treated successfully for their

cancer.

• Though very high dose per weight teriparatide is associated with sarcoma

developmentinrats,thereisnoevidence,atdosesusedinhumans,thatthere

isanincreasedrisk.

• Thefollowinghavenotbeenassociatedwithanincreasedriskofmalignancy

(as of 2016): sulfasalazine, leflunomide, rituximab, abatacept, apremilast,

ustekinumab,secukinumab,belimumab,anddenosumab.

Neurologicalconditions

Entrapment neuropathies and radicular lesions are discussed in  Chapter 3.

Also,radiculopathyisincludedin Chapter21.

Inflammatoryperipheralneuropathy

• Inflammatory neuropathies can occur as part of any AICTD, though are

probably most likely to occur in association with SLE and Sjögren’s

syndrome.

• Vasculitis(andprobablyAPS)cancausesmallvesselvascularlesionswhich

compromiseperipheralnervefunctionandcausesensory,andifsevere,motor

featuresofnervedamage.

• Nerveconductionstudiesmayformpartoftheinvestigationsattheoutsetof

characterizingsystemicvasculitisandsevereAICTDs.

• Mononeuritis occurring as part of RA is possible but nowadays is very

unlikelyunlesssevereRAdiseaseisleftuntreated.

Entrapmentneuropathies

• Entrapmentneuropathiesarecommoninrheumatologicalpractice.Symptoms

arising from these lesions include paraesthesiae, a feeling of swelling,

numbnessandaburningqualitytopaininthedistributionofthetrappednerve.

• Median nerve irritation/entrapment may be secondary to carpal OA or

inflammationsecondarytoinflammatoryarthritis.

• Ulnar nerve irritation (fourth and fifth finger territory symptoms) is most

commonlyassociatedwithmedialelbowlesions.

Spinalcordlesions

Spinal cord lesions usually arise due to intrinsic spinal canal or extrinsic

compressionorinflammation.

• Tumours andischaemicspinal cord lesionsoftenpresent acutely withupper

motor neuron features distal to the affected level and issues of bladder and

bowelsphinctercontrol.

• Sometumoursandsyrinxes(thoracic,neck)cancausesubacuteevolutionof

pyramidalfeaturesinthelegs(oftennotpainbutstiffnessandmotorfunction

problems).

• Extrinsic cord compression can occur secondary to tumours, osteoporotic

vertebral and a combination of (usually degenerative) lesions. In the latter,

spinalcordcompressionisrarelyacuteandbecauseitevolvesveryslowlyis

oftenoverlookedintheelderly.

• Transverse myelitis causes acute focal back pain and distal spinal cord

symptoms and features including acute lower limb motor symptoms. It is a

featureofSLEandAPS.

Cerebrovascularlesions

• Acute cerebellar or stroke-like symptoms can be a presenting feature of

ischaemiclesionssecondarytoAPS.Ifoccurringinthenon-elderly<60years

thenscreeningforAPSandSLEismandatory.

• Cerebrallupuscanbepresentwithprofoundsymptomsofconfusionandbrain

functiondecompensationormaybesubtlerpresentingwithmildcognitiveor

frontalcortexdysfunction.

• Conventional stroke disease is a complication of many inflammatory

rheumatic diseases, probably most associated with APS and ongoing poorly

controlledinflammatorydiseaseandinthecontextofotherriskfactors(e.g.

smoking, metabolic syndrome in PsA, glucocorticoid-associated

hyperlipidaemia).

Headache

• Among the causes of headache in rheumatological practice, neurological

causesareprobablyrare.

• The hemicranialheadache (withscalp sensitivity)of GCA anddrug-induced

headachearethemostlikelycausesofheadacheencounteredinrheumatology

patients.

• Other causes of headache occasionally encountered are the global headache

fromcranialsinusthrombosisinBehçet’sdisease,andmeningeallesions(e.g.

inneurosarcoid).

Neuromyopathy

• Neuromyopathies may present to rheumatologists with focal pain or

generalizedpainandweakness.

• Focal neuromyopathies can occur after nerve trauma or infection. Marked

acutewastingwithpain,often withraisedCKand amyositis-typesignalon

MRI,canbeseen.

• Fluctuatingneuromyopathiceffectscanoccurinmyastheniagravis.Theremay

beavariationofeffectsoveradaywithmusclefatigueinfluencingthetiming,

characteristics, and severity of weakness. Symptoms can be focal—as in

orbital muscle myasthenia, which can present initially with diplopia—or

generalinvolvinglargermusclegroups.

Ophthalmicconditions

Blepharitis, conjunctivitis, uveitis, and ischaemic lesions can all occur with

rheumaticMSKdiseases.

Dryeye(xerophthalmia)

• Xerophthalmiaoftenpresentswithsoreorgrittyeyesandsensitivityincertain

atmospheric environments (e.g. air-conditioning). Oddly patients can get

epiphoraeiftearfilmisnotdrainedbecauseofinferiororbitalductblockage

throughtothesinuses.

• Blepharitisisoftenaconsequenceofdryeye—lidscanget‘sticky’.

• XerophthalmiaismostsevereinprimarySjögren’ssyndromebutcanoccurin

SOX syndrome and all autoimmune joint and connective tissue diseases

(secondarySjögren’ssyndrome).

Uveitis

• Anterior uveitiscanbe acuteorchronic. Symptomsincludeocular painand

photophobia.Theeyebecomesvisiblyerythematous.

• The most common associations of anterior uveitis include SpAs, sarcoid,

Behçet’sdisease,andJIA.

• All children and adolescents diagnosed with any form of JIA, regardless of

ANAstatus,shouldhaveaneyeexaminationtoruleoutuveitis.

Ischaemicophthalmiclesions

• Retinalexaminationisthemostdirectandaccessiblewaytovisualizeblood

vesselsinvivo.

• Ophthalmicexaminationisvaluableintheassessmentofsystemicvasculitis.

• The input of an experienced medical ophthalmologist is essential in

departmentsthatofferaservicetomanagevasculitispatients.

• The ischaemic lesions of GCA can present variably but most typically with

amaurosissymptoms(visualfieldcurtaining).

Scleralandcornealdisease

• Lesions ofthe scleraand corneaare rarein rheumatologypatientsexceptin

severe(usuallyhigh-titreseropositive)RApatients.

• ScleralorcornealdiseaseinanRApatientshouldpromptconsiderationofthe

presenceofsystemicRAvasculitis.

Other

• ProptosisisarecognizedfeatureofAAVandisusuallyduetogranulomatous

inflammationintheretro-orbitalspace.

• Conjunctivitis can accompany many diseases but is an acute lesion insome

casesof(SpA-associated)reactivearthritis.

• Ophthalmoplegiaisarecognizedpresentingfeatureofmononeuritisassociated

with systemic vasculitis. Cerebrovascular disease (thus APS and GCA also)

shouldbeconsideredaspossibleinrelevantpatientsalso.

PartII

Theclinicalfeaturesand

managementofrheumaticdiseases

Chapter5

Rheumatoidarthritis

Introduction

Clinicalfeatures

Investigations

Management

Introduction

Epidemiology

Rheumatoidarthritis(RA)isthemostcommoninflammatoryarthritis,withan

incidence in the general UK population of 1.5 and 3.6 per 10,000 people per

year,formaleandfemalesrespectively.

• RAaffectspeopleworldwideandaffectsfemalesmorefrequentlythanmales,

withaF:Mratioof~3:1.

• RAmostcommonlyoccursatage45–65yearsalthoughitcanoccuratanyage

—occurringasadistinctdiseaseinchildhood.

Classification

The updated ACR/EULAR 2010 classification criteria (Table 5.1) have been

designedtoidentifyearlyRA.However,theyshouldnotbeusedtoexcludethe

diagnosisifallcriteriaarenotmet;clinicaljudgementshouldbeused.

Pathogenesis

RA is an autoimmune inflammatory disease, manifest primarily in synovial

tissues, mediated by interaction between T lymphocytes, B lymphocytes, and

synovialfibroblasts,leadingtodysregulationoftheinflammatorycascade.

• SmokingincreasestheriskofdevelopingRA.

• FamilialRAdoesexistbuttheoddsratioofdevelopingRAifthereisafirst-

degreerelativewiththediseaseisonly1.1.

Immunopathology

Overproductionofinflammatorycytokines,inparticulartumournecrosisfactor-

α(TNFα)andinterleukin-6(IL-6),iscentraltothepathologyofRA.

• Persistentinflammationleadstoincreasedvascularityandinflammationofthe

synovialliningofjoints(synovitis),andsecondarycartilagedegradation(joint

spacenarrowing)andboneerosion.

• Autoantibodies are seen in 50–80% of RA cases, in particular rheumatoid

factor(RF)andanticitrullinatedpeptideantibodies(ACPA).

• ThesensitivityandspecificityofACPAforidentifyingRAisgreaterthanthat

ofRF(67%and95%forACPAvs69%and85%forRF,respectively).

• PositivityforbothRFandACPAhasanear100%positivepredictivevaluefor

subsequentdevelopmentofRA.

• Genetics also contribute to the risk of developing RA. HLA-DRB1 is most

commonlyassociatedwithRA,andisoftenreferredtoasthe‘sharedepitope’.

Table5.1ACR/EULAR2010classificationcriteriaforrheumatoidarthritis

Target population is patients who have ≥1 joint with definite clinical

synovitis(swelling)*withthesynovitisnotbetterexplainedbyanother

disease.

Classification criteria for RA. Add score of categories A–D; a score of

≥6/10isneededforclassificationofapatientashavingdefiniteRA.

‡

Score

A.Jointinvolvement

1largejoint

2−10largejoints

1−3smalljoints(±involvementoflargejoints)**

4−10smalljoints(withorwithoutinvolvementoflargejoints)

>10joints(>1smalljoint)

B.Serology(atleast1testresultisneededforclassification)

‡‡

NegativeRFandnegativeACPA

Low-positiveRForlow-positiveACPA

High-positiveRForhigh-positiveACPA

C.Acute-phasereactants(atleast1testresultisneeded)

§§

NormalCRPandnormalESR

AbnormalCRPorabnormalESR

D.Durationofsymptoms

<6weeks

≥6weeks

*Criteriaareaimedatclassificationofnewlypresentingpatients.Patientswitherosivediseasetypical

ofRAplushistorycompatiblewithfulfilmentofthe2010criteriaandpatientswithlong-standing

disease,shouldbeclassifiedashavingRA.

‡

Althoughscores<6/10arenotclassifiedashavingRA,criteriamaybereassessedandfulfilled

cumulativelyovertime.

Jointinvolvementreferstoanyswollenortenderjoint,whichmaybeconfirmedbyimagingevidence

ofsynovitis.DIPJs,1stCMCand1stMTPjointsareexcluded.

‘Largejoints’areshoulders,elbows,hips,knees,andankles.

**‘Smalljoints’areMCPJs,PIPJs,2ndto5thMTPJs,thumbIPJsandwrists.

‡‡

‘Negative’referstointernationalunit(IU)valuesthatare≤totheupperlimitofnormal(ULN)forthe

laboratoryassay;low+vereferstoIUvaluesthatarehigherthantheULNbutlessthan3×theULNfor

thelaboratoryandassay;high+vereferstoIUvaluesthataremorethan3×theULNforthelaboratory

andassay.Ifonly+veor−veRFinformationisavailable,a+veresult=low-positiveforRF.

§§

Normal/abnormaldeterminedbylocallaboratorystandards.

ACPA,anti-citrullinatedproteinantibody;CRP,C-reactiveprotein;ESR,erythrocytesedimentationrate

GuidelinesreproducedfromAletahaDetal.2010‘RheumatoidArthritisClassificationCriteria’(2010)

Arthritis&Rheumatism62:92569–2581withpermissionfromJohnWileyandSons.

Synovialpathology

Theexactreasonwhysynoviumistargetedisunknown.Synoviuminjointsand

tendons becomes inflamed and local tissue damage of cartilage, bone, and

surroundingtissuesensues.

• Thereisincreasedsynovialvascularity,influxofmonocytesandplasmacells,

andactivationoftissuemacrophagesandfibroblasts.

• Synovialplasmacellsarenumerousandproduceantibodieswhichwillhavea

proinflammatorylocaleffect.

• Cellular activation of cytokines locally results in bone resorption activating

osteoclastscausingboneerosion.

• Inseverecases,cellularaggregationcanleadtolymphoidfolliclesformingin

thesynovialtissue.

• Extra-synovial inflammation includes rheumatoid nodule formation and

inflammationoflungandcardiactissue.

Reference

1. NishimuraK,SugiyamaD,KogataY,etal.Meta-analysis:diagnosticaccuracyofACPAandRFfor

RA.AnnInternMed2007;146:797–808.

Clinicalfeatures

RAischaracterizedbyswelling,pain,andstiffnessofsynovialjoints,systemic

features,andinvolvementofextra-articularorgansandtissue.

Jointsandtendons

RA typically affects the small joints of the hands and feet, but can affect any

joint (bursa or tendon) where there is synovial tissue (e.g. elbows, shoulders,

ankles,knees,hips,andTMJs).

• Symptomscharacteristicallyincludestiffnessworseinthemorning,andlasts

for>30min.

• Joint symptoms develop over weeks, but can also do so over a few days.

Occasionally symptoms can have a migratory onset over months, with

temporaryperiodsofresolution/improvement.

• Movementoftheaffectedjointsoftenalleviatesstiffnessanddiscomfortinthe

earlystagesofthedisease.

• Active movement ofaninflamed joint can cause‘gelling’ wherethepatient

describesanabruptmomentary‘paralysis’ofmovement.

• The functional impact of joint symptoms should be assessed. The Health

Assessment Questionnaire (HAQ) is helpful to provide a standardized

assessmentofdisability.

• Examinationshouldfocusonanyaffectedjoints,assessingforthedegreeof

swelling,warmth,andrangeofmovement.

• Joint or tendon synovitis may not be detectable clinically in the early/mild

stages of disease. Boggy swelling over the joint line is indicative of joint

synovitis.Ballotablejointeffusionscanbepresentiflargerjointsareinvolved.

• In the early stages of the disease, deformities are not seen; however, in

aggressive,longstanding,oruntreateddisease,deformitycanoccurandleadto

significantdisability.

• DeformitiesseeninRAinclude:

• ulnardeviationatthewrist,oftenaccompaniedbyadepressibleprominent

ulnastyloid(piano-keysign).

• swan-neckandboutonnieredeformitiesmay beidentifiedinthefingersin

advanceddisease.

• fixedlossofextensiondeformities.

• limited shoulder movement, due to joint erosion, effusion, or ligament

rupture.

• lateraldeviationofthetoes.

• subluxation of the metatarsal heads leads to discomfort when walking.

Callosities, skin degradation, soft tissue infection, and osteomyelitis may

ensue.

• Attheatlanto-axialjoint,erosionoftheodontoidcanleadtoanunstableC1–

C2 articulation, with potentially life-threatening consequences from cord or

brainstemcompression.

• Symptoms of atlanto-axial joint involvement can include occipital pain,

syncope,andheadaches.

• Theconsequencesofsmallcervicalfacetjointinvolvementcanbeupperlimb

radicular symptoms and hand weakness, and if the spinal cord is affected,

stiffness(includingoflegs).

• The differentialoflower cervicalradiculopathyiscarpal tunnelsyndrome—

alsoasecondarylesioninRAfromwristjointdisease.

Extra-articularfeatures

• Rheumatoid nodules are associated with seropositivity (RF and ACPA) and

canoccuranywhereinthebody,butaremostcommonlyfoundonthehands,

feet,andelbows.Whenasmallmass/noduleisidentifiedinanyinternalorgan

in a RA patient, cancer must be excluded before attributing the lesion to a

rheumatoidnodule.

• RA is associated with pulmonary fibrosis, exudative pleural effusions, and

pleurisy.

• Splenomegaly is common, and may be part of Felty’s syndrome (RA,

neutropenia,andsplenomegaly).

• LymphadenopathycanbeduetoRAbutpatientsalsohaveagreaterlikelihood

ofdevelopinglymphomacomparedtothegeneralpopulation,soinvestigation

of‘Bsymptoms’isveryimportant.

• Neurological examination may reveal nerve impingement due to synovitis,

tenosynovitis (e.g. carpal tunnel syndrome), joint damage, or bony

impingement(e.g.spinalnerverootimpingement).

• Rheumatoidvasculitiscanpresentasamononeuritismultiplex.

• Leucocytoclasticrashesarerarebutmaycauseskinulceration.

• Themostcommonophthalmicmanifestationisdryeyes(sicca).

• Painful scleritis, leading to scleromalacia, is a serious sight-threatening

condition. Scleral thinning may manifest as a darkening of the sclera, and

requiresurgentophthalmicinput.

Systemicfeaturesandassessment

• Fatigueisoftenaprominentsymptomandischallengingtomanage.

• Disease activity should be assessed using a standardized clinical outcome

measure at each clinical review. The most commonly used measure is the

DiseaseActivityScoreof28joints(DAS28).

• Other disease activity measures include the Clinical Disease Activity Index

(CDAI),andtheSimplifiedDiseaseActivityIndex(SDAI).

Associatedclinicalmanifestations

• PatientswithRAhaveanincreasedriskofdevelopingsepticarthritisdueto

pre-existingjointdamageanduseofimmunosuppressants.

• Active RA commonly is associated with muscle atrophy, primarily due to

reduceduse,butalsoduetosystemicinflammation.

• Osteoporosis is more common in RA than the general population, due to

systemicinflammation,reducedmobility,andsteroids.

• Osteoporosisriskshouldbeassessedinpatients>40yearsusingFRAX

(

http://www.shef.ac.uk/FRAX) and in postmenopausal women and men >50

yearsusingFRAX

andDXAscanning.

• Patients with RA have an increased cardio- and cerebrovascular risk profile

due to chronic inflammation promoting atherosclerosis. Active risk

managementisimportant.

• Secondaryamyloidosisisincreasinglyuncommon,butshouldbeconsideredin

patientswithlong-standingactivedisease.

Investigations

RA is primarily a clinical diagnosis. However, a set of baseline investigations

can assist in making the diagnosis, and provide a point of reference for

monitoringdiseaseprogression,drugresponse,andtoxicity.

• Laboratory tests should be done to aid diagnosis, as a baseline before and

when monitoring disease-modifying antirheumatic drugs (DMARDs; Table

5.2).

• Imagingcanconfirmaclinicaldiagnosisandcharacterize synovitisin joints

andtendons,evaluatejointandbonedamagefromjointinflammation,andcan

helpexcludealternativediagnoses(Table5.3).

• Key to diagnosis is detection of ACPA and RF. ACPA are as sensitive for

diagnosisofRAasRFbutaremorespecific.

Table5.2SuggestedbaselinelaboratoryinvestigationsforRA

Investigation Interpretation

Fullblood Hb↓/↔ Duetochronicinflammation/bonemarrow

count suppression.OftenlowMCVandMCHowing

topoorutilizationofironintoerythrocyte

precursors

Platelets↑/

↔

Duetoinflammatoryresponse

WCC↑/↔

Neuts↑/↔

Lymph↓

Eos↑/↔

Total WCC/neut count often ↑ from

inflammatoryresponse,with infection andin

haematologicalmalignancies.

GCscause↑neuts(↓vascularmargination).

Mild ↑ in eosinophils. If persistent ↑ then

investigate alternative causes (e.g. EGPA,

parasiticorhelminthinfection).

Renaltests Creat↑/↔

GFR↓/↔

Urea↑/↔

K ↔; Na

↔

NSAIDs can cause renal impairment. Many

DMARDsarerenal-excreted∴baselinerenal

functionimportant.

If unexplained renal dysfunction, consider

amyloidosisordrugcause.

Liverfunction

tests

ALT↔

ALP↔

Albumin

↔

INR↔

MostDMARDsaremetabolizedinliver.If↑

considerdrugeffect

Inflammatory

markers

CRP↑

ESR↑

TypicallyelevatedinactiveRA,although

normalinflammatorymarkersdonotexcludea

diagnosisofRA

Autoantibodies RF

ACPA

ANA

One/both/neither may be present but if both

negative be rigorous about making a correct

diagnosis (differential inflammatory OA,

CPPD polyarthritis, PsA). The autoantibody

titresarenotrelatedtodiseaseactivity.

ANApositivitycanoccurwithoverlap(SLEor

primarySjögren’s)

ALP,alkalinephosphatase;ALT,alanineaminotransferase;AST,aspartateaminotransferase;CPPD,

calciumpyrophosphatedihydratediseaseCr,creatinine;CRP,C-reactiveprotein;EGPA,eosinophilic

granulomatouswithpolyangiitis;ESR,erythrocytesedimentationrate;GFR,glomerularfiltrationrate;

Hb,haemoglobin;K,potassium;Na,sodium;WCC,whitecellcount.

Table5.3BaselineimaginginvestigationsusefulinRA

Investigation Interpretation

Radiographs Hands

and

feet

Hands (including wrists) and feet to assess for

erosions, periarticular osteopenia and soft tissue

swelling

CXRtoassessforpulmonaryfibrosispriortostarting

DMARDs

Flexion/extensionsagittalC-spinefilmstoassessfor

C1/C2instability

CXR

Other

Ultrasound Hands

and

wrists,

feet

and

other

joints

Helpfulforassessingforsynovitis,hypervascularity,

effusion,andearlyerosions.Canaiddiagnosisiflittle

clinicalsynovitispresent,orifitisunclearifjoint

painisduetoinflammationorstructuraldamage.

Effectiveatprovidingdynamicjointimaging(e.g.

shoulder,ankle,wrist)

MRI C-

spine,

specific

joints

EssentialtoassessforcervicalmyelopathyifC1/C2

instabilitysuspected

Joint MRI helpful to confirm joint and tendon

synovitis, identify pre-erosions and erosions, and

rule out other MSK lesions at (symptoms/sign-

affected)sites

DXA RAisariskfactorforosteoporosis.DXA(hipandspine)

shouldbedoneatanyageifthepatientisonsteroidsorhashad

afragilityfracture,andinallpostmenopausalwomenandmen

>50yrsold

CXR,chestX-ray,MRI,magneticresonanceimaging.

Management

Generalconsiderations

Intensive target-driven treatment of RA, aiming for disease remission, is

recommended.



AllpatientswithRAshouldhaveaccesstoregularmeetings

with a rheumatologist. Patient involvement and shared decision-making is

essentialintreatmentplanning.Forexample,foraguidetoRAmanagementby

auditablestandards,seeNICEClinicalGuideline79.

• Remissionisdefineddependingonthediseaseactivityscoreused(e.g.<2.6

usingDAS28).

• Early institution of DMARD therapy, usually with conventional synthetic

DMARDs(csDMARDs)initiallybeforetheonsetofjointdamage,isessential

(see Chapter23forDMARDnomenclature).

• A‘treat-to-targetapproach’hasbeenshowntoimproveoutcomesinRAand

involvessettingarealistictreatmenttarget(e.g.remission)withthepatientand

escalatingtreatmentuntilthegoalisreached.Thisapproachcanbeintensive

andrequiresfrequentpatientmeetingsorcontactstoassesstreatmentresponse

untilthetargetisachieved.

• Whileremissionisanappropriatetargetinearlydisease,patientswithlong-

standing disease may require a more pragmatic target, such as low disease

activity.

• AmultidisciplinaryapproachisessentialwhenmanagingRA:

• Earlyandregularspecialistpractitionerconsultscanhelpbothdiseaseand

medicinesmanagement,aswellasself-managementthrougheducationand

adeeperunderstandingofthepatientoftheirRA.

• Earlyreferraltophysiotherapyandoccupationaltherapyisrecommendedto

advise patients on appropriate exercises to maximize joint movement,

function,andstrength.

• Livingaids,pacing,copingskills,andself-managementofdiseaseactivity

flares/fatiguecanalsobelearnedthroughtherapyandpractitionerinput.

• Early institution of strategies to help patients to continue to participate in

workandsocialactivitiesisessentialtomaintainingagoodqualityoflife

forindividualswithRA.

• Podiatric orfoot orthoticsinput canbe helpfultoalleviatefootsymptoms

anddeformity.

• RA can lead to problems with low mood and depression so screening for

psychologicaldysfunctionandreferralforspecialistinputisveryimportant.

• Patients with RA have a higher risk of developing cardiovascular and

cerebrovasculardisease.Anannualreviewandmanagementofriskfactorsis

thereforemandatory.

Figure5.1SummaryofUKNationalInstituteforHealthandCareExcellence(NICE)guidanceforthe

managementofRA*ThissummarizesUK(NHScare)NICEguidelines.Local/regionalguidelinesmay

vary.GuidelinesadaptedfromNICEhttps://www.nice.org.uk/guidance/cg79.

Generalpain-relievingmeasuresandanalgesia

Analgesia can help manage symptoms while csDMARD and/or biologic

DMARDtherapy(bDMARD)takeseffect,andtotreatflaresofdiseaseactivity.

• Paracetamoland/orweakopiates(orincombination)willreducepainandcan

bewelltolerated.

• ConcomitantNSAIDs(preferentiallyselectiveCOX-2inhibitorsareinvariably

effectivethoughtheyaretoleratedvariably.

• NSAIDsshouldbeprescribedatthelowesteffectivedoseandfortheshortest

timepossible.

• Aprotonpumpinhibitortoreducetheriskofgastrointestinal(GI)ulcersand

toreduceGORDsymptomsshouldbeconsidered, especiallyinpatientaged

>65years,orwithahistoryofGIdisease.

• WhenchoosingaNSAID/COX-2inhibitor,considerapatient’sindividualrisk

factors,andchooseadrugwhichleastincreasestheserisks.Patientsshouldbe

counselledaboutthepossiblecardiorenal,GI,andliversideeffects.

• Transcutaneouselectricalnervestimulation(TENS)canbeahelpfulmeasure

to manage local/regional pain, and poses few side effects. Broken skin and

areaswithreducedsensation(i.e.diabeticneuropathy)shouldbeavoided.

SyntheticDMARDmedications(sDMARDs)

Foramoredetaileddiscussion,see Chapter23.

RA immunotherapeutics need planning with each patient. Objectives and a

time-frameforachievingobjectiveshouldbesetbyagreement.Thereneedsto

be a baseline safety assessment (Box 5.1) and careful monitoring of disease

activity,anydisability,comorbidity,anddrugeffects(Box5.2).

• Methotrexate (MTX) is the first-line conventional sDMARD of choice.

sDMARDdosesshouldbeescalatedrapidlyiftolerated.

• All sDMARDs and bDMARDs have a variable time to onset of efficacy,

between3and6months.

• Combinationtherapy(>1sDMARD),ideallyincludingMTX,isrecommended

iftolerated.

• Thereisgoodqualityevidencethatusinglow-doseGCtherapyduringthefirst

6months(e.g.‘COBRA-lite’30mgprednisolonedailyinitially),inorderto

achieveearlydiseasecontrol,reduceslong-termstructuraljointdamage.

• Once disease control is achieved, GCs should be tapered and stopped as

quicklyaspossible.

• Intra-articular (IA) GC injections can be efficacious for particularly swollen

joints.IMandIVGCscan behelpful tomanage flaresofjointpain/disease

activity.

• IfcombinationsDMARDtherapyisineffective,earlyescalationtobiological

therapyshouldbeconsidered.

• MTX should be co-prescribed with biologic therapy (particularly with anti-

TNFα)wherepossible,asitimprovesanti-TNFαresponseandpersistence.

• If first-line biologic therapy is inefficacious, switching to another biological

agentisrecommended.

Box5.1Investigationsandassessmentstoconsiderbeforestarting

sDMARDsforRA

Height,weight,bloodpressure

SomesDMARDscause↑bloodpressure,soabaselinemeasureisrequired.

Heightandweightarerequiredfordrugsprescribedby(‘ideal’)bodyweight.

Laboratorytestsandimaging

SeeTable5.2andTable5.3,respectively.

Comorbidities

Reviewcomorbidities,especiallyanyrespiratory,hepatic,orrenalconditions

thatmayaffectsDMARDchoice.Considerscreeningforoccultviralinfection

(suchashepatitis/HIV).

Pregnancy,fertilityandbreastfeeding

Discuss current and future plans for pregnancy and breastfeeding and tailor

treatmentaccordingly.

Vaccinations

VaccinationsagainstpneumococcusandinfluenzabeforestartingsDMARDs

or biologicsarerecommended.Live vaccines are not recommended(except

withhydroxychloroquineorSSZ).Theshinglesvaccineisalivevaccineand

evidence is limited on the use in immunocompromised individuals. Local

recommendations and clinician discretion should guide decisions. Prior to

commencinganti-TNFα, hepatitis Bvaccinationshould be considered inat-

riskindividuals.

DatafromLedinghamJetal.BSRandBHPRguidelinefortheprescriptionandmonitoringofnon-

biologicdisease-modifyinganti-rheumaticdrugs.Rheumatology2017;56(6):865–8.

Methotrexate(MTX)

• Once-weeklyoralpreparation,orsubcutaneous(SC)injection.Folicacidco-

prescription,oftenthedayafterMTXadministration.

• Therapeuticrangeisapproximately10–25mgweeklyandtimetotherapeutic

effect:8–12weeks.

• Toxicity(stomatitis,GIdisturbance,dysphoria-lassitudeeffects,andalopecia)

maybeaddressedbytheadditionoffolicaciddaily(apartfromdayofMTX

dosing).

• SCadministrationisausefuloptioniforaltreatmentisnottolerated.Thereis

some evidence of improved efficacy with SC compared with oral

administration,duetothehigherbioavailability.

• Milddrug-inducedhepatitisisrelativelycommonandisoftencorrectedbythe

additionoffolicacid.Routineliverbiopsyisnotnecessary,butcanbehelpful

in patients with other liver disease or persistent low-grade liver function

abnormalities.

• Liverfunctionabnormalitiesfluctuateandmayrequirethedrugtobestopped

forashortperiodiftransaminaselevelsriseabove2–3timestheupperlimitof

normal, with re-introduction after a period of time when levels have

normalized,withclosemonitoring.

• Myelosuppressionisrarelysevere.Antifolatedrugssuchastrimethoprimand

folatedeficiencyincreasetheriskoftoxicity.

• RenalimpairmentreducesMTXclearanceandmayleadtotoxicity.

• Concomitant NSAID use is not contraindicated, but monitoring for

hepatotoxicityisrecommended.

Sulfasalazine(SSZ)

• Dailyoralpreparation.Therapeuticrange1.5–3gdailyintwice-dailydoses.

• Timetotherapeuticeffect:12weeks.

• Toxicity:maycauseleucopenia,pancytopenia,haemolysis,aplasticanaemia,

andhepatictransaminitis.Bonemarrowtoxicityunusual.

• SSZ can rarely cause a hypersensitivity reaction characterized by LFT

abnormalities,lymphadenopathy,andrash.

• Spermatogenesis and libido can be affectedbySSZ,butitisreversible.No

apparentadverseeffectonfemalefertility.

Hydroxychloroquine(HCQ)

• Dailyoralpreparationwithusualtherapeuticdose200mgtwicedaily.

• Timetotherapeuticeffect:about12weeks.

• Retinal toxicityandmaculopathy are rare. Therisk increases with abnormal

liver or kidney function; after a cumulative dose >1000 g; and treatment

duration>5–7years.

Leflunomide(LFN)

• Dailyoralpreparation.Therapeuticdose20mgdaily.

• Timetotherapeuticeffect:12weeks

• LFNisaninhibitoroftheenzymedihydro-orotatedehydrogenaseandshows

antiproliferativeactivity,inhibitingpyrimidinesynthesis.Ithasalonghalf-life

of2weeks.

• Initially,itwasadministeredwithaloadingdoseof100mgdailyfor3days

followedbymaintenancetherapywith10–20mgdaily.Theloadingdosewas

associated with diarrhoea in many patients, and clinicians now use

maintenancetherapydosefromthestart.

• Side effects include myelosuppression, elevation of liver transaminases,

diarrhoea,andhypertension.Severehepatitisisuncommonandusuallyoccurs

inthefirst6monthsoftreatment.

• The long half-life has implications for drug withdrawal. If rapid washout is

required,cholestyramineforbetween14daysto6weeksshouldbeprescribed,

followedbytwobloodteststoensuredruglevelsarebelow0.02mg/L.

Azathioprine(AZA)

• Daily oral preparation dose range 2–2.5 mg/kg/day in twice-daily or three

timesadaydoses.

• Timetotherapeuticeffect:12weeks.

• InfrequentlyusedforRAastherapeuticeffectrelativelyweak.

• Toxicity: may cause leucopenia, pancytopenia, haemolysis, and aplastic

anaemia; especially in individuals with low/absent thiopurine

methyltransferase(TPMT)activity.AZAshouldnotbeprescribedforpatients

with‘low-activity’-associatedTPMTalleles.

Gold(myocrisin)

• IMpreparationwithloadingdosesthenusually50mgmonthly.

• Timetotherapeuticeffect:variable.

• Infrequently used for RA nowadays (and auranofin, the oral gold salt

preparation,isevenlessseldomused).

• Toxicity: hypersensitivity to injections, permanent blue/grey skin

discoloration,renalandliverdysfunctioncanoccuruncommonly.

Glucocorticoids(GCs)

• Oral,IM,IV,orIAuse.

• Timetotherapeuticeffect:dependsonthemodeofadministration;hours/days.

• IM and oral GCs can be very effectiveto manage flares and as a bridge to

sDMARDstakingeffect.

• IAinjectionsareofvalueinsymptomcontrol,inbothearlydiseaseandflares.

However,theireffectistransient,withlittleimpactontheoverallprocessof

RA,andshouldnotberepeatedanymorethan3-monthly.

• Caution should be exercised if considering IA injection in anticoagulated

patientsastheriskofhaemarthrosisisincreased.

• Thereisnoevidencetosuggestanincreasedriskofjointinfection,aslongas

anaseptictechniqueisused.

• Long-term systemic GCs can have sequelae, including cataracts, premature

coronary artery disease, osteoporosis, muscle atrophy, insulin

resistance/diabetes,andosteonecrosis.Appropriatefracturepreventiontherapy

should be given to patients expected to be on glucocorticoid therapy for >6

weeksatadose≥7.5mg.

Box5.2ManagingandmonitoringsDMARDs:BritishSocietyfor

RheumatologyUKrecommendations

Methotrexate(MTX)

Co-prescribedwithweeklyfolicacid(e.g.5mg/dayafterMTX).

Teratogenic. Notsafe inbreastfeeding. Adviselow alcoholintake.Rarely

causes pneumonitis (caution with pre-existing lung disease/poor respiratory

reserve).Rarelycausesmyelosuppression.

Monitoring: FBC, Cr/GFR, ALT, albumin all 2-weekly until dose/results

stablethenmonthlyfor3monthsthen3-monthlythereafter.

Sulfasalazine(SSZ)

GIsideeffectsearlyintreatmentcoursegenerallymildanddooftensubside.

Very rarely causes leucopenia, pancytopenia, haemolysis, and aplastic

anaemiainearlytreatment.Reducedpotencyinmen.

Monitoring:FBC,Cr,ALT,albuminall2-weeklyuntildose/resultsstable,

then monthly for 3 months, then 3-monthly until 12 months and no routine

monitoringrequiredthereafter.

Hydroxychloroquine(HCQ)

Cumulativedoseshouldnotexceed6.5mg/kgofbodyweight.

Monitoring: no routine lab monitoring required. Eye screening within 1

yearofstartingandthenannuallyifondrugfor>5years.

Leflunomide(LEF)

Diarrhoearelativelycommonsideeffect.Cancausehypertensionsoavoidif

BPuncontrolled.Notrecommendedinpregnancyorbreastfeeding.Longhalf-

lifedrugand requiresactive washoutifthere isseveretoxicity(e.g.10-day

cholestyramine).Rarelycausespneumonitis.

Monitoring:FBC,Cr,ALT,albumin:all2-weeklyuntildose/resultsstable

thenmonthlyfor3monthsthen3-monthlythereafter.BPmonthly.

Azathioprine(AZA)

Assess thiopurine methyltransferase (TPMT) genotype before treatment. If

likelyabsentTPMTactivitydonotprescribeAZA.Avoidco-prescriptionwith

allopurinol(blocksexcretionofAZA).GIdisturbancerelativelycommonbut

oftenmild.Relativelysafeinpregnancy.

Monitoring: FBC, Cr, ALT, albumin: 2-weekly until dose/results stable,

thenmonthlyfor3monthsthen3-monthlythereafter.

IMgold

Can cause bone marrow and liver disturbance. Contraindicated in

pregnancy/breastfeeding. Rarely: hypersensitivity reactions from injections.

Long-termtreatmentcancausechrysiasis(grey/blueskinpigmentation).

Monitoring:FBC,Cr,ALT,albumin:all2-weeklyuntildose/resultsstable

thenmonthlyfor3monthsthen3-monthlythereafter.Urinalysisforbloodand

proteinpriortoeachdose.

DatafromLedinghamJetal.BSRandBHPRguidelinefortheprescriptionandmonitoringofnon-

biologicdisease-modifyinganti-rheumaticdrugs.Rheumatology2017;56(6):865–8.

Anti-tumournecrosisfactorαtherapy(anti-TNFα)

Baselineassessmentisadvisable(Box5.1andBox5.3).

• GivenSC(e.g.etanercept,adalimumab)orIV(e.g.infliximab).

• Timetoeffect:2–24weeks.

• TNFαisapotentpro-inflammatorycytokinewhoselevelsareelevatedinRA.

• Anti-TNFα therapiesare availableasoriginator orbiosimilar drugs—mainly

either monoclonal antibodies or receptor fusion proteins (infliximab,

etanercept,adalimumab,certolizumab,golimumab).

• Common adverse effects include infection, headache, nausea, and injection-

sitereactions,andincreasedriskofinfection.

• Rarely can trigger a (ANA-positive) lupus-like syndrome responsive to

therapywithdrawal.

• Veryrarelycancausedemyelination.

• Withdrawifcardiacfailureworsens.

• Considerwithdrawalifinterstitiallungdiseasedevelopsorworsens.

• CancausepsoriasiswhenusedtotreatRAandevenworsenspsoriasisinPsA

patients(‘paradoxicalpsoriasis’).Thisisaclasseffectandwillre-occurifan

alternativeanti-TNFαistried.

• Antibodies can develop versus the therapeutic antibody/fusion protein. Such

antibodies can be detected by specific immunoassays. MTX therapy may

reduceanti-anti-TNFαdrugantibodyformation.

B-celldepletion(anti-CD20):rituximab(RTX)

Baselineassessmentisadvisable(Box5.1andBox5.3).

• GivenIV.Adoseconsistsof1ggiventwicebyinfusionsgiven2weeksapart.

Mostrheumatologistsadvocateaminimumof6monthsbetweensubsequent

doses, but often required less frequently. Usually co-administered with IV

GCs.

• Timetotherapeuticeffect:12–24weeks.

• BcellsplayanimportantroleinthepathogenesisofRAandadministrationof

rituximab leads to rapid CD20 positive B-cell depletion in the peripheral

blood.NormalB-cellrepopulationoccurswithinthenext3months.

• The best responses are seen in RF-seropositive patients, and when co-

prescribedwithMTX.IfpatientsareunabletotakeMTXthenconsiderLFN

orRTXmonotherapy.

• RTXiscontraindicatedifthereishypogammaglobulinaemia.

• Veryrarelycausesprogressivemultifocalleucoencephalopathy.

CTLA4-Ig:abatacept(ABA)

Baselineassessmentisadvisable(Box5.1andBox5.3).

• GivenSC(125mgweekly)orIV(maintenancedoseevery4weeksaccording

toweight).

• Timetoeffect:12–24weeks.

• Abatacept disrupts the CD80/86 co-stimulatory signal required for T-cell

activationbycompetingwithCD28forbinding.

• Co-prescriptionwithMTXisadvisable.

Box5.3Investigationsandconsiderationsbeforestartingbiologictherapy

TBinfection

Allpatientsshouldbescreened(history,CXR,T-spot/IgRAtest)forpresence

of active or latent mycobacterial infections and treated according to current

guidelinesbeforestartingbiologictherapy.

Hepatitis

ScreenallpatientsstartingabiologicforhepatitisBandC.Increasedriskof

infusionreactionsinpatientswithhepatitisCtreatedwithRTX.

HIV

Athoroughhistoryisrequiredandifanyriskfactorsarepresent,HIVtesting

shouldbeundertaken.

Malignancy

See ‘RA-associatedcancerrisk’,p.260.

ANAtesting

Anti-TNFα therapy has been associated with development of lupus-like

syndromeinrarecases.ObtainabaselinetestofANA.

Demyelination(includingopticneuritis)

Anti-TNFαtherapyhasbeenassociatedwithdemyelination,anditshouldnot

beprescribedtopatientswithahistoryofdemyelination.

Cardiacfailure

Anti-TNFαisnotrecommendedwithNYHAgrade3/4cardiacfailure.

Interstitiallungdisease(ILD)

There is mixed evidence on the association of anti-TNFα therapy and ILD.

Monitoringlungfunctionshouldbeconsidered.

Uveitis

Anti-TNFα should be used cautiously in patients with pre-existing uveitis.

Somestudieshaveidentifiedanincreasedriskofuveitis.

Fastinglipids

Patients starting on tocilizumab (TCZ) should have a baseline fasting lipid

profile. A repeat profile is recommended after 3 months of treatment. If

worsening lipid level, consider reviewing treatment. Ongoing monitoring

shouldbeinlinewithlocalguidelinesandindividualriskfactors.

Immunoglobulins

Immunoglobulins should be checked in patients starting RTX, 4–6 months

after an infusion, and before each treatment. There’s an increased risk of

infectionwithIgG<6g/L.

ANA,antinuclearantibodies;NYHA,NewYorkHeartAssociation;RTX,rituximab.

InformationsummarizedfromDingT,etal.BSRandBHPRrheumatoidarthritisguidelinesonsafetyof

anti-TNFtherapies.Rheumatology2010;49:2217–9.

Anti-interleukin-6receptorblocker:tocilizumab(TCZ)

Baselineassessmentisadvisable(Box5.1andBox5.3).

• GivenSC(162mgweekly)orIV(8mg/kgevery4weeks).

• Timetoeffect:12–24weeks.

• IL-6 is a potent pro-inflammatory cytokine. High levels have beenfoundin

serum and synovial fluid of RA patients, and levels correlate with disease

activity.

• Tocilizumabbindsspecificallytobothsoluble(sIL-6R)andmembrane-bound

IL-6receptors(mIL-6R).

• Best results are when it is co-prescribed with MTX, but is licensed as

monotherapy.

• Use with caution inpatientswitha history of diverticulitis duetoincreased

riskofgutperforation.RiskiselevatedifpatienttakingGCsand/orNSAIDs.
Patientsneedcounsellingabouttherisk.
Box5.4TheBritishSocietyforRheumatologyconsensusguidelinesfor
biologictherapiesforRA
Anti-TNFα*
Local guidelinesvaryon blood monitoring requirementfor anti-TNFα. It is
prudent to check FBC with WCC regularly to screen for neutropenia and
malignancysuchaslymphoma.
4
Anti-IL-6receptor(TCZ)
Check WCC and neutrophil count monthly for 6 months. If no neutropenia
occursinthefirst6months,monitoringcanbereducedto2-3monthly.For
TCZmonotherapy,checkLFTsmonthlyforthefirst6-months,thenevery2-3
monthsifresultsarestable.ForTCZco-prescribedwithsDMARDs,monthly
LFTmonitoringisrecommended.
5
Abatacept(ABA)
Noneavailable.Forsafetyandmonitoring,seeinformationonitsSPCat
http://www.medicines.org.uk
Anti-CD20(RTX)
Check immunoglobulins 4–6 months after each infusion. If there is active
infection, IgG levels <6g/L or very low CD4/CD8 counts, withhold
treatment.
6
SeealsoitsSPCat http://www.medicines.org.uk
FBC,fullbloodcount;LFTs,liverfunctiontests;RTX,rituximab;WCC,whitecellcount.
*2010BSRGuidelinestobeupdatedin2017.PleaseseeBSRwebsite:
https://www.rheumatology.org.uk/
BiologicDMARDbiosimilars
TheEuropeanMedicinesAgencydefinesbiosimilarsas‘abiologicalmedicine
thatissimilartoanotherbiologicalmedicinethathasalreadybeenauthorisedfor
use’.Thisusuallyoccursafterapatentexpiresonanoriginatordrug.SeeBox
5.4.
• Sincebiologictherapiesarederivedfromyeastorbacterium,biosimilarsare
notidenticaltotheoriginatordrugandassuch,cannotbeclassedasageneric
drug.
• For this reason, caution should be exercisedifswitchingbetween originator
andbiosimilarcompounds.

• At the time of writing, three anti-TNFα biosimilar therapies were available.

Experienceinthewidespreaduseofbiosimilarsislacking.

• Therearecurrentlynolong-termdataontheuseofbiosimilars.Ifstartingor

switchingapatientintoabiosimilardrug,considerenrollingthepatientontoa

patient(national)registry.

• Guidanceregardingusage(includingswitching)ofbiosimilarsvarieswidely,

soitisadvisedtofollowlocalpolicies.

Novelmedicationsonthehorizon

• Inadditiontocurrentlylicenseddrugs,numerousdrugsareindevelopmentfor

useinRA.Mostnotableofthesearesmallmoleculesthattargetintracellular

processesinvolvedinRA.

• Smallmoleculedrugscanbeadministeredorally.

• Januskinase(JAK)inhibitorshavebeenextensivelyinvestigatedandoneJAK

inhibitor (tofacitinib) is currently available in the USA for the treatment of

RA.

• Further biologic therapies continue to be developed and trialled in RA,

includingIL-17inhibitorsandvariationsonIL-6blockade.

Managinginfectionswhileonimmunosuppression

Themainriskofimmunosuppressionisinfection.‘Seriousinfection’isgenerally

definedasan infection thatrequires hospitalizationorparenteral antimicrobial

treatment.

• Seereferences4and7attheendofthechapterforfulldetails.

• Generally, all sDMARDs (with the exception of HCQ) should be stopped

duringanyseriousinfection,anduntilrecoveryiscomplete.

• BiologicDMARDsshouldbediscontinuedduringseriousinfection.

• Anti-TNFα therapy increases the risk of getting a serious infection, and

infectioncanpresentatypically,sovigilanceisrequired.

• A careful review of the risks and benefits of anti-TNFα therapy should be

undertaken,especiallyinpatientswith:

• chronicinfectedlegulcers.

• septicarthritisofanativejointwithinthelast12months.

• sepsis of a prosthetic joint within the last 12 months (if removed) or

indefinitely(ifjointremainsinsitu).

• persistent/recurrentchestinfections.

• indwellingurinarycatheter.

• bronchiectasis.

• hypogammaglobulinaemia.

Tuberculosis(TB)

• IfapatientdevelopssymptomssuggestedofTBinfectionwhileonanti-TNFα,

anti-mycobacterialtreatmentshouldbeinitiated.

• If the patient remains systemically well, anti-TNFα therapy may continue

whiletheTBinfectionistreated.

• Patientsonanti-TNFαtherapyaremorelikelytodevelopextra-pulmonaryTB.

• Non-TBmycoplasmainfectionsarerareandrequireexpertadvice.

• Evidencefor theoccurrenceofTBwithotherbiologicagentsislimited,but

appearstobelessthanforanti-TNFα.

Opportunisticinfectionriskissues

• Whilerare,monitorforopportunisticbacterial(e.g.Listeria,Salmonella)and

fungal (e.g. histoplasmosis, candidiasis, aspergillosis, Coccidioides,

Pneumocystisjirovecii)infectionsinpatientstreatedwithanti-TNFα.

• Consider treatment with varicella zoster immunoglobulin in all

immunocompromised RA patients who have had significant contact with an

individualwithvaricellazoster.

• Treatshinglesandherpeszosteraccordingtostandardguidance.

RA-associatedcancerrisk

ThereisanincreasedriskofmalignancywithRA,withastandardizedincidence

ratio(SIR)of1.1.TheriskisgreatestforHodgkin’s(SIR3.21)andlungcancer

(SIR1.64).

• ArecentstudyfromtheBSRBiologicsRegisterforRAreportednoincreased

riskofsolidtumourswithanti-TNFαtherapywhencomparedtoRApatients

treatedwithsDMARDs.

• Thereissomeevidencethatskincancers(bothnon-melanomaandmelanoma)

maybemorelikely.

• There is a theoretical increased risk of cancer in patients treated with anti-

TNFα therapy who have previously had a cancer, or have risk factors for

cancer(e.g.smoking).Treatmentdecisionsshouldbemadeonacase-by-case

basis. However, because patients with previous cancer have been excluded

frommostRCTs,littleisknownabouttheriskinthiscontext.

• Data on cancer risk are scarce for other biologics; primarily due to smaller

numbersofpatientstakingthesedrugsandshorterexposuretimessincedrug

licensing.

PregnancyandbreastfeedingwithRA

Thetopichasbeenextensivelyreviewedquiterecently.

• RAoftenimprovesinpregnancy,particularlyinthethirdtrimester.

• Preconceptioncounsellingisessential,asmanysDMARDsarecontraindicated

inpregnancyandbreastfeeding,andsomesDMARDscanaffectfertility.

• Ideally, conception should be planned and medications optimized prior to

conception.

• ThemanagementofRAinpregnancyshouldbediscussedwithallwomenof

childbearingage,andmenconsideringhavingchildren.

• Itisimportanttoreviewhowthepregnancyandbirtharelikelytoproceed.If

possible,earlyreferraltoaspecialistobstetricclinicwithexpertisemanaging

pregnantwomenwithRAisrecommended.

• If RA affects the hip, pelvis, or spine, an obstetric review is necessary to

discussbirthplansandanalgesia.

• RAmaymakecertaintasksmoredifficultforthenewmotherorfatherwith

RA(e.g.changingnappies,bathingthebaby).Planningandaddressingthese

problemsprospectivelyisrecommended.

• Patients should have a method of contacting the rheumatology team (e.g.

telephoneadviceline)shoulddifficultiesarise.Amanagementstrategyshould

beagreedwiththepatientandobstetricandprimarycareteamshouldtheRA

flareintheperinatalperiod.Arrangementforanearlyrheumatologyreviewin

thepostnatalperiod,toensureoptimaldiseasemanagement,isrecommended.

• Drug use in pregnancy needs careful planning. Guidelines updating practice

havebeenrecentlypublished(Box5.5).

• Paracetamolissafeinpregnancyandbreastfeeding.Intermittentusemightbe

reasonable given restrictions on NSAID use (see Box 5.5). Avoid regular

paracetamoluse duringweeks8–14 ofpregnancy asthere isasmallriskof

cryptorchidism. There are no data on paternal exposure, but paracetamol is

likelytobesafe.

• Biologictherapyexperienceisemergingforanumberofthetherapiesbutfor

abatacepttherearestillveryfewdataonitssafety.

Box5.5TheBritishSocietyforRheumatology2016guidelinesfor

prescribingNSAIDs,GCs,sDMARDs,andbDMARDsinpregnancyand

breastfeeding

NSAIDs(includingCOX-2selectiveNSAIDs)

Limited evidence. Possible ↑ risk of miscarriage and fetal malformation ∴

caution in first trimester. Stop NSAID by 32 weeks’ gestation to avoid

premature closure of ductus arteriosus. NSAIDs are excreted in breast milk

butnoevidenceofharm.Compatiblewithpaternalexposure.

Glucocorticoids(GCs)

Compatiblewithpregnancyandbreastfeeding.

Hydroxychloroquine(HQC)

Compatiblewithpregnancyandbreastfeeding.

Methotrexate(MTX)

Contraindicatedinpregnancyandbreastfeeding.StopMTX>3monthsbefore

conception. In accidental pregnancy, stop MTX and start folic acid (5

mg/day).Low-doseMTXpaternalexposureprobablynotrisky.

Sulfasalazine(SSZ)

Compatiblewithpregnancy(usefolicacid5mg/day)andbreastfeeding.

May↓fertilityinmen,however,don’tstopSSZtoimprovefertilityunless

conceptionisdelayed>12months.

Leflunomide(LEF)

Notrecommendedin pregnancyor whenbreastfeeding.Women considering

pregnancy should undergo cholestyramine washout prior to conception. If

accidental conception occurs, cholestyramine washout should be instituted

untilLEFplasmalevelsareundetectable.

Azathioprine(AZA)

Compatiblewithpregnancyatdoses≤2mg/kg/dayandinbreastfeedingand

withpaternalexposure.

Anti-TNFα

Infliximab:stopafter16weeks’gestation.Compatiblewithpaternalexposure.

Etanercept: stop by third trimester. Compatible with paternal exposure.

Adalimumab: stop by third trimester. Compatible with paternal exposure.

Certolizumabpegol:compatiblewithalltrimestersofpregnancy.Compatible

with paternal exposure. Breastfeeding probably safe on any anti-TNFα

therapy,althoughevidenceislimited.

Rituximab(RTX)

Stop6monthsbeforepregnancy.NoevidenceonRTXduringbreastfeeding.

Second/third trimester exposure associated with neonatal B-cell depletion.

Limitedevidenceonpaternalexposure—likelynotharmful.

Tocilizumab

Stop3months<conception.Nodataonbreastfeeding.

DatafromFlintJetal.BSRandBHPRguidelineonprescribingforrheumatologicalconditionsin

pregnancyandbreastfeeding.Part1andII.

https://www.rheumatology.org.uk/Knowledge/Excellence/Guidelines

SurgeryinRApatients

Athoroughperioperativeplanshouldbemadeforallpatients.

• Inform the surgical and anaesthetic team of the diagnosis of RA and any

relevantcomplications/comorbidities.

• Spinal involvement should be highlighted to the anaesthetist, to inform

intubation,positioning,andspinalanaesthesia.

• Respiratory involvement may make artificial ventilation challenging, and

increasetheriskofpostoperativeinfection.

• Postoperative occupational and physiotherapy will need to be tailored to

accommodatethepatient’sRA.

• For elective procedures, advance assessment and preparation of the home

environmentshouldbeundertakentofacilitaterehabilitation.

• Generally, sDMARDs should be continued throughout the perioperative

period,tominimizetheneedforGCs(asthelatterincreaseriskofsurgicalsite

infectionandnon-healing).

• For high-risk (‘dirty’/lengthy) procedures and when patients have

comorbidities,sDMARDsmayneedtobestopped.

• Closemonitoringofrenalfunctionisessentialintheperioperativeperiod,to

monitorforsDMARD-relatedtoxicity.

• Anti-TNFα therapy should be stopped before surgery. ‘Washout’ times for

biologicsvarydependingonhalf-lifeofthedrug.

• Biologics can be restarted after surgery once good wound healing has

progressed and there is no evidence of infection. Please refer to local

guidelines,but atypical currentpractice isto stopbiologic therapy2 weeks

priortosurgery,andrestart2weeksaftersurgery.

ComplementarytherapiesforRA

• Some patients will want treatment from complementary therapists, either in

advanceorduringtheirlong-termmanagementofRA.

• Some commonly used complementary therapies include acupuncture,

chiropractic,homeopathy,aromatherapy,andfaithhealing.

• Patientsoftenfindtreatmentsbeneficial,andprovidedtheydonoharm,there

isgenerallynoreasontoadvisepatientstostoptreatment.

• Itisimportanttohighlighttheabsenceofrobustevidenceforthesetreatments,

andtheyarenotasubstitutionforstandardmanagement.

• Spinal/neck manipulation is generallynotrecommended, especially if RA is

knowntoaffectthespine.

• Inquire about any supplements, herbal, or other medication use that might

interferewiththemetabolismofanalgesicsandsDMARDs.

• Please refer to  Chapter 9 for information on juvenile RF-positive

polyarthritis.

References

2. NICE.RheumatoidArthritisinAdults:Management(Lastupdated:December2015).London:NICE.

http://www.nice.org.uk/guidance/cg79

3. SmolenJS,LandewéR,BijlsmaJ,etal.EULARrecommendationsfor the managementofRAwith

synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis

2017;76:960–77. http://ard.bmj.com/content/early/2017/03/06/annrheumdis-2016-210715

4. Ding T, Ledingham J, Luqmani R, et al. BSR and BHPR RA guidelines on safety of anti-TNF

therapies.Rheumatology2010;49:2217–9.

5. Malaviya AP, Ledingham J, Bloxham J, et al. The 2013 BSR and BHPR guideline for the use of

intravenous tocilizumab in the treatment of adult patients with rheumatoid arthritis. Rheumatology

2014;53:1344–6.

6. Bukhari M, Abernethy R,Deighton C, et al. BSR and BHPR guidelines on theuse of rituximab in

rheumatoidarthritis.Rheumatology2011;50:2311–3.

7. LedinghamJ,GullickN,IrvingK,etal.BSRandBHPRguidelinefortheprescriptionandmonitoring

ofnon-biologicDMARDs.Rheumatology2017;56:865–8.

8. SimonTA,ThompsonA,GandhiKK,etal.Incidenceofmalignancyinadultpatientswithrheumatoid

arthritis:ameta-analysis.ArthritisResTher2015;17:212.

9. MercerLK,LuntM,LowAL,etal.Riskofsolidcancerinpatientsexposedtoanti-tumournecrosis

factortherapy:resultsfromtheBritishSocietyforRheumatologyBiologicsRegisterforRheumatoid

Arthritis.AnnRheumDis2015;74:1087–93.

10. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing for rheumatological

conditions in pregnancy and breastfeeding. Part 1 and II.

https://www.rheumatology.org.uk/Knowledge/Excellence/Guidelines

Chapter6
Osteoarthritis
Introduction
Epidemiology
Pathology
Aetiology
Clinicalfeatures
Investigation
Management
Prognosis
Introduction
Osteoarthritis (OA) is a chronic disorder characterized by cartilage loss, bone
remodelling,jointdeformity,andsynovialinflammation.Itisthemostcommon
jointdiseaseinhumans.
Epidemiology
• Itisestimatedthat8.5millionpeopleintheUKhavejointpainattributableto
OA, and that 15% of the UK population aged >55 years have symptomatic
kneeOA.
• TheprevalenceofradiographichandOAintheUKisestimatedat4.4million
people,significantradiographickneeOAat0.5millionpeople,andsignificant
radiographichipOAat0.2million.
1
• By 2020, OA is expected to be the fourth leading cause of disability in the
world.
• OA poses a significant economic burden on the UK economy, using 1% of
grossdomesticproduct,andcausing36millionworkingdaystobelosteach
year.
2

References

1. Arthritis and Musculoskeletal Alliance. Standards of Care for People with Osteoarthritis. London:

ARMA,2004.

2. NICE. Osteoarthritis: Care and Management of Osteoarthritis in Adults. Clinical Guideline 59.

London:NICE,2008.

Pathology

• Although there are recognized associations between OA, age, and trauma,

advances in knowledge of cartilage biochemistry and the recognition of

crystal-associateddiseasehaverenewedinterestinOAasadynamiccondition

ofcartilageloss(chondropathy)withperiarticularbonereaction.

• Atpresent,OAisassessedandmanagedclinicallyasastructural,ratherthan

physiologicalcondition,withanemphasisonestablisheddiseaseanddisease

prevention.

• Chondrocyte dysfunction leads to changes in the extracellular matrix, and

metalloproteinaseenzymerelease.

• Proteoglycandegradationleadstooedemaandmicro-fissuresinthecartilage.

Micro-fissuresprogresstosubchondralcystsanderosions.

• Cartilage degradation products stimulate synovial inflammation and the

productionofpro-inflammatorycytokines(e.g.IL1andTNFα).

• MacroscopicchangesinOAincludecysticbonedegeneration,cartilageloss,

andgrowthofboneatjointmargins(osteophytes).

• Microscopicchangesincludeflakingandfibrillationofarticularcartilagewith

variations in vascularity and mineralization of subchondral bone, leading to

sclerosisandnewboneformation.

• MostsurveysofOArelyonradiographicfeaturesfordefinitionandseverity—

this is problematic because of poor correlation of radiographic change with

clinicalstatus,symptoms,orfunction.

• Radiographic staging is best done at the hip and knee, but is poorest in the

handandspine.Thecorrelationbetweenpathologyandradiologyisshownin

Table6.1.

Table6.1Radiographic–pathologycorrelatesinOA

Pathologicalchange Radiographicabnormality

Cartilagefibrillation,erosion Localizedjoint-spacenarrowing

Subchondralnewbone Sclerosis

Myxoiddegeneration Subchondralcysts

Trabecularcompression Bonecollapse/attrition

Fragmentationofosteochondralsurface Osseous(‘loose’)bodies

Aetiology

• FemalesareathigherriskofOA(relativerisk(RR)2.6)andtendtodevelop

structuraldamagemorequickly,andaremorelikelytoproceedtoatotalhip

arthroplasty.

• Hip OA is more common in Europeans than in Asians or in African

Americans.

• TheFraminghamstudyfoundthat27%ofpeopleaged63–70years,and44%

ofpeopleaged>80yearshadradiographickneeOA.

• AUKstudyshowedthat50%ofadultsaged>50yearswithradiographicknee

OAhadsymptoms.SimilarfiguresareseeninhipOA.

• Notably only 3–7% of people with radiographic features of hands OA, are

symptomatic.

• RiskfactorsassociatedwithOAincludethefollowing:

• Familyhistory;particularlywithgeneralizednodalOA.

• Genetics:increasedconcordanceforOAinmonozygoticvsdizygotictwins,

andparticularlyfornodalOA.

• Genome-wide association studies have identified genetic loci associated

withOA:handOAwithchromosomes1,7,9,13,and19;kneeOAwiththe

LRCH1 gene on chromosome 13; hipOA with chromosome 11 (RR 1.4–

1.6).

• Geneticsofboneorarticularcartilagestructure(COL2A1gene).

• Highbonedensity.

• Calciumcrystaldepositiondiseaseandacromegaly.

• Obesity(closeassociationwithonsetandprogressionofkneeandhandOA,

butnothipOA).

• Femoraldysplasia(hipOA).

• Trauma(repeatedorsingleevent).

• LowvitaminCandDlevels(progressionofkneeOA).

• Factorswithless,orno,evidencefortherebeingariskforOA:

• For hip OA: previous hip disease (e.g. Perthes disease), acetabular

dysplasia, avascular necrosis of the femoral head, severe trauma,

generalizedOA,andoccupation(e.g.farming).

• ThereislittleevidencetolinkOAwithrepetitiveinjuryfromoccupationor

sports, such as running in those with normal joints, except perhaps knee-

bendinginmen.

Clinicalfeatures

Thesymptoms,andtoadegree,mostfeaturesofOA(Table6.2),oftendonot

correlatewithfunctionaloranatomicalchangejudgedradiographically.

Table6.2Clinicalfeaturesofosteoarthritis

Parameters Features

Symptoms Painoftenworseafteruse,betterwithrest

‘Gelling’afterinactivity

Withoutsignificantinflammatoryfeatures

Minimalstiffness,evenings>mornings

Signs Bonyenlargement

Crepitus

Reducerangeofmovement

Tendernessonpalpation

Malalignmentorinstability

Site 1stcarpometacarpaljoint(CMCJ)

Proximal(PIPJ)anddistalinterphalangealjoints(DIPJ)

1stmetatarsophalangealjoint(MTPJ)

Largejoints:hip,knee

1stmetatarsaljoint

Cervicalorlumbarspine

• Severalpotentialmechanismsmayberesponsibleforthepainassociatedwith

OA.

• Since cartilage is aneural, pain may arise from a number of other sites:

inflammatory mediators causing intra-articular hypertension, capsular

distension, and/or stimulation of synovial and subchondral bone nerve

fibres.

• Concomitantenthesopathyorbursitismayleadtopain.

• Morningstiffnessof<30miniscommoninOA.

• Muscleweaknessandatrophyduetoalteredjointuseiscommon.

• SeveralsubsetsofOAexist,withmigrationbetweenpatterns:

• PrimaryOA.

• GeneralizednodalOA(GNOA).

• Inflammatory/erosiveOA(iOA).

• LargejointOA(kneeandhip).

• SpinalOA.

• SecondaryOA(Table6.3).

GeneralizednodalOA(GNOA)

• This common condition (see  Plate 7d), more common in women than in

men,ischaracterizedbypolyarticularinvolvement.

• ItischaracterizedbyHeberden’snodes(DIPJ)andBouchard’snodes(PIPJ).

• GNOApredisposestoOAofknee,hip,andspine.

• Theisoftenastrongfamilyhistory.

• ThereisoftenMCPJinvolvement,particularlythesecondandthird.Ifthereis

MCPJinvolvement,furtherinvestigationtoexcludecausesofsecondaryOA

arerecommended.

Inflammatory/erosiveOA(iOA)

• Sometimes called erosive OA, iOA is characterized by interphalangeal joint

involvement,flaresofinflammatorysymptomswithrapidprogression,anda

tendencytojointankylosis.

• Centraljointsubchondralerosionsandassociatedbonyremodelling.

• Thepeakonsetisaroundthemenopause.

• FunctionalimpairmentismorelikelythanwithnodalOA.

• The key differential diagnosis is psoriatic arthritis. Unfortunately, the two

conditions can be indistinguishable on plain radiographs in the early stages

and on ultrasound unless there are other psoriatic disease features such as

skin/nailpsoriasisortenosynovitis.

LargejointOA

• The knee is commonly affected; most often the patellofemoral and medial

tibiofemoralcompartments.

• Severeboneandcartilagelossleadstoinstabilityandvarus(bow)deformity.

• Instability and ‘giving way’ of a knee may be exacerbated by quadriceps

weakness.

• Hip OA tends to present as groin, buttock, or anterior thigh pain on weight

bearing,ratherthanlateralhipdiscomfort.

• Differential diagnosis for hip and groin pain include iliopsoas dysfunction,

ischialbonelesions,symphysis,andtrochantericpainsyndrome.

• SubdivisionofhipOAisusuallymadeonthebasisofacetabularcartilageloss

patterns:

• Superiorpole:commonpattern,oftenunilateral,morecommoninmen,and

likelytoprogress.

• Central(medial):lesscommon,usuallybilateral,morecommoninwomen,

andlesslikelytoprogress.

• Indeterminateacetabular-concentricpatternsarealsodescribed.

SecondaryOA

SecondaryOAisassociatedwithawidevarietyofdisordersaslistedinTable

6.3.

Table6.3SecondaryOA

Trauma Inflammatoryarthritis

Metabolic/endocrine:

Haemochromatosis

Acromegaly

Hyperparathyroidism

Ochronosis(alkaptonuria)

Crystaldepositiondisease:

Calciumpyrophosphate

Uricacid

Hydroxyapatite

Neuropathicdisorders:

Diabetesmellitus

Anatomicalabnormalities:

Bonedysplasia

Investigation

• ThediagnosisofOAisbasedonclinicalandradiologicalfindings.Thereare

nospecificlaboratorytests.

• As the disease progresses, other findings may appear and aid diagnosis,

includingosteophytes,subchondralbonesclerosis,andsubchondralcysts.

• Radiographscorrelatepoorlywithsymptomsandclinicalfunction.Manyolder

patients will have radiographic changes consistent with OA, but will be

asymptomatic.

• MRI is better at identifying early articular cartilage loss, subchondral bone

oedema,andlow-gradesynovitis,butitisrarelyused.

• Laboratorytests(includingsynovialfluidanalysis)maybeusefultoexclude

other causes of joint pain, such as RA, though abnormalities and pattern of

acute phase may be similar for PsA and calcium pyrophosphate deposition

disease.

• There are biomarkers of tissue destruction and inflammation that may

eventuallytranslatefromresearchsettingstoclinicaluse,including:

• cartilageoligomericmatrixprotein(COMP).

• pyridinolineandbonesialoprotein.

• metalloproteinases.

• hyaluronan.

• C-terminalcross-linktelopeptideoftypeIIcollagen(CTX-II).

• Opticalcoherencetomography(OCT)imaging:usesinfraredlight(inasimilar

waytosonography)toproducehigh-resolutiondynamicimages.Thisresearch

toolmaytranslatetoclinicalpractice.

Management

Management is based on symptoms and the impact of symptoms and joint

structuralchangesincluding the effect on qualityoflife, function, occupation,

leisure,andsleep.

• Functional requirements are addressed by therapists following therapy

assessment(occupationalandphysiotherapy).

• Occupational therapy can provide splints, aids, safe environment, and joint

protectiontechniques.

• Exerciseisakeytreatmentinmanycasesasitimprovesmusclestrength,joint

proprioception,andaerobicfitness.

• Patient expectations influence the use of analgesia and referral for surgical

procedures.

• Weight isassociatedwith anumber of typesof OA inweight-bearingjoints

and islinkedto poor prognosis. Weightlossistherefore important asakey

intervention.

• Psychosocial factors (mood and relationships) may influence symptoms and

impactofOAandrequiretherapeuticinputoccasionally.

• A multi-disciplinary approach is sensible. In the UK, NICE has produced

guidelinesformanagementofOAinadultsthatemphasizeaholisticapproach

tailoredtothepatient’sspecificneeds.

• NICE identifies core treatments that should be offered to all patients, in

addition to the use of pharmacological and adjunctive treatments based on

patientneeds(Box6.1).

Pharmacotherapies

• NSAIDsandCOX-2inhibitorsmaycanbeeffectiveforuseinshortperiods

duringinflammatorydiseaseflares.

• UK NICE guidance emphasizesNSAIDusefor the shortest time and atthe

lowestdosepossibleandwithcautioninolderpatients.

• Cardiovascular adverse events appear equal between conventional NSAIDs

andCOX-2inhibitors.

• The addition of local anaesthetic to intra-articular GC injection does not

improveefficacy,butmayreducepainfromtheinjections.

• Asymptomaticeffusionsdonotrequireintra-articularinjection.

• Most jointinjection dataarefor kneeOA.Infection israre (<1:10,000),but

care should be taken to clean overlying skin and avoid injecting through

infectedskinorpsoriaticlesions.Patientsshouldbewarnedoftheriskofskin

depigmentationandfatatrophy.Itisadvisedthatpatientsreceivenomorethan

3–4injectionsperyear,each≥3monthsapart

• Intra-articularinjectionofhyaluronicacidderivatives(viscosupplementation)

isnotsupportedbyrobustdataandisnotsupportedbyUKNICEguidance.

• Oralglucosamineandchondroitinsulphatesupplementshavebeenshownin

RCTs and meta-analyses to be no better than placebo, and are not

recommendedbyNICEintheUK.

• Evidence that avocado/soybean unsaponifiable supplementation, evening

primroseoil, rosehipextract,blue-lipmusselextract,and omega-3fish oils

improvepainislimited.

Box6.1OA:Diseasemanagementprinciples

Coretreatments

• Holistic,patient-centredcareplan.

• Provisionofwrittenandverbalinformation.

• Adviceonfootwear.

• Exercise.

• Weightloss.

Adjunctivetreatments

• TENSmachine.

• Braces,walkingaids,andinsoles.

• Thermotherapy:cold/warmmeasurestoreducesymptoms.

Pharmacologicaltreatments

Initial

• Regularparacetamol1g3–4timesdaily.

• Topicalanti-inflammatorygels(NSAIDs).

• Topicalcapsaicincream.

Subsequent

• OralNSAIDs/COX-2inhibitors±protonpumpinhibitor.

• Intra-articular glucocorticoids (useful during flares; duration of benefit

variable).

Rarely

• Codeine–paracetamolcombinationanalgesics.

• Buprenorphine.

• Gabapentinorpregabalin.

Surgical

• Arthroscopiclavage/debridementifmechanicallocking.

• Jointreplacementforactivity-limitingsymptomaticOA—mayreducepain

ratherthanincreasefunction.

Futuretherapeuticstrategies

CurrentOAresearchisfocusingondisease-modifying anti-osteoarthritisdrugs

(DMOADs),withtheaimofpreventingjointdamage.Approachesinclude:

• Inhibition of RANK ligand-mediated subchondral bone resorption using

monoclonalantibodies.

• Bisphosphonates reducing bone loss—putatively anti-(subchondral bone)

resorption.

• InhibitionofcathepsinK,apotentproteaseinvolvedindegradationoftypeI

collageninbonematrix.

• Vitamin D supplementation, which will optimize calcium absorption and

reducePTH,slowingboneresorption.Studiesareyettobedone.

• Diacerein,anIL1blocker,hasbeenshowntoreducejointspacelossinhipOA

over3yearsinoneRCT.Furtherstudiesneedtobeperformed.

• Mesenchymal stem cell therapy—precursor cells capable of differentiating

intoosteogenic,chondrogenic, or adipogeniccells. Several clinicaltrials are

ongoinginearlyphases.

Reference

3. NICE. Osteoarthritis: Care and Management. Clinical Guideline 177. London: NICE, 2014.

https://www.nice.org.uk/guidance/cg177

Prognosis

KneeOA

• Progressioninthekneemaytakemanyyears.Cohortstudieshavefoundthat

radiographicdeteriorationoccursinone-thirdofcases.

• BMIpredictsprogressionofpatellofemoralOA.

• For tibiofemoral compartment OA, patients with contralateral knee OA, a

baselineindexkneeOAgradeof1,higherbodymassindex(BMI)andhigher

baseline Western Ontario and McMaster Universities arthritis index total

scoresaremorelikelytodevelopKellgren&Lawrencegradeof3or4within

5years.

HipOA

• Progressionofhipdiseaseisvariable.ADanishstudyfoundthat66%ofhips

worsened radiologically over 10 years, although symptomatic improvement

wascommon.

• Heterogeneity of prediction factors is found across studies and within study

populations.

• Clinicalcharacteristics(highercomorbiditycountandpresenceofkneeOA),

healthbehaviourfactors(nosupervisedexerciseandphysicalinactivity),and

sociodemographics(lowereducation)havebeenfoundtopredictdeterioration

ofpain(weakevidence).

• Ahighernumberofcomorbiditieshavebeenfoundtopredictdeteriorationof

physicalfunctioning(strongevidence).

Chapter7

Crystal-inducedmusculoskeletaldisease

Goutandhyperuricaemia

Calciumpyrophosphatedepositiondisease

Basiccalciumphosphatecrystal-associateddisease

Calciumoxalatearthritis

Goutandhyperuricaemia

Goutisacommon,painful,andpotentiallydestructiverheumatologicdisorder,

related to hyperuricaemia. The clinical consequences of uric acid or urate

(monosodium urate (MSU)) crystal deposition include acute and chronic

arthritis,tophusformation,nephrolithiasis,andgoutynephropathy.

Epidemiology

• Several epidemiologic studies from different countries suggest that the

incidence and prevalence of gout is increasing, perhaps related to better

recognition,andchangesinlifestyleanddiet.

• In the UK, gout affects 25 per 1000 of the population, and accounts for

250,000 GP consultations per year. Prevalence data from the USA on self-

reportedgoutestimatethat13.6per1000adultmalesand6.4per1000adult

femalesareaffected.

• Goutismorecommoninmiddle-agedandelderlypeople.

• Theriskfactorsforgoutarethesameasthoseforhyperuricaemia(Table7.1).

Classificationcriteria

• ThecurrentACR/EULARguidelinesstipulate,for theclassificationof gout,

the occurrence of ≥1 episode (‘attack’) of joint or bursal swelling, pain or

tenderness.

• MSUcrystalsin(symptomatic)synovialfluidorfromatophusissufficientfor

diagnosisofgout.

• Thedomainsofthecriteriainclude:

• clinical (pattern of joint involvement, characteristics, and time course of

symptomaticepisodes).

• laboratory(serumuricacid(SUA)levels).

• synovialfluid(aspirateanalysisforcrystals).

• imaging (radiographic gout-related erosion, double-contour sign on

ultrasound,orMSUcrystalsondual-energyCT).

Clinicalfeatures

• Thefirststageoftheconditionisusuallyasymptomatichyperuricaemia(SUA

>680mg/L)oftenstartingyearsbeforesymptomsdevelop.

• Thisconcentrationmarksthephysiologicalpointabovewhichuratesaltsare

no longer soluble in the serum at physiologic pH and temperature. Not

everyonewithhyperuricaemiadevelopsgout,however.

• Inflammation to MSU crystals is typically sudden and severe and is often

referredtoasan‘attack’ofgout.

• Theinitialattackcommonlyoccursinthefourthtosixthdecadeoflifeinmen,

andinpostmenopausalwomen.

• The initial attack is usually monoarticular, affecting the first

metatarsophalangealjoint(podagra)inupto60%ofpatients.

• Otherfrequentlyinvolvedjointsincludetheankle,midfoot,knee,wrist,elbow

(olecranonbursa),andthesmalljointsofthehands.

• Axialandlargejointsandspinalstructuresarerarelyinvolved.

• With an attack, pain reaches its maximum intensity in 4–12 hours, with

marked limitation of physical function. Symptoms usually resolve in 3–14

days.

• 70–80%ofindividualswillhaveanotherattack(s)within2years.

• Theinitialattacksareusuallyseparatedbyasymptomaticinter-criticalperiod,

lastingmonthstoyears.

• Asthediseaseprogresses,acuteattacksmaybecomemorepolyarticular,with

associated joint damage and deformity. Intervals between attacks tend to

shorten. Disability, chronic pain, and tophi formation can be observed if

treatmentissuboptimal(see Plate7).

• TophiaredepositsofMSUembeddedinamatrixcomposedoflipids,proteins,

andcalcificdebris:

• Tophi are usually subcutaneous, but have been reported to occur in bone,

eyes,andotherorgans.

• Classicsitesfortophiformationincludeearpinna,elbowandkneebursae,

Achillestendon,anddorsalsurfaceoftheMCPJs.

• Tophi are usually painless, although the overlying skin may ulcerate and

becomeinfected.

• Those most at risk of tophi are patients with prolonged severe

hyperuricaemia,polyarticulargout,andtheelderlywithprimarynodalOA

ondiuretics.

• Someclinicianswilltreatasymptomatichyperuricaemiatopreventtheonset

of‘uratenephropathy’;butthisiscontroversial.

• Hyperuricaemia and gout are associated with the metabolic syndrome

(dyslipidaemia,hypertension,obesity,andinsulinresistance).

Investigation

• Synovialfluidanalysisisthemostimportantinvestigation.

• Negativelybirefringent,needle-shapedcrystalsonpolarizedlightmicroscopy

confirmsthediagnosis.

• Crystalsmaybeextra-orintracellular.However,theabsenceofcrystalsdoes

notruleoutthediagnosis.

• MSU crystals are identifiable in the synovial fluid from previously affected

joints and about 70% of those receiving SUA-lowering therapy during the

asymptomaticinter-criticalperiod.

• SUA concentrations may be normal during an acute attack in up to 30% of

cases, and may not reflect pre-flare levels. Therefore, SUA concentration

cannotbeusedtoexcludethediagnosisduringanacuteflare.

• SUAconcentrationsareofvalueinassessingthepatientonlyoncetheacute

flare has subsided; either to confirm hyperuricaemia or to monitor the

effectivenessoftherapy.

Table7.1Thecausesofhyperuricaemiaandriskfactorsforgout

Primarygout Malegender

Increasingage(inwomen)

Ethnicity

Beingoverweight

Diet(purinerichdiet)—particularlyredmeat,oily-fish,

shellfish,sugarydrinks,andfructose-richfoods

Alcoholuse(beerappearingtoposethehighestrisk)

Renalinsufficiency

Hypertension

Inherited

metabolic

syndromes

X-linkedHPRTdeficiency(Lesch–Nyhan),X-linked

raisedPRPPsynthetaseactivity.AutosomalrecessiveG6P

deficiency(vonGierke’sdisease)

Uricacid

overproduction

Cell lysis: tumour lysis syndrome, myeloproliferative

disease,haemolyticanaemia,psoriasis,trauma.

Drugs:alcohol,cytotoxicdrugs,warfarin

Uricacid

underexcretion

Renalfailure

Drugs:alcohol,salicylates,diuretics,laxatives,ciclosporin,

levodopa,ethambutol,pyrazinamide

Leadtoxicity Renalimpairmentandalteredpurineturnover

G6P,glucose-6-phosphatase.G6Pdeficiencyleadstoincreasedactivityofaminophosphoribosyl

transferaseandpurineformation;HPRT,hypoxanthineguaninephosphoribosyltransferase—asalvage

enzymeconvertinghypoxanthinebacktoprecursorsandthereforecompetingwithitsconversionto

xanthineandthenuricacid;PRPP,phosphoribosylpyrophosphatesynthetase—acomponentenzymein

purineringsynthesis.

Imaging

• Imagingfindingsvaryatdifferentstagesofgout.

• Plainradiographsareoftennormalduringtheearlyphaseofthedisease,but

softtissueswellingcanbeapparent.

• Radiographs are useful to assess for other conditions such as trauma or

infection (Box 7.1). Subcortical bone cysts may be suggestive of tophi or

erosions. Para-articular erosions with ‘overhanging edges’ of bone are

characteristicofgout.

• Later in the disease, radiographs may demonstrate tophi near joints, tissue

swelling, para-articular erosions, periosteal new bone formation, and joint

deformity.ManyfeaturesmimicRA.

• US can be useful to detect early disease and monitor treatment. Diagnostic

featuresincludea lineardensity paralleltothe jointsurface (double-contour

sign), or tophaceous deposits which appear as oval stippled signal

(hyperechoiccloudyarea).

• Dual-energyCTspecificallyidentifies MSUdepositsanddistinguishesthem

fromcalciumdeposition.

Box7.1Clinicalconditionsthatcanmimicgout

• CPPDdisease(pseudogout)

• Basiccalciumphosphate(BCP)arthritis

• Cellulitis

• Infectious(septic)arthritis

• Trauma(cancoexistwithgout)

• Rheumatoidarthritis(polyarticular)

• Psoriaticarthritis(monoarthritis/dactylitis)

• Erythemanodosum

• Reactivearthritis(monoarthritis/dactylitis).

Management

Themanagementofgoutshouldbeapproachedintwophases:thetreatmentof

theacuteattackandthetreatmentofchronicortophaceousgout(Fig.7.1).

Theacuteattackofgout

• Rest,elevation,andicepackscanpartlyeasesymptoms.

• The principal therapies are NSAIDs, colchicine, and oral and intra-articular

(IA)glucocorticoids(GCs).

• SUA-loweringdrugsareineffectivein acutegout. Patientsalready onSUA-

loweringdrugs,shouldcontinuewithoutinterruption.

• NSAIDsdecreasepain,swelling,anddurationofgoutattacks.

• All NSAIDs, including COX-2 selective NSAIDs, have potentially similar

efficacyforgout.

• NSAIDsaremosteffectivewheninitiatedwithin48hoursofsymptomonset.

Thedosemaybereducedafterareductioninsymptoms,anddiscontinued1–2

daysaftercompleteresolutionofsigns.

• The typical duration of NSAIDs required for an acute attack is 5–7 days.

NSAIDsarecontraindicatedinrenalinsufficiency(e.g.CKD3b–5).NSAIDs

shouldbeusedwithcautionintheelderlyandpatientswithGIriskfactors.

• Colchicine can be very effective in acute gout, and have a rapid onset of

action. Oral colchicine 0.5 mg, two to four times daily, for 5 days can be

effectivebutmaycausediarrhoeaathigherdoses.

• ColchicineisoftengiveninadditiontoNSAIDs,althoughthereisnoevidence

to support this. IV colchicine is no longer used due to high risk of bone

marrowsuppressionanddeath.

• Oralprednisone10–30mgdailyiseffectiveforimmediatereliefofgout,with

dosethentaperedover7–10days.

• ParenteralGCsmaybeusedinindividualsunabletotakeoralformandwith

polyarticulargout.A study comparingintramuscular triamcinolonewith oral

indometacinfoundnosignificantdifferenceintimetorecovery.

• IAGCsareusefulif≤4jointsareaffected.Asystematicreviewonthesafety

andefficacyofIAGCsforacutegoutcouldnotidentifyanyRCTsoftheiruse.

• IAGCsshouldbeavoidedifsepticarthritisispossible.

• IL-1 inhibitors are under study for acute gout. IL-1β is the predominant

mediatorofacuteinflammation.

• Anakinra 100 mg SC daily has been used until symptoms improve with

goodeffect.

• Canakinumab150mgSCislicensedforacutegoutinEurope.

• In one study comparing SC canakinumab with IM triamcinolone,

canakinumabachievedbetteroutcomesintermsofpainrelief,jointswelling

reduction,andpatient-assessedglobalresponse.

• Canakinumab is effective in patients either with multiple gout ‘flares’ or

whosedisease isrefractory toother treatmentorhavecontraindicationsto

othermedications.

• However, canakinumab is associated with increased infections, and at the

timeofwritingis5000×thecostoftriamcinolone.

Fig7.1Themanagementofgout.GC,glucocorticoid;IM,intramuscular;NSAID,non-steroidalanti-

inflammatorydrug;PPI,protonpumpinhibitor;SUA,serumuricacid.

Treatmentofchronicortophaceousgout

• Addressing adverse lifestyle factors and comorbidities should be a priority,

includingto:

• attainanormalBMI(20–25)/reducecentripetalobesity.

• reduce, orpreferentiallystop, consumptionofalcohol, red meat,shellfish,

andsugarydrinks.

• managehypertensionandassociatedhypertriglyceridemia.

• encouragetodrinklow-fatmilkdaily(anaturaluricosuric).

• remainwellhydrated.

• consider how best to minimize treatments which can aggravate

hyperuricaemia (e.g. thiazide, furosemide, indapamide, ciclosporin,

levodopa,theophylline).

• The target SUA with all drug therapy is <360 µmol/L (6 mg/dL) or <300

µmol/L(5mg/dL)wherethereisseveregout.Goutattacksareveryunlikely

whereSUAisbelowtarget.

• DrugsthatdecreaseSUAlevelsareindicatedinindividualswithfrequentor

disabling attacks of gout, clinical or radiological evidence of chronic gouty

arthropathy, tophaceous disease, with secondary renal impairment, or

urolithiasis.

• SUA-loweringdrugsareinitiated2–4weeksafteranacuteflaresubsides,as

theymayprolongorworsentheacuteflare.

• Allopurinol(axanthineoxidaseinhibitor)isthefirst-linetreatment:

• Allopurinolisinitiatedat100mgdailywithincrementaldosetitrationevery

month,aimingtolowerSUAto≤300mg/L.

• Thedoserangeofallopurinolis100–900mgdaily.

• Mostpatientsrespondto400mgdailyofallopurinol.

• Dosingshouldbeadjustedforrenalimpairment.

• Allopurinoltakes4daysto2weekstotakeeffect.

• Approximately 5–10% of patients develop significant drug intolerance:

nausea,diarrhoea,elevatedtransaminaselevels(3–5%).

• Severe hepatic disease including granulomatous hepatitis, cholestatic

jaundice,andhepaticnecrosisarerare.

• About2%ofpatientsdevelopapruritic,maculopapularrash.Pruritisalone

canheraldtheonsetofrash.

• Bonemarrowsuppressionoccursrarely—athighdoses.

• HLA-B*5801 status increases the risk of developing allopurinol drug

reactioneosinophiliaandsystemicsymptoms(DRESS).

• Inmildtomoderateintolerance,allopurinolcanbereintroducedatverylow

levels(e.g.10mgdaily)andtitratedupslowly.

• Allopurinolcaninterferewiththemetabolismofazathioprineandwarfarin,

increasingtheriskofsideeffects.

• Concomitant colchicine (0.5 mg twice daily orally) is recommended as

prophylaxis against acute flares for the first 3–6 months of allopurinol

treatment.

• Febuxostatisanon-purinexanthineoxidaseinhibitor:

• FebuxostatismoreeffectiveatloweringSUAthanallopurinol,andmaybe

usedinpatientsallergictoallopurinol,patientsnotattainingtargetSUAat

maximalallopurinoldose,andinpatientswithmoderaterenalinsufficiency.

• Dosesrangefrom40to120mg/day.

• Dosereductionisrequiredinpatientswithrenaldysfunction.

• Sideeffectsincludenausea,liverdysfunction,arthralgia,andrash.

• Somestudieshaveshownahigherincidenceofcardiovascularsideeffects

withfebuxostatcomparedwithallopurinol.

• Febuxostatissubstantiallymoreexpensivethanallopurinol.

• Some patients may respond to allopurinol and a uricosuric agent (e.g.

probenecid)wheneitheralonehasbeenineffective.

• Uricosuric drugs should be avoided in patients with renal insufficiency or a

historyofnephrolithiasis.

• Fenofibrate decreases SUA by increasing renal uric acid clearance. It may

haveanunlicensedroleinpatientsresistantorintoleranttoothertreatments.It

should be avoided in hepatic and biliary disease, hypothyroidism and

pregnancy.Sideeffectsincludemyoarthralgias.

• Sulfinpyrazoneisauricosuricdrugwhichiseffectiveandwelltolerated,butis

contraindicated in patients with renal stones and is ineffective in those with

renalinsufficiency.

• Benzbromarone is a uricosuric agent available in Europe. It is effective in

patientswithrenalinsufficiency.Liverfunctionmustbemonitoredfordrug-

inducedhepatitis(fulminantliverfailurereported).

• Pegloticase is a porcine uricase reserved for patients with severe gout, in

whomothergouttreatmentshavebeenineffective.Administrationis8mgIV

every 2 weeks.Concomitantcolchicine prophylaxis is recommended forthe

first6monthsofuse.Anti-pegloticaseantibodieshavebeenreported.

• Rasburicase is a non-pegylated recombinant uricase. It may be more

immunogenicthanpegloticase.

• Patients with uric acid stones are best managed with adequate hydration,

urinary alkalization, and allopurinol. This regimen is also effective in

preventingcalciumoxalatestones.

• Goutytophimaybeamenabletosurgicalremoval.

Calciumpyrophosphatedepositiondisease

• SeeBox7.2foranoverviewofEULARdefinitionsandclinicalpresentations.

• Precipitationofcalciumpyrophosphate(CPP)crystalsintissuesisextremely

common and arguably the most common reason why previously ill

hospitalizedpatientsdevelopMSKproblemswhenunwellinhospital.

• The spectrum of CPP crystal deposition disease includes acute and chronic

arthropathy, inflammation and symptoms at entheses or within/involving

tendons, soft tissue and bursal inflammation, asymptomatic cartilage

calcification,andsymptomsfromspinalcanalandintervertebraldisccrystals.

Box7.2EULARdefinitionsofcalciumpyrophosphate(CPP)deposition

(1–3)andclinicalpresentationsofCPPdeposition(CPPD)disease

1.CPPcrystals

Simplifiedtermforcalciumpyrophosphatecrystals.

2.CPPD

TheumbrellatermfordepositionofCPPcrystals.

3.CC

Cartilage calcification, identified by imaging or histology—but not always

duetoCPPD.

AsymptomaticCPPD

Maybeofnoclinicalconsequence;butthedegreetowhichcartilageorother

soft tissue CPP crystals increase the risk of significant MSK lesions (e.g.

osteoarthritis, intervertebral disc degeneration, chronic enthesopathy, spinal

stenosis)islargelyunknown.

AcuteCPPDarthritis

Acuteself-limitingsynovitis.

CPPDdiseasewithosteoarthritis(OA)

CPPcrystalsinajointwhichisosteoarthritic.

ChronicCPPDarthritis

Typicallyaffectswrists,2nd/3rdMCPJs,hips,knees(mimicsRAbutisACPA

negative).

SpinalCPPDdiseasetypes

Inflammation proven or suspected around the odontoid (‘crowned dens

syndrome’),causingorcomplicatingintervertebraldiscdiseaseorassociated

with ligament flavum thickening contributing to spinal and/or lateral recess

stenosis.

OtherCPPD(possiblyallCC)-relatedlesions

Tendoninsertion/enthesis-basedinflammationassociatedwithCPPD;boxing-

glove-likehand/wristswellingfeaturesofacutedisease.

• TheriskofCPPD-relateddiseaseincreaseswithage.Presentationinayoung

adult<50yearsoldshouldpromptasearchforanassociatedmetaboliccause.

• Definite associations with CPPD disease and chondrocalcinosis (i.e.

calcificationof fibrocartilageandhyaline cartilagetypically oftheknee and

wrist)include:

• Hypomagnesaemia (check Mg, PTH, vitamin D, bone profile and renal

function).

• Hypophosphatasia (low ALP, raised serum pyridoxal-5 phosphate and

increasedurinaryphophoethanolamine).

• Haemochromatosis (positive family history, abnormal LFTs, raised

haemoglobin, ferritin and transferrin saturation, and disease-associated HFE

genotype).

• Wilson’s disease (neurological disease, abnormal LFTs, eye disease, and

abnormallylowserumcaeruloplasmin).

• Hyperparathyroidism (primary, secondary, and tertiary in renal disease). So

checkPTH,boneprofile,renalfunction/estimatedGFR,andvitaminD).

• Vitamin D deficiency—chronic (through causing secondary

hyperparathyroidism).Checkasforhyperparathyroidism.

• Possible CPPD disease associations include gout, ochronosis, hypocalciuric

hypercalcaemia,diabetes,DISH,andXLHR.

• ThemainprecipitantsofanacuteCPPDdiseaseepisode(ifinajointhistorical

termwas‘pseudogout’)arelistedinBox7.3.

Box7.3FactorsthatmaytriggeracuteCPPD-inducedinflammation

• Acuteillness(e.g.chestorurinaryinfection).

• Directtrauma(e.g.jointcartilagedamageortendontear/strain).

• Post-surgical.

• Especiallypost-parathyroidectomy.

• BloodtransfusionorIVfluids.

• Commencementofthyroxinereplacement.

• Jointlavage.

Investigation

• CPPDdiseaseisdefinedbythepresenceofpositivelybirefringent,rhomboid-

shaped crystals under polarized light microscopy of synovial fluid. Crystals

maybeintra-orextracellular.

• Radiographs of the affected joints may not be helpful in establishing the

diagnosis.However,thepresenceofchondrocalcinosisincreasesthelikelihood

of CPPD disease. Radiographic clues that may help to distinguish CPPD

diseasefromOAinclude:

• axialinvolvement.

• sacroiliacerosions.

• corticalerosionsofthefemur.

• osteonecrosisofthemedialfemoralcondyle.

• associated hyperparathyroid disease signs: endocortical erosions of long

bonesinthehandsandfeet,corticaltunnelling,andosteopeniainphalanges.

• US features indicative of CPPD include a thin hyperechoic band along the

cartilage, running in parallel to the bony cortex (‘tram-lines’). Sites can

include the MCPJs, wrists, knees, and tendons. Nodular deposits in bursae,

entheses,andhyperechoiclinesparalleltotendonscanalsobeobserved.

• BothCTandMRImaybeneededtodisclosediseaseinspinalstructures:MRI

to show inflammatory changes and CT to disclose the distribution of

calcification(see Plate22).

Management

AcuteCPPD-relatedarthritis

• ThemanagementofacuteCPPDdiseaseissummarizedinFig.7.2.

• Rest,ice,andsplintingintheacutephasewillhelpsymptoms.

• NSAIDsintheacutephase.

• Oralcolchicine(0.5mg,twotofour timesaday)canbe usedinpatients in

whomNSAIDsarecontraindicatedintheacutesettingorasprophylacticuse

topreventrecurrentflares(seeFig.7.2).

• JointaspirationandIAGCinjectionforacutejointinflammation,oncejoint

infectionhasbeenexcluded(see Chapters24).

• Oral GCs will undoubtedly help in the acute setting but the dose should be

reviewedandminimizedtoavoidlong-termuseandsteroiddependency.

• AnakinrahasbeenusedinpolyarticularacuteCPPDdisease,unresponsiveto

othermedications.

• AsinallCPPDcases,identifyandmanageassociatedmetabolicabnormalities.

ChronicCPPDarthritis/disease

• DiseasemaymimicRAifpolyarticularandcancausepersistentinflammatory-

typespinalsymptoms.

• Ongoing metabolicinfluencesof CPPDdiseasemay need addressing.Renal

disease, hyperparathyroidism (primary, secondary, or tertiary (but for

secondaryalsoconsidervitaminDdeficiency)),andchronicdehydrationmay

allplayarole.

• Hydroxychloroquine(200–400mgdailyintwice-dailydosesfortrialperiodof

4monthsforexample)ormethotrexate(e.g.15mgweeklyfortrialperiodof6

monthsinitially)maybetriedinpatientswithresistantdisease.

• Arguably there is more evidence to support the use of methotrexate than

hydroxychloroquine.

Fig.7.2Managementofcalciumpyrophosphatedeposition(CPPD)disease.GC,glucocorticoid;GORD,

gastro-oesophagealrefluxdisease;IA,intra-articular;NSAID,non-steroidalanti-inflammatorydrug;PPI,

protonpumpinhibitor.

Reference

1. Zhang W, Doherty M, Pascual E, et al. EULAR recommendations for calcium pyrophosphate

deposition.PartII:management.AnnRheumDis2011;70:571–5.

Basiccalciumphosphatecrystal-associated

disease

• Basiccalciumphosphate(BCP)crystalsincludehydroxyapatite,octacalcium

phosphate,andtricalciumphosphate.

• BCP and associated crystals are associated with several rheumatological

diseases(Table7.2).

• ThetreatmentoftheseconditionsisasperCPPDdisease,withNSAIDsand

colchicine(see Chapter23,forfurtherdetails).

Table7.2BCPcrystal-associatedconditions

Articular

disease

Milwaukeeshouldersyndrome(severedegenerative

arthropathy,morecommononthedominantsideandinelderly

women)

Osteoarthritis(synovialfluidcrystalsfoundin60%ofOA

patients)

Erosivearthritis

Mixedcrystaldeposition

Periarticular

disease

Pseudopodagra,calcifictendonitis,andbursitis

Calciumoxalatearthritis

• Crystals are positively birefringent and bipyramidal under polarized light

microscopyofsynovialfluid.

• Radiographsandlaboratorytestsarenotdiagnostic.

• Mostlabswillnothavetheexpertisetospecificallyidentifythesecrystalson

synovialsamples.

• TreatmentisasforCPPDdisease.

• Severalconditionsareassociatedwithcalciumoxalatearthritis(Box7.4).

Box7.4Conditionsassociatedwithcalciumoxalatearthritis

• End-stagerenaldiseaseondialysis.

• Shortbowelsyndrome.

• Dietrichinrhubarb,spinach,andascorbicacid.

• Thiaminedeficiency.

• Pyridoxinedeficiency.

• Primaryoxalosis:recessivetrait,earlyrenalfailure(inthethirddecadeof

life),arthritis,tendonitis.

Chapter8
Thespondyloarthritidesincludingpsoriatic
arthritis
Introduction
Spondyloarthritis(SpA):aparadigmshift
AxialSpAincludingankylosingspondylitis
Psoriaticarthritis
SpA-associatedreactivearthritis
Inflammatoryboweldisease-relatedSpA
Juvenilespondyloarthritis
Introduction
Allspondyloarthropathies(SpAs)arecommonlycharacterizedbyinflammatory
backandaxialskeletalpains,enthesitis,andanassociationwithHLA-B27.
• TheSpAsare:
• Axialspondyloarthritis(axSpA).
• Ankylosingspondylitis(AS;encompassedbyaxSpAdefinition).
• Psoriaticarthritis(PsA).
• Reactivearthritis(ReA).
• Inflammatoryboweldisease-relatedSpA.
• JuvenileSpA/enthesitis-relatedarthritis(ERA;see Chapter9).
• Considered together the SpAs are the most common form of chronic
inflammatoryarthritis;morecommonthanRA.
• AllSpAsarepotentiallymanifestby:
• enthesitis.
• inflammatorybackpain.
• asymmetricperipheralarthritis.
• inflammatorybowellesions.
• psoriasis.

• dactylitis.

• osteitis.

• sterileurethritis.

• uveitis(typicallyacuteanterioruveitis).

• aorta/aorticvalvelesions(rare).

• abnormalantigenpresentationassociatedwithHLA-B27.

• Similarities exist between SpAs and the SAPHO (synovitis, acne,

palmoplantar pustulosis, hyperostosis, aseptic osteomyelitis) syndrome;

SAPHOisnotconsideredtobeaSpA;see Chapter16.

• Pathologicalchangesaremainlyatenthesesbutalsointissuesofthegut,uveal

tract,urethra,aorta,bone,synovium,andskin.

• Acommoninflammatory‘target’orprecisecommonreasonwhysuchtissues

mightbeaffectedispostulatedthoughnotyetproven.

• Linesofimmunopathologyresearchcurrentlyfocusongeneralandlocaltissue

resident Th17 cell activation by Il-23 and subsequent activating effects

specifictothelocaltissueenvironment.

Spondyloarthritis(SpA):aparadigmshift

KeytoclassifyingallSpAsisthepresenceofinflammatorybackpain(Box8.1)

and,forday-to-dayclinicalrecognition—thepresenceofenthesitis(Box8.2).

• Sadly,thereisstilla7–10-yeardelayinasizablenumberofpatientsbetween

symptomonsetanddiagnosisofankylosingspondylitis(AS)—similardatato

data derived>30years ago. One reason isthatit takes many years insome

patientstoconfirmASasitisbasedpartlyonradiographiccriteria(ofSIJs)

whichcantakeyearstoevolve(Box8.3).

• The classification of axial spondyloarthritis (axSpA; see the Assessment of

Spondyloarthritis International Society (ASAS) working group criteria:

http://www.asas-group.org)includesclassicalASaswellasearlierstagesand

abortive courses of the disease, in which structural alterations have not yet

occurred.

• ASAS has facilitated classification of SpA in terms of axial or peripheral

predominantdisease.

• The new ASAS criteria (for axSpA; Box 8.4) potentially allow all patients,

who will ultimately develop AS, to be identified earlier in their disease

comparedwiththemodifiedNewYork(mNY)criteria.

• However, it is likely that not all ASAS axSpA classifiable patients will

progresstoanASphenotypeclassifiablebythemNYcriteria.

• Previously, early SpA disease was recognizable formally only through a

definition (ESSG) of ‘undifferentiated SpA’ (USpA). Many such patients

would now be classifiable by the newer ASAS working group criteria for

(peripheral)SpA(Box8.5).

• Recently,classificationcriteriaforPsAhavealsobeendeveloped(CASPAR;

see ‘Psoriaticarthritis’,pp.308–313).

Box8.1Inflammatorybackpain(IBP)

AhistoryofIBPiskeytoconsideringaxialsymptomsassecondarytoSpA—

forpeopleinwhomitstartsat<40yearsofage.Applicableforbackand/or

posterior pelvic symptoms.A number of descriptionsexist(e.g.after Calin,

Rudwaleit,orASAS).Typically,IBP:

• comesongraduallyovertime(insidiousonset).

• isimprovedwithexercise.

• doesnotimprovewithrest.

• causespainatnightwithimprovementongettingup.

• isreportedbypatientsasoccurringwith“stiffness”.

• improveswitha(‘once-daily’)modified-releaseNSAIDtakenatbedtime.

Box8.2Enthesitis

Anenthesisisthenamegiventospecializedtissuewhichattachesaligament

ortendontoabone.ExamplesincludetheattachmentsoftheAchillestendon

to os calcis, the origin of the finger extensor tendons at lateral humeral

epicondyle, the gluteus tendon insertion at the greater trochanter, or the

attachmentsofthepatellaligament.

AxialSpAincludingankylosingspondylitis

The diagnosis of axial spondyloarthritis (axSpA) includes classicalankylosing

spondylitis(AS)aswellasearlierstagesandabortivecoursesofthedisease,in

which(radiologicalevident)structuralalterationshavenotyetoccurred.Cases

ofthelattermightbealsoclassifiedasnon-radiographicaxSpA(nr-axSpA).

For a comparison of the ASAS criteria for classification for axSpA and

peripheralSpA,seeBox8.4andBox8.5.

EpidemiologyofAS(onmodifiedNewYorkcriteriaorearlierdefinitions)

• There isanextensive wealthofdata ontheepidemiology ofASdefined on

mNYandearliercriteria.

• Patientsaretypically<40yearsofagewithaM:Fratioof3:1.

• TheconditionoccursmostfrequentlyinCaucasians.

• In Pima American Indians, where HLA-B27 prevalence is high, AS is

particularly frequent, whereas the condition is less common in African

Americans, and rarer still in sub-Saharan Africans, reflecting the low

prevalenceofHLA-B27inthesegroups.

• Prevalenceestimateis0.5–0.8/100,000inCaucasianadults.

• Epidemiology data necessarily depend on patients satisfying criteria for

diagnosisthatnecessarilymeanstheyhavehadtheirdiseasearelativelylong

time(tohaveradiographicchangesatSIJs).

EpidemiologyofaxSpA

• OneimplicationofthisparadigmshiftisthatadefinitionofaxSpAresultsina

definedpatientprevalencemuchhigherthanhasbeenacceptedforAS(based

onmNYcriteria,forexample).

• There is an evolving understanding of the prevalence of axSpA based on

ASAScriteria.

• Studies of modelling disease prevalence suggest that axSpA is considerably

morecommonthanAS.

• ItislikelythatthefrequencyofaxSpApatientsinanygivencohortofIBPor

chronic back pain patients, is higher than previously defined for an AS

definition (e.g. 29% of patients with IBP met the criteria for nr-axSpA and

39%ofpatientswithchroniclowbackpainhadIBP).

Box8.3ModifiedNewYork(mNY)criteriaforclassifyingAS

Clinicalcriteria

• Lowbackpainandstiffnessfor>6months,improvingwithexercise,butnot

relievedbyrest.

• Limitationoflumbarspinemovementsinsagittalandfrontalplanes.

• Limitationofchestexpansionrelativetonormalvaluesforageandsex.

Radiologicalcriteria

• Greaterthanorequaltograde2bilateralsacroiliitis.

• Grade3or4unilateralsacroiliitis

Combineddiagnosticcriteria

• DefiniteASifradiologicalandclinicalcriterion.

• ProbableASifthreeclinicalcriteriaoraradiologicalcriterionwithoutsigns

orsymptomssatisfyingtheclinicalcriteria.

Adapted from Van der Linden et al. ‘Evaluation of diagnostic criteria for

ankylosingspondylitis.’ArthRheum,1984;27:361–368withpermissionfrom

Wiley.

Box8.4ASAScriteriaforclassificationofaxialSpA

Inpatientswith≥3months’backpainandageatonset<45years:

either

Sacroiliitisonimagingplus≥1SpAfeature

HLA-B27plus≥2otherSpAfeatures.

SpA features: IBP, arthritis, enthesitis (heel), uveitis, dactylitis, psoriasis,

Crohn’s/colitis,NSAIDresponse,familyhistoryofSpA,HLA-B27,CRP+

Sacroiliitis on imaging: either active (acute) inflammation on MRI highly

suggestive of sacroiliitis associated with SpA, or definite radiographic

sacroiliitisaccordingtothemNYcriteria

InformationfromRudwaleitMetal.ThedevelopmentofAssessmentofSpondyloArthritisinternational

Societyclassificationcriterialforaxialspondyloarthritis(partII):validationandfinalselection.Ann

RheumDis2009;68:777–783.

Box8.5ASAScriteriaforperipheralSpA

Arthritisorenthesitisordactylitis

(clinicallyassessed)

plus

≥1SpAfeature

(uveitis,psoriasis,Crohn’s/colitis,precedinginfection,

HLA-B27,sacroiliitisonimaging)

≥2otherSpAfeatures

(arthritis,enthesitis,dactylitis,IBP(ever),

familyhistoryforSpA)

InformationfromRudwaleitMetal.ThedevelopmentofAssessmentofSpondyloArthritisinternational

Societyclassificationcriteriaforperipheralspondyloarthritisandforspondyloarthritisingeneral.Ann

RheumDis2009;70:25–31.

Pathogenesis

HLA-B27andgenetics

• HLA-B27 is associated with the SpAs in 50–95% of patients. In most

populations,HLA-B27isprevalentinabout10%.

• HLA-B27isinheritedasautosomalco-dominant:50%offirst-degreerelatives

ofprobandswithHLA-B27possesstheantigen.

• 5–10%ofHLA-B27-positivepeopledevelopASovertime.

• 20% of people with HLA-B27 develop a reactive arthritis after bacterial

infectionwithChlamydiaorSalmonella.

• About 50% of patients with psoriatic or inflammatory bowel disease-related

spondylitisareHLA-B27positive.

• 50%ofnon-CaucasianswithASareHLA-B27positive(<theprevalenceof

HLA-B27inCaucasianswithAS;95%).

• Concordanceinmonozygotictwinsis70%vs13%indizygotictwins.

• HLA-B27 isfound inupto 40%of casesof uveitis,evenin theabsence of

underlyingrheumaticdisease.

• ThereisanexcessofHLA-B27prevalenceinpatientspresentingwithisolated

aorticrootorvalveinsufficiency.

• HLA-B27 has been found in 90% of males with a combination of aortic

regurgitationandconductionsystemabnormalities.

• GenotypingstudieshaveshowntwoASsusceptibilitylociinadditiontoHLA-

B27:ERAP1andthegeneencodingtheIL-23receptor.Theformercodesfor

anaminopeptidaseoftheERinvolvedintrimmingpeptidestoanoptimalsize

forbindingtoMHCclassImolecules.

• HLA-B27 is probably relevant to pathogenesis by (possibly non-exclusive)

mechanismscurrentlysummarizedaseither:

• allowingabnormallyrestrictedT-cellimmuneresponsestoself-antigensor

arthritogenicpeptides.

• itself misfolding during assembly and leading to endoplasmic reticulum

stressandautophagyresponses.

• itself triggering innate T-cell, NK cell pro-inflammatory responses by

presentingonthecellsurfaceashomodimersandbeingrecognizedbythese

cells.

Immunopathology

• Thereisdebateoverwhetheroneoranumberofmicroorganismscontributeto

pathophysiology.

• IncreasedfaecalcarriageofKlebsiellaaerogeneshasbeenreportedinpatients

with established AS and may relate to exacerbation of both joint and eye

disease.

• ThereisincreasingevidencethataxSpAandASareduetoanabnormalhost

response to the intestinal microbiota with involvement of Th17 cells, which

playakeyroleinmaintainingmucosalimmunity.

• ThisleadstoproductionofvariousinflammatorycytokinesincludingIl-12,Il-

23,Il-17,andTNFαwhichplaykeyrolesinthepathogenesisofenthesitisand

otherinflammatorylesions.

• Th17cellsmayberesidentintissuesandactivatedtherecausinglocaltissue

inflammationandtriggeringlocaltissuechanges.

ClinicalfeaturesofaxSpAandAS

• HallmarkfeaturesofaxSpAareIBP,fatigue,andenthesitis.

• MostaxSpAlesionsoccuratentheses,subenthesialbone(osteitis),intendons

andsynovium(see Plate24).

• Typical entheses affected include plantar fascia origin at os calcis medial

calcanealtubercle,Achillesinsertionsatoscalcis,extensordigittendonorigin

at lateral humeral epicondyle, and gluteus medius insertion at greater

trochanter(seealsoTable8.4).

• Synovitiscanoccur,typicallyinthelargerperipheraljoints(hipsandkneesin

particular).Though20–40%ofpatientshaveperipheraljointdiseaseatsome

stage,studieshavenotpreviouslyshownwhetherthefeaturesaresynovitisor

enthesitisorboth.

• About50%ofpatientswithadultASwilldevelophiparthritis.

• The standardized mortality ratio for AS is 1.5, due to cardiac valve and

respiratorydisease,amyloidosis,andfractures.

• ASpatientsarehighriskforhavingtoalterorgiveupwork.

• Although recognizedastypical ofAS,few patientsprogressto the classical

late‘bamboospine’.

• When spine segments do fuse in AS (syndesmophytes bridging the gap

betweenvertebralbodies),microfracturescanoccurleadingtoacuteepisodes

ofseverepain.

• Spondylodiscitisisanuncommonthoughseverelesion:acuteasepticdiscand

end-plateinflammation.

• Theburdenofspinaldiseaseistypicallyvariablechroniclow-gradeIBPand

stiffnesswithevidenceofreductioninspinalmobility.

Non-musculoskeletalclinicalfeatures

• Constitutionalfeaturesof fatigue,weight loss,low-grade fever,andanaemia

are common. Fatigue is often the most troublesome symptom for many

patients.

• IBD lesionsarepresent inabout50% ofASpatients thoughlesionsare not

symptomaticinallpatients.

• Uveitis occurs in up to 40% of cases, but has little correlation with disease

activityinthespine.

• Therearenoknowntriggersforuveitisandalthoughself-limiting,topical,or

systemic steroids may be required in severe cases. The uveitis is

predominantlyanteriorandmostlyunilateral.

• Upperlobe,bilateralpulmonaryfibrosisisarecognizedbutrarefeatureofAS.

Occasionally, the fibrotic area is invaded by Aspergillus with changes

mimickingtuberculosis.

• InlateAS,fusionofthethoracicwallleadstorigidityandreductioninchest

expansion. Ventilation is maintained by the diaphragm; however, there is a

threefoldincreasedriskofdeathfromarespiratorycausecomparedwiththe

normalpopulation.

• Cardiac involvement includes aortic incompetence, cardiomegaly, and

conductiondefects.Ofthe20%ofASpatientswithaorticvalvedisease,the

majorityareclinicallyundetectable.

• NeurologicallesionsarearareconsequenceofspinalMSKdisease:nerveroot

entrapmentandcaudaequinasyndrome.

• Sterileurethritisisanunder-recognizedSpAlesion.

• RenalinvolvementisrarebutcanbeduetoNSAIDuse(interstitialnephritis)

orrenalamyloidosis.

• Osteoporosisisanunder-recognizedfinding:

• ASpatientsareathighriskofvertebralfracture.

• Micro-fractures may occur with trauma and fractures can occur through

syndesmophytes.

• Systemic osteoporosis occurs and is identifiable through hip and forearm

BMDmeasurement.

• Estimates of osteoporosisprevalencerange from 20–60%, increasingwith

ageanddiseaseduration.

• DXAevaluationoflumbarspineBMDwillbeinaccurateinadvancedAS

duetothepresenceofsyndesmophytes.

• Studies suggest that bone loss occurs early and during the acute

inflammatorystageofthedisease.

InvestigationsinaxSpA

• Systemicmeasuresofacute-phaseresponseareoftendetectedthoughtypically

alsocanbenormaldespitesymptoms.

• Plain AP, or ‘coned’ view radiographs of the posterior pelvis are

conventionallyusedtodetectestablishedsacroiliitis.

• RadiographicSIJchangesmayinitiallybeasymmetric.Latechangesinclude

subchondralsclerosis,erosions,andfinallyankylosis.

• Conventional axial skeletal signs on spine and pelvis radiographs include

squaringofvertebrae,syndesmophytes,spinalligamentossification,Romanus

lesions,pelvicenthesophytes,andosteitispubis.

• Radiograph detection of syndesmophytes requires a distinction to be made

between DISH and AS syndesmophytes. Generally, DISH patients present

later than AS patients, have paramarginal syndesmophytes, frequently

asymmetric in thoracic spine and have OA (DISH may be associated with

chondrocalcinosisandCPPDdisease).

•

99m

Tc-MDPbonescintigraphyissensitiveforSIJinflammation,andscanscan

identify significant peripheral skeletal lesions from a single study through

obtaining‘spot’peripheralviews.

• CTprovidesexcellentimagesoftheSIJsandsensitivelydetectspreviousSIJ

lesionsbutcannotdatethelesionsandisnotaninvestigationtousetodetect

currentinflammation.

• MRI of SIJs show active inflammatory lesions but subtle previous SIJ

pathologycanbemissed.

• MRIdiscriminatesspinalDISHfromASindoubtfulcases.

• Bothfat-suppressedMRIandUScandetectinflammationatenthesesthough

theabsenceofinflammatory‘signal’onMRIorDopplersignalonUS,does

notruleoutenthesisdiseaseaspartofSpA.

DiseasestatusandprognosticindicatorsinaxSpA/AS

TherearevalidatedinstrumentsmeasuringdiseasestatusinASincludingBath

indices,ASASresponsecriteria,andqualityoflifeindicators.

• Historically,forstagingandmonitoringAS,theBathindiceshavebeenused

(devisedinBath,UKbyAndreiCalin’sgroup):

• BathAnkylosingSpondylitisFunctionalIndex(BASFI).

• BathASDiseaseActivityIndex(BASDAI;Box8.6).

• BathASMetrologyIndex(BASMI).

• BathASRadiologyIndex(BASRI)(seeTable8.1).

• The AS disease activity score (ASDAS) combines simplified self-reported

clinicalindiceswithameasureofESRorCRP.TheperformanceofASDASto

discriminatelowandhighdiseaseactivityandcut-offvaluesarequitesimilar

in patients with AS and axSpA (  http://www.asas-

group.org/clinicalinstruments/asdas_calculator/asdas.html).

• ASAS have defined response criteria for therapies used in AS.

 These

measures (ASAS 20, ASAS 40, ASAS 5/6; see Box 8.7) incorporate some

Bathmeasures,areincreasingusedandmorewidelyvalidated(inanaxSpA

definition of disease), and may update the BASDAI (alone) as favoured

disease(treatment)responsemeasures.

• Anumberofqualityoflifemeasurescanbeused(e.g.ASQoL

• A number of enthesitis indices have been developed (Table 8.1). In clinical

practice,eitherMASESorSPARCCaremostuseful:

• Themostfrequentlyusedradiographicindexofskeletalspinechangesisthe

Modified Stoke AS Spinal Score. It is based on the degree of vertebral

erosion, sclerosis, and squaring and the presence of syndesmophytes and

theirdegreeofvertebralbridging.

• MRIspinalosteitisscoringforresearchpurposes:SPARCCindex.

• ThemainpredictivefactorsofpooroutcomeinASaretobe:

• hipinvolvement,earlylossoflumbarspinemobility.

• oligoarticulardisease;lowsocial–educationalbackground.

• sporadicdiseaseratherthanfamilial;onset<16years;ESR>30.

• poorinitialresponsetoNSAIDs;presenceofdactylitis.

Box8.6MeasuringdiseaseactivityinASandaxSpA:BathASDisease

ActivityIndex(BASDAI)andASdiseaseactivityscore(ASDAS)

BASDAIdescription

The assessment comprises six questions. Patients score each as 0–10 on a

linearscale.Scoresareweightedandacompositescoreisgenerated.

ASDASdescription

Ona0–10scale,thepatientscoresbackpain,durationofmorningstiffness,

their assessment of global disease, a score of peripheral pain and stiffness,

thenacontributionofeitherCRPorESRisaddedandacompositescoreis

generated.

Availability

ABASDAIcalculatorisavailableonlineat http://basdai.com/

ASDAS is available online at  http://www.asas-group.org/clinical-

instruments/asdas_calculator/asdas.html

Performanceofindices

• In AS, BASDAI has long since been shown to have validity in

discriminatinghighandlowdiseaseactivityindifferentpopulationsandis

responsive to change over a practical duration of disease. BASDAI has

historicallybeenadoptedwidelyasausefulindexofASdiseaseactivity.

• ASDAS-CRP and ASDAS-ESR have similar performance to BASDAI in

discrimination of high and low disease activity, and change in disease

activitygenerallyandwithanti-TNFαtherapy,bothinASandinaxSpA.

Table8.1Enthesitisindices(EIs)forASassessment

Enthesitisindex

(reference)

Comments

MANDER(Ann

RheumDis

1987;46:197–

202)

TheoriginalEI.Scorestendernessat66entheses.

Impracticalandusedlittleinresearch

MASES(Heuft-

Dorenbosch.

AnnRheumDis

2003;62:127–

32)

Relativelywellvalidated.Scores13enthesesaseither

‘tenderornon-tender’.IncludesASIS,PSIS,iliaccrest,

Achillesinsertion,sternalattachment1stand6th/7thrib

andoveruppersacrum

SPARCC

(Maksymowych.

AnnRheumDis

2009;68:948–

53)

Scores18enthesesaseither‘tender’or‘non-tender’

(superiomedialgreatertrochanter,quadricepsinsertionat

patella,inferiorpatellapole,tibialtuberosity,Achilles

insertion,plantarfasciaorigin,medialandlateral

epicondylesandsupraspinatusinsertion)

BERLINEI

(Braun.Lancet

2002;359:1187–

93).

Notextensivelyvalidated.Scores12entheses.

UCSFEI

(Gorman.NEngl

JMed

2002;346:1349–

56).

Scores17entheses.Performswellinassessmentofanti-

TNFαinAS

Box8.7ASASresponsecriteria

ASAS improvement criteria (ASAS-IC). Four domains, based on the

discriminationbetweentreatment(originallyNSAID)andplacebo:

• Physicalfunction,measuredbytheBASFI.

• Spinalpain,measuredona0–100mmvisualanaloguescale(VAS).

• Patientglobalassessmentinthelastweek,ona0–100mmVAS.

• Inflammation,measuredasthemeanofthelasttwoBASDAIquestions

ASAS20%responsecriteria(ASAS20).Treatmentresponsedefinedas:

• ≥20% and ≥10 mm VAS on a 0–100 scale in at least 3 of 4 ASAS-IC

domains,andnoworseningof≥20%and≥10mmVASona0–100scalein

4thdomain.

ASAS40%responsecriteria.Treatmentresponseisdefinedas:

• ≥40%and

• ≥20mmVASona0–100scaleinatleast3of4ASAS-ICdomains,andno

worseningof≥40%and≥20mmVASona0–100scalein4thdomain.

ASAS5outof6responsecriteria(ASAS5/6).Developedforuseintrialsof

anti-TNFα therapy. Treatment response defined as improvement in 5 of 6

domainswithoutdeteriorationinthe6thdomain,usingpredefinedpercentage

improvements:

• Pain

• Patientglobalassessment

• Function

• Inflammation

• Spinalmobility

• C-reactiveprotein(acute-phasereactant).

ThetreatmentofaxSpAincludingAS

Generaltreatment

• UKNICEguidelineformanagementofaxSpA2017.

• Treatmentprinciplesareindicatedandincludethefollowing:

• Patienteducation.

• Exercises(see http://www.nass.co.uk).

• Otherphysicaltherapyandhydrotherapy.

• Avoidsmokinggivenitspro-inflammatoryeffects.

• NSAIDsforIBPandenthesitis.

• Oralglucocorticoid(GC)orIMmethylprednisolone.

• With exercise the emphasis is placed on the need to maintain posture and

physical activity. Spinal extension exercises are important as the natural

historyofthediseaseotherwiseleadstospinal‘stoop’,lackofbackextension,

andlossofheight.

• Physiotherapy provides benefit in the short term. Spa treatment improves

functionforupto9monthsandreduceshealthresourceuse.

• Fatigue isnot easilytreatedthough someeffort toimprovesleep healthand

maintainsomeaerobicexercisemayplayapositiverole.

NSAIDsandsyntheticDMARDs(sDMARDs)

• Forthemajorityofpatients,NSAIDsremainthetreatmentofchoice.Regular

full-doseNSAIDuseisoftenrequired.

• Continuous, rather than intermittent NSAID (including COX-2 selective

NSAIDs)mayslowradiographicprogressionofaxialskeletalchangesbutthe

researchevidenceoverallisweak.

• Sulfasalazine(SSZ)hasbeenshowninameta-analysistobeefficaciouswhen

compared with placebo for peripheral joint disease only. However,

improvementinsymptomsandqualityoflifeisnotdramatic.

• Mixedresultshavebeenfoundwithmethotrexate.ACochranemeta-analysis

concludedthatthereisinsufficientevidencetosupportitsuseinAS.Benefit

maybelimitedtopatientswithperipheraldisease.

• Joint inflammation can be managed in acute, severe cases with IA GC

injections.

• CareshouldbetakeninjectingGCaroundtendons,asrupturecanoccurifthe

injectionisplacedintothetendonitself.

• Steroid injection around the Achilles tendon can help/is safe if there is

paratenoninflammationalone(precedingimagingadvisable).

• TopicalGCeyedropsshouldbeusedtotreatuveitis.Ifthesymptomspersist

for>3daysanophthalmologicalopinionshouldbesought.

• IV bisphosphonates can help spinal osteitis symptoms. Pamidronate 90 mg

monthlycanbeused.Zoledronicacidcanresolveosteitislesionsfor3months

inamajorityofpatients.

BiologicDMARDs(bDMARDs)

• Anti-TNFα bDMARDs are effective in AS in reducing symptoms and

inflammation though there is debate on whether they can reduce the

progressionofstructuralskeletalchanges(infliximab,etanercept,adalimumab,

certolizumab,andgolimumab).

• IntheUK,NHSanti-TNFαisrecommendedfortreating‘severeactive’ASin

adultswhosedisease hasresponded inadequatelyto,or whocannottolerate,

NSAIDs.Infliximabisrecommendedonlyiftreatmentisstartedwiththeleast

expensiveinfliximabproduct.

• Infliximab is licensed to treat AS at a dose of 5 mg/kg (compared with 3

mg/kg used in RA), though published data suggest AS can be frequently

treatedtoremissionwith3mg/kgdosing.

• Remission of disease following anti-TNFα treatment is more common the

earlier in the disease course anti-TNFα is used. These consistent findings

highlight the need for early identification of AS and prompt treatment plan

implementation.

• Evidence overall now supports the efficacy and safety of anti-TNFα in nr-

axSpA. Secukinumab is the first drug targeting the Il-17 pathway in

radiographic-axSpA(AS)thathasshownefficacy.

• Anti-TNFα therapy recommendations in UK (NICE TA383)

 are now

availablebasedontheASASdefinitionofnr-axSpA.

• Secukinumab (monoclonal anti-IgG1

 ) is the first drug targeting the Il-17

pathway(ittargetsIl-17A)andislicensedtotreatASandPsA.Atadoseof

150 mg(monthly SCafter 4initial weeklydisease) ithas shownefficacyin

twophaseIIIRCTs(NNTtoachieveASAS40response:3–4).

• Ustekinumab(monoclonalantibodytargetingthecommonsubunitofbothIl-

12 and Il-23) and tofacitinib (JAK inhibitor) have shown positive results in

phaseII/proof-of-concepttrials.

References

1. Burgos-Vargas R, Wei JCC, Rahman MU, et al. The prevalence and clinical characteristics of

nonradiographicaxialspondyloarthritisamongpatientswithinflammatorybackpaininrheumatology

practices:amultinational,multicenterstudy.ArthritisResTher2016;18:132.

2. Zochling J, Braun J. Assessment of ankylosing spondylitis. Clin Exp Rheumatol 2005;23(Suppl

39):S133–41.

3. DowardL,SpoorenbergA,SCookS,etal.DevelopmentoftheASQoL:aqualityoflifeinstrument

specifictoankylosingspondylitis.AnnRheumDis2003;62:20–6.

4. NICE.SpondyloarthritisinOver16s:DiagnosisandManagement.[NG65]London:NICE,2017.

https://www.nice.org.uk/guidance/ng65

5. NICE. TNF-alpha Inhibitors for Ankylosing Spondylitis and Non-Radiographic Axial

Spondyloarthritis.[TA383]London:NICE,2016. https://www.nice.org.uk/guidance/ta383

Psoriaticarthritis

Epidemiology

Psoriasis(Ps)affectsupto3%ofthepopulation.Theheterogeneityofclinical

featuresofpsoriaticarthritis(PsA),thenumerousclassificationcriteriaexisting

forithistorically,anduntilrecentlypoorunderstandingofitslesionsandtheir

detection,haveimpliedgreatuncertaintyinknowingthetrueprevalenceofPsA

(seeBox8.8).

• HistoricestimatesoftheprevalenceofPsAsuggestitispresentinupto40%

ofpatientswithPs.MoreconservativeestimatessuggestPsAoccursinabout

10–20%ofthePspopulation(i.e.0.5–1%ofthewholepopulation).

• However, estimates have not adequately considered the overall likely

prevalenceofPsAinallitsforms,andgivenobviousdifficultiesinidentifying

PsA sine Ps and defining disease without peripheral joint synovitis (e.g.

enthesopathic forms and forms characterized by tendonitis and/or enthesitis

and/orspinaldiseasealone).

• Theconditionaffectswomen andmen equallywithusualonsetbetween the

agesof20and40years.

Box8.8CASPARclassificationcriteriaforPsA

CASPAR updates previous criteria: Moll and Wright 1973; Vasey and

Espinoza1984;Gladman1987,McGonagle1999,Fournie1999.

Inflammatoryarticulardisease(joint,spineorenthesis)

with≥3pointsfromthefollowing:

(1pointeachunlessstated)

• CurrentPs(scores2points)

• HistoryofPsin1st-or2nd-degreerelative

• Psoriaticnaildystrophy

• IgMRFnegative*

• Currentdactylitis

• Historyofdactylitis

• Juxta-articularnewbone.**

*Byanymethodexceptlatex.

**Ill-definedossificationnearjointmargins(excludingosteophytes)onradiographsofhandsorfeet.

Pathophysiology

Genetics

• Ps is familial. There are about 40–50 genes which are associated with an

increasedoddsratioofdevelopingpsoriasis.

• Genetic factors also have an important role in PsA and family studies have

suggestedthattheheritabilitymayexceed80%.

• VariantsintheHLA-BandHLA-Cgenesarethestrongestgeneticriskfactors

butothervariantsexist.

Immunopathogenesis

• Many variants overlap with those implicated in Ps where there may be >40

susceptibility loci, and lie within or close to genes in the IL-12, IL-23, and

NFκBsignallingpathways.

• Itisthoughtthatanenvironmentaltrigger,probablyamicroorganism,triggers

thediseaseingeneticallysusceptiblepeople,leadingtoactivationofdendritic

andTcells.

• CD8+Tcells,whichrecognizeantigenpresentedinthecontextofHLAclass

I,aremoreabundantthanCD4+Tcellswithinthejointwhichisinkeeping

withthegeneticassociationbetweenPsAandHLA-Cand-Bvariants.

• Il-23/Il-17pathwayplaysapivotalroleinPsA.

• A triggering stimulus maycauseover-production of Il-23bydendriticcells,

which then promotes differentiation and activation of Th17 cells which

produceIl-17A.

• Il-17Aand Th1cytokinessuchasIFNγ andTNFα,act onmacrophages and

tissue-resident stromal cells at entheses, in bone, and within the joint to

produce additional proinflammatory cytokines and other mediators which

contributetoinflammationandtissuedamage.

Clinicalfeatures

• Ps-relatedMSKsymptomscanpresentwith,before,oraftertheonsetofPs.

The situation for nail disease is the same. In some cases, gaps between

presentationsofthedifferentaspectsofPsdiseasecanbemanyyears.Some

patientscangothroughlifewiththeirPsAandnevergetPs.

• MSK imaging research has shown lesions exist at entheses of tendon and

ligaments,inthenailbed,inbone,andonbonesurfaces(adjacenttoentheses,

probablyperiostea).Synovitismaywellbeasecondarylesionduetoadjacent

enthesitisandbynomeansanessentiallesionofPsA.

• Naillesionsarenotalwayspresentbutdistinctive.Naillesionsoccurin40%

ofpatientswithPsalone.See Plate8.

• FatigueisaconsistentandoftenseveresymptomofPs-relateddisease.

• Dactylitis,swellingofthewholefinger,occursinoverone-thirdofclassically

definedPsApatients.

• In about 20% of PsA cases there is a chronic, progressive, and deforming

arthropathy with an often-asymmetrical pattern including DIPJ involvement,

orarthritismutilans,and/orpolydactylitisand/orlargejointdeterioration.

• Some clinical patterns of PsA that have been written about historically are

listedasfollows.However,itisprobablethatpatternsdonotalwayspersistin

anyindividualandasyetnodistinctgenotypeorimmunopathologicalfeatures

segregateinassociationwiththesedescriptivepatternsofdisease:

• DIPJpredominantdisease.

• Asymmetricoligoarthritis.

• Symmetricalpolyarthritis.

• Spinepredominantdisease(estimates2–40%).

• Enthesopathicpredominantdisease.

• Arthritis mutilans is a classic but uncommon manifestation of PsA. Bone

resorption leads to collapse of the soft tissue in the digits, creating

‘telescopingfingers’.

• It is not clear, however, if the patterns of disease have any prognostic

significanceinthemselves.

• Adverse prognostic factors in the 1995 Toronto cohort were polyarthritis,

greaterHAQ,andincreaseinuseofsDMARDs.

• Persistentdactylitisisamarkerofassociateddigitsmalljointdeterioration.

• TheradiologicalfeaturesassociatedwithPsAthathelptodifferentiateitfrom

RAandinflammatorygeneralizedOAinclude:

• absenceofjuxta-articularosteoporosis.

• absenceofsubchondralplatechangesinearlydisease.

• DIPJ disease (with marginal changes initially and an absence of early

subchondralplatechanges).

• ‘whittling’(lysis)ofterminalphalanges.

• asymmetryofjointinvolvement.

• ‘pencil-in-cup’deformities.

• ankylosis.

• periostitis (often ‘fluffy’ juxta-articular periosteal new bone—see  Plate

23).

• spondylitis (asymmetric ‘floating’ syndesmophytes, spondylodiscitis, facet

joint(FJ)changes—thoughFJappearancesinPsAarenotatallwell-defined

givenapresumedcommonfindingofOAaffectingFJsandpoordefinition

todateofjuxta-articularnewboneinPsAFJs).

ClinicalassessmentinPsA

• The variationin clinicalfeaturesbetween patients,the potentialformultiple

MSK lesions, and involvement of spine structures has historically led to a

difficulty in establishing agreed and universal classification criteria for PsA

andconsequentlyindesigningapplicabletreatmentoutcomeassessmenttools

forPsA.

• Typically,assessmentshavebeenadoptedfromtheiruseinRA.Somesalient

pointsare:

• DAS68shouldbeusedratherthanDAS28forassessingjointtendernessand

swelling.

• Though all have been developed for AS, different enthesitis indices (see

Table8.4)canbeappliedtoPsA.

• Thoughrepresentingsomemethodologicalchallenges,thePASIremainsthe

bestassessmentofPsskinresponsetotreatment.

• Comprehensive PsA assessment requires an index (indices) to allow

measurementofthe responseofjoint, tendon, enthesis,nail, spine, andskin

diseasetotreatment,butalsotomeasuregeneralhealthandfunctionchanges

capturingtheeffectsoffatigueandmood.

• Composite indices have been proposed. DAPSA: Disease Activity for

Psoriatic Arthritis; PsAJAI: Psoriatic Arthritis Joint Activity Index; CPDAI:

CompositePsoriaticDiseaseActivityIndex.Indiceshavebeensummarized.

• TheonlyenthesitisindexwhichhasbeendevelopedspecificallyforPsAisthe

LeedsEnthesitisIndex(LEI).Itscoressixenthesesscoringtenderness(1)or

no tenderness (0) at lateral humeral epicondyles, over medial femoral

condyles,andatAchillesinsertions.

• An index of minimaldiseaseactivity(MDA) has been proposed.

 A patient

withPsAisdefinedashavingMDAwhen5of7ofthefollowingarepresent:

• Tenderjointcount≤1.

• Swollenjointcount≤1.

• PASI≤1orBSA≤3.

• PatientpainVAS≤15/100.

• PatientglobalactivityVAS≤20/100.

• HAQ≤0.5.

• Tenderentheses≤1.

Theextendedpsoriasis-relateddiseasecomorbidities

• Comorbidities, which require screening for in Ps patients, include arterial

hypertension, dyslipidaemia, obesity, diabetes mellitus, metabolic syndrome,

non-alcoholic steatohepatitis (NAFLD), depression, nicotine abuse, alcohol

abuse,chronicinflammatoryboweldisease,andlymphoma.

• In the UK, screening Ps patients for PsA using PEST is currently

recommended( http://www.bad.org.uk/library/).

• TheassociationofmetabolicsyndromewithPsAinpatientswithorwithoutPs

isunknown.

• Hyperuricaemia is associated with Ps and PsA. An association of PsA with

gouthasbeenrecognizedforalongtime.

TreatmentofPsA

Generaltreatment

• Patient education about the various lesions of PsA, their relapsing and

remitting nature, and about the risk of long-term comorbidity risk is of

increasingimportance.

• Encouraging patient group participation may be helpful (e.g. in the UK:

PAPAA( http;//www.papaa.org).

• Localizedlesionsmayrespondtorest,ice,andphysiotherapy.

• Comorbidities need to be addressed: obesity, cardiovascular risk,

hyperuricaemia,depression(e.g.screenwithHADS).

• PhysiotherapyassessmentparticularlyifthereisIBP.

NSAIDsandsyntheticDMARDs(sDMARDs)

• TreatmentistailoredtothesiteandnumberofMSKlesions.

• NSAIDswouldbeexpectedtohelp.

• sDMARDs have conventionally been reserved for patients who have

inflammatory disease threatening joint integrity; however, with multiple site

and/or severe symptoms, fatigue, Ps, and a potential impact from multiple

symptoms on function and contributing to comorbidities, many specialists

regardsDMARDtherapyintroductionwhollyreasonablewhenbasedonsuch

symptom-basedand‘holistic-view’criteria.

• Evidence for unequivocal sDMARD efficacy is not strong though some

evidenceexistsformethotrexate(MTX),leflunomide(LEF),andciclosporin.

Evidence is weaker still for SSZ, hydroxychloroquine (HCQ), gold,

penicillamine,andazathioprine(AZA).

• The first-line sDMARD choice of many rheumatologists for PsA remains

MTX.ThisisreflectedintheEULARguidelineformanagingPsA.

• Essentially,theEULARguideadvocates:

• Phase1:NSAIDsandGCinjections.

• Judgephase1responseagainsttreatmenttarget.

• Iftargetnotreached:phase2—startMTX.

• IfcontraindicationstoMTX:startLEF.

• Iftargetnotreached:phase3—startanti-TNFα.

• Ifaxialdiseasealone,onfailureofphase1:startanti-TNFα.

• Many clinicians would advocate relevant efficacy only occurs at the higher

weeklydosesofMTX(20–25mg/week).

• HCQcanaggravatepsoriasis(seeSummaryofProductCharacteristicsforthe

drug).

• Oral and IM GCs might be generally avoided in patients with Ps because

althoughtheskindiseaseresponds,afterthesteroidsthere canbearebound

worseningofskindisease.

• GoodefficacyonjointdiseaseinPsAisestablishedwithallanti-TNFαdrugs;

however, criteria for study recruitment and judging outcome with all anti-

TNFαdrugshasbeensetfairlyconventionallyandhasfocusedonjoints,and

therefore to a significant degree, on synovial disease (i.e. using ACR 20/50

outcome criteria or DAS28—both adopted from their development in

assessingRA,notPsA).

• In the UK, etanercept, infliximab, adalimumab and golimumab (see NICE

TechnologyappraisalguidanceTA199andTA220)



areapprovedbyNICE

for the treatment of PSA. All have positive effects on skin, as well as joint

disease.

• For UK NHS funded anti-TNFα treatment, PsA patients need to have

peripheral arthritis with ≥3 tender and ≥3 swollen joints and have not

respondedto,orfailedtotolerate,atleasttwostandardsDMARDsaloneorin

combination.

• EssentiallymergingUKNICErequirementsandEULARguidancesuggests

UKcliniciansneedtochooseMTXfirstthenLEFsecond,pre-anti-TNFα.

• IntheUK,NICErequiresanti-TNFαtreatedPsApatientsareassessedat12

weeks using validated outcome measures such as Psoriatic Arthritis

ResponseCriteria(PSARC)measurements.

• NICE rules do not require PsA patients to be simultaneously treated with

MTXwhilereceivinganti-TNFα.

• Forpatientswithsignificantnaildiseaseforwhomtopical(GC±calcipotriol)

therapy has failed, treatment with adalimumab, etanercept, intralesional

steroid,ustekinumab,MTXandacitretinarerecommended.

• Certolizumab pegol has shown efficacy in PsA also with specific effect

demonstrated on different MSK lesions and nail disease; however, it is not

authorizedfortreatmentinUKbyNICE.Someconcernhasbeenraised

that

this anti-TNFα drug is associated with greater risk for adverse effects

comparedwithotheranti-TNFαdrugs.

• Ustekinumab, a monoclonal antibody which binds to, and neutralizes IL-23

(specifically binds the p40 subunit common to Il-12 and Il-23 preventing

receptorbinding)hasbeenlicensedtotreatPsforsomeyears.

• Efficacy of ustekinumab in PsA importantly shows significant responses in

joint,dactylitis,andenthesitisextendingtoayearaftertreatmentinphaseIII

trials.

• IntheUK,NICEhasauthorizeduseofustekinumabforPsApatientswhohave

failedanti-TNFα.

• ThefindingthatIl-23stimulatedTh17cellactivation(includinggeneratingIl-

17) in SpAs and psoriasis has heralded a new approach to developing

bDMARDs targeting this immune activation pathway (e.g. the anti-Il-17A

monoclonalsecukinumabinphaseIIIdevelopment).

• Apremilast,anorallyavailablesmallmoleculeinhibitorofphosphodiesterase

4(PDE4),waslicensedbytheFDAintheUSAin2014andintheEuropean

UnionfortreatingPsA.

• In the UK, NICE has not authorized the use of apremilast (in the USA

marketedasOtezla

forPsandPsA)forbothPsandPsA.

• Apremilast compares favourably to placebo in patients failing previous

sDMARDtherapyinPsAbuthasnotdirectlybeencomparedwithhigh-dose

MTXtherapyalone.Apremilastisassociatedwithfrequentmildtomoderate

adverse effects but also weight loss, worsening depression, and suicidal

ideation.

References

6. WongPC,LeungYY, Li EK,etal.Measuringdiseaseactivityinpsoriaticarthritis.IntJ Rheumatol

2012;2012:839425.

7. CoatesL,FransenJ,HelliwellPS.Definingminimaldiseaseactivityinpsoriaticarthritis:aproposed

objectivetargetfortreatment.AnnRheumDis2010;62:48–53.

8. GossecL,SmolenJS,Gaujoux-VialaC,etal.EuropeanLeagueAgainstRheumatismrecommendations

forthemanagementofpsoriaticarthritiswithpharmacologicaltherapies.Ann RheumDis2012;71:4–

12.

9. NICE. Etanercept, Infliximab and Adalimumab for the Treatment of Psoriatic Arthritis. [TA199]

London:NICE,2010. https://www.nice.org.uk/guidance/ta199

10. NICE. Golimumab for the Treatment of Psoriatic Arthritis. [TA220] London: NICE, 2011.

https://www.nice.org.uk/guidance/ta220

11. SinghJA,WellsGA,ChristensenR,etal.Adverseeffectsofbiologics:anetworkmeta-analysisand

Cochraneoverview.CochraneDatabaseSystRev2011;2:CD008794.

SpA-associatedreactivearthritis

Backgroundandclinicalfeatures

• SpA-associated reactive arthritis (ReA) is a (‘lesion-aseptic’, i.e. lesions not

directly infected) inflammatory condition affecting spine and axial skeletal

structures, joints, tendons, and entheses triggered by infection with certain

bacteriaincludingChlamydia,Campylobacter,Salmonella,Shigella,Yersinia,

andpossiblyalsoClostridia,Ureaplasma,andMycoplasma.

• The risk of developing ReA after having one of these infections is ~1–4%

generallybut20–25%inpeoplewhoareHLA-B27positive.

• Non-SpA-associatedReAcanoccurafterviruses(particularlyparvovirus)and

Streptococcus (β-haemolytic), gonococcus, HIV, Borrelia (Lyme disease),

Mycobacterium (Poncet’s disease) and possibly other pathogens but the

characteristicsofReAfollowingtheseinfectionsarenotSpA-likeinclinical

featuresnorimmunopathologyandhavenoassociationwithHLA-B27.

• SpA-associatedReAisbasicallyanacuteformofSpA.Indeed,itispossible

that ReA is the triggering event in developing long-term SpA—a semantic

issue perhaps when considering the alternative—‘chronic ReA’, which

historicallyisregardedtooccurinasmallminorityofpatientswithacuteReA.

• A high index of suspicion of sexually acquired ReA (SARA) is required

particularlyinwomenwheregenitalChlamydiainfectioncanbeasymptomatic

inupto50%.

• The onset of reactive arthritis is usually acute with systemic symptoms and

inflammatoryMSKsymptoms.

• Differentialdiagnosisincludessepticarthritis,gout,andotherSpAs.

• Non-MSK symptoms worth noting are mucocutaneous features including

painless circinate balanitis of the glans penis, conjunctivitis, and pustular

psoriasisofthepalmsorfeet(keratodermablennorrhagica).

• InGIinfection-triggeredReA,theacuteGIsymptomsmayprecedetheMSK

symptomsby1–4weeks:

• InitialGIsymptomsmaybesomildastobeignoredbythepatientandoften

the provoking bacterium has cleared from the gut before the MSK

symptomsarise.

• Persistent bowel symptoms, particularly pain and diarrhoea should raise

suspicionofinflammatoryboweldisease.

• Recurrent or repeated infections do not always lead to a recurrence of ReA

MSKlesionsand,inthecaseofSARA,mayoccurintheabsenceoffurther

sexualintercourse.

InvestigationofSpA-associatedReA

• Acute-phaseresponsemeasuresareinvariablyhigh.

• IfSARAissuspectedfromsymptomaticurethritis,prostatitis,orcervicitis,or

if suspicion of SARA is high based on MSK and non-genitourinary (GU)

symptomsalone,referralforrigorousGUinvestigationisrecommended.

• Withtriggeringbowelinfections,oftenbythetimeReAisapparent,thenstool

culturewilllikelybenegative.

• Serological evidence of recent Yersinia or Campylobacter can be sought

(IgM+) but often delays from initial infection to ReA issues with assay

specificityimpedeuse.Forexample,recentparvovirusB19infectionleadsto

false-positiveELISAsforanumberofthesepathogens.

• SerologyforChlamydiainfection—C.pneumoniaeorC.trachomatis—isnot

recommended.

• Radiographs are of limited use. The distribution of inflammatory lesions at

SIJs,joints,andenthesescanbeconfirmedwithbonescintigraphy.

• Lumbar spinous processes and posterior pelvis MRI may show typical SpA

inflammatorylesions(osteitis,sacroiliitis,enthesitis).

• Regional MSK US may be useful in selected cases (e.g. of ‘hindfoot’ may

showenthesitisatAchillesinsertion,plantarfasciaorigin,anysynovitis,and

its site and fluid can be aspirated under US guidance for Gram stain and

cultureandforpolarizedlightmicroscopyexamination,toruleoutgout).

ManagementofSpA-relatedReA

• NSAIDs and local joint or enthesis GC injections are the mainstay of

therapeuticintervention.

• If symptoms persist >6 months and there is clinical evidence of ongoing

synovitisandjointdestruction,thenasyntheticDMARD(sDMARD)suchas

SSZormethotrexatemaybeconsidered.

• PhysiotherapyshouldbeconsideredifthereispersistentIBP.

• The majority of patients are in complete remission at the end of 2 years of

sDMARDtherapy,mostwithin6months.

• Balanitis and keratoderma may persist—predictors of poor prognosis. Other

factors that may be predictive of poor outcome include arthritis of the hip,

persistentlyraisedESR,B27positivity,poorresponsetoNSAIDs,dactylitis,

andlumbosacralspineinvolvement.

• Asepticurethritisandearlyconjunctivitisresolvequicklyandspontaneously.

• Antibiotictherapywillclearunderlyinginfections,butthismaynothaveany

effectonthedurationofReAdisease.

• Uveitis should be treated in the usual way with topical steroid drops and a

referraltoanophthalmologistiftherehasbeennoresponsewithin3days.

• Patienteducation,particularlyinthecontextoffoodhygieneandpreventionof

exposuretosexuallyacquiredinfection,isimportant.Contacttracingisvitalin

casesofsexuallytransmittedinfection.

• Anti-TNFαisreservedforcasesofsDMARDfailure.IntheUK,thereareno

specificNICEguidelinesfortreatingSpA-relatedReA.

Inflammatoryboweldisease-relatedSpA

Clinicalpresentation

• The clinical characteristics of inflammatory MSK symptoms presenting in

patientswithactiveCrohn’sdiseaseand(ulcerative)colitisareoftentypicalof

SpAlesionsandoccur,broadlyspeakingconsideringallstudies,inasizeable

minorityofIBDpatients.

• Epidemiologydatadependonwhetherpatientgroupsaredefinedfirstbytheir

IBDorbytheirSpA.

• InoneseriesofIBDpatients,sacroiliitiswaspresentin17%detectedbyMRI;

thoughofnote,non-inflamed,non-currentSIJdiseasemaybemissedbyMRI.

• Bycontrast,whenASoraxSpApatientsareinvestigatedforIBDrigorously,

bowellesionsareseeninabout50%ofpatients.

• WhetherIBD-relatedSpAisdistinctfromaxSpA(newASASdefinition)will

needtobeestablished;however,pre-ASASaxSpAdefinition,many,ifnotall

IBD-relatedSpApatientsmightbeclassifiedusingtheESSGcriteriaforSpA.

• In summary, there is still some uncertainty as to whether all cases of IBD-

relatedarthritisaretrueSpAs.

• The association of the inflammatory arthritis with IBD is arguably stronger

with Crohn’s disease than with UC. The association might be more visible

giventhelikelihoodthatthecorrelationbetweenactivityofIBDandseverity

ofMSKsymptomsisgreaterforCrohn’sthanitisforUC.

• In Crohn’s-associated inflammatoryarthritis/SpA, thearthritis tendstoremit

after surgical removal of diseased bowel tissue or tight control of enteric

inflammation.

• It is observed that MSK symptoms associated with IBD are greater if the

integrity of the ileocecal valve is lost. Speculatively, then, it may be that

bacterialcolonizationofpreviouslybacteria-freesmallbowelisakeytrigger

inpathogenesisoftheSpA.

• Lesionscanbediscordantbysomeyears.IBDcanevolve(sometimesyears)

followingtheonsetofSpA(e.g.seereference12).

• Non-MSKextra-intestinalfeaturesofIBDinclude:

• aphthousstomatitis.

• fatigue.

• anaemia.

• uveitis(inabout10%).

• erythemanodosum.

• pyodermagangrenosum.

ManagementofIBD-relatedSpA

• NSAIDsareusuallycontraindicatedifthereisknownIBD.

• IA or IM GCs are used relatively early in the disease course given the

avoidanceofNSAIDs.

• Mesalazine and AZA, used to treat IBD, is not recognized for its effect on

MSK symptoms but SSZ and MTX do have effect. Their use may require

liaison with the gastroenterologist as mesalazine/AZA needs to be

discontinuedinmostcases.

• Anti-TNFαchoicesneedtobemadecarefullygivenbothSpAandIBDlesions

inrelevantpatients.EtanercepthasnoefficacyinIBD.

• The use of anti-TNFα in UK NHS patients with IBD-related SpA requires

qualificationforfundingfortreatmentbasedoneitherAS,PsA,orIBDcriteria

alone.

Reference

12. Vavricka SR, Rogler G, Gantenbein C, et al. Chronological order of appearance of extraintestinal

manifestationsrelativetothetimeofIBDdiagnosisintheSwissInflammatoryBowelDiseaseCohort.

InflammBowelDis2015;21:1794–800.

Juvenilespondyloarthritis

Epidemiologyandclassification

• JuvenileSpA(JSpA)isan‘umbrella’termencompassingagroupofdiseases

withsharedgeneticpredispositionthataffectchildren<16yearsofage.

• The classification of JSpA (International League of Associations for

Rheumatology(ILAR);Table8.7)acceptedbymostis:

• enthesitis-relatedarthritis(ERA).

• juvenile psoriatic arthritis (JPsA), which can be sub classified into SpA

similartoPsAinadultsorperipheralarthritissimilartoANA-positiveJIA.

• undifferentiatedSpA(ifERAandJPsAfeaturesarepresent).

• JuvenilePsAandERAareclassifiableusingtheILARclassificationendorsed

byWHOin1999(see Table8.2,p.318).

• OtherJSpAsnotspecificallyaccountedforintheILARclassificationinclude

juvenile AS (JAS) who fulfil the mNY criteria before they are 16 years,

reactivearthritis,andIBD-relatedSpA.

• Estimates of JSpA prevalence are based on data for JIA and do not include

JAS.

• ERAandJPsAtogetheraccountfor10–20%ofJIA,whichgivesanestimated

2–60casesper100,000children.

• OfadultswithAS,8–15%haveonsetinchildhood.

• JSpA mostly occurs in late childhood or adolescence with peak onset at 12

years;60%aremale.

• Approximately50%ofJSpApatientsareHLA-B27positiveand20%havea

familyhistoryofHLA-B27-associateddisease.

• RheumatoidfactorandANAcharacteristicallyarenegative.

Clinicalpresentation

• Arthritis is usually oligoarticular, asymmetric, and primarily of the lower

extremity.

• Hip and midfoot arthritis are suggestive of JSpA and dactylitis is typical of

JPsA.

• Enthesitisispresentin66–82%ofJSpApatients,affectingmainlytheinferior

pole of the patella, Achilles tendon insertion, plantar fascia origin and

insertions at metatarsal heads, and gluteus medius insertion into the greater

trochanter.

• Axialinvolvementatonsetoccursin10–24%ofchildrenfrequentlypresenting

assacroiliacpainandstiffness.

• Two-thirdsofMRI-positivesacroiliitismaybeasymptomatic.

• Byage10years,two-thirdsofJSpApatientshaveaxialdisease.

• Othermanifestationsincludeacuteanterioruveitis(unilateralpainfulredeye

with photophobia in 25% of children over time), bowel inflammation,

psoriasis,nailpitting,and,rarely,cardiacdisease.

Table8.2ILARclassificationofJIA—SpArelevantcriteria

Inclusioncriteria Exclusioncriteria

JPsA Arthritispluspsoriasis(Ps)

arthritisplus≥2of:

• dactylitis;

• nailpitting/onycholysis;

• psoriasis in a 1st degree

relative.

• Arthritis in a HLAB27 positive

male>6y.

• AS, ERA, or IBD with sacroiliitis,

reactive arthritis or acute anterior

uveitis or history of one of these

disordersina1stdegreerelative.

• • Presence of IgM RF on ≥2

occasions>3monthsapart.

• Systemic-onsetJIA.

ERA Arthritisplusenthesitis

arthritisorenthesitisplus≥2

of:

• Presence or history of SIJ

tendernessand/orIBP;

• HLAB27positive;

• onsetofarthritisinboy>6y;

• acute symptomatic anterior

uveitis;

• Psoriasisorahistoryofpsoriasisin

thepatientora1stdegreerelative.

• PresenceofIgMRF≥2occasionsat

least3monthsapart.

• SystemicJIA.

• history of: AS or ERA or

sacroiliitis with IBD or

reactive arthritis or anterior

uveitis - in a 1st degree

relative.

Approachtodiagnosis

• Thereisnostandardizedenthesitisindexforpaediatricpatients.

• Recent evidence suggests a role for whole-body MRI as enthesitis can be

overestimatedinchildrenbyphysicalexamination.

• TypicalclinicalfindingsinJSpAinclude:

• insidious onset of low back pain with morning stiffness of >30 min that

improveswithexercise.

• tendernessondirectcompressionovertheSIJ.

• decreasedlumbarflexion.

• positive FABER (Patrick) test (  http://www.physio-

pedia.com/FABER_Test).

• MRIutilityinasymptomaticandsymptomaticdiseaseisunclear.Correlation

of positive MRI findings with symptomatic improvement on bDMARD

therapyhasyettobeshown.GadoliniumenhancementofMRIispreferredby

somepaediatriccentres.

• WhereJSpAfulfilstheNewYorkcriteriaforAS,adiagnosisofjuvenileASis

made.

ManagementofJSpA

• JSpAconditions,likeallformsofJIA,canbeseverelydebilitatingandplaces

aheavyphysicalandpsychologicalburdenonchildrenandfamiliesaffected

bythedisease.Multidisciplinaryteam(MDT)supportisessential.

• The principles of treatment include patient and parental education, physical

therapy,splints,orthotics,NSAIDs,andIAGCforperipheralarthritis.

• With joint involvement, there is a high risk of permanent joint contractures

withpersistentdisease.IntensivephysiotherapyandjudicioususeofIAsteroid

isimportant.

• Treatment guidelines for JIA, including JSpA, have been published by the

AmericanCollegeofRheumatology.

• MTX, SSZ, and LEF are used for peripheral arthritis, but efficacy for

enthesitisandaxialdiseasehasnotbeenfullyassessedinERA.

• Responsetoanti-TNFαtherapyappearstobesimilartothatofASandaxSpA

in adults. It is not clear whether treatment halts progression of structural

damage.

• DrugsthattargetIl-12/23andIl-17mayhavearoleinJSpAtreatmentbutare

notyetapprovedinJSpAorJIA.

OutcomeofJSpA

• JSpA may have a poorer overall prognosis than JIA and <20% of patients

experiencediseaseremissionwithin5years.

• Persistent disease activity is associated with midfoot arthritis/disease, hip

arthritiswith6monthsofdiseaseonset,familyhistoryofAS,HLA-B27,and

HLA-DRB1*08.

Furtherreading

Colbert RA. Classification of juvenile spondyloarthritis: enthesitis-related arthritis and beyond. Nat Rev

Rheumatol2010;6:477–85.

GmucaS,WeissPF.Juvenilespondyloarthritis.CurrOpinRheumatol2015;27:364–72.

Hugle B, Burgos-Vargas R, Inman RD, et al. Long-term outcome of antitumor necrosis factor alpha

blockadeinthetreatmentofjuvenilespondyloarthritis.ClinExpRheumatol2014;32:424–32.

Rachlis AC, Babyn PS, Lobo-Meuller E, et al. Whole body magnetic resonance imaging in juvenile

spondyloarthritis:willitprovidevitalinformationcomparedtoclinicalexamalone?ArthritisRheum

2011;63:S292.

Chapter9
Juvenileidiopathicarthritis
Introduction
ManagementofJIA
Transitionservices
JIAsubtypesandtheirspecificfeatures
Macrophageactivationsyndrome
Uveitis
Introduction
Inflammatory arthritis, resulting in stiffness, swelling, joint restriction and
damage,wascharacterizedinchildrenin1896byGFStillandisnowrecognized
asoneofthe commonestcausesofdisabilityinchildhood.Juvenile idiopathic
arthritis(JIA)isthe ‘umbrella’term,acceptedbytheinternationalcommunity,
for several forms of arthritis (summarized into subtypes for practical terms in
Table 9.1; for JSpA conditions there are many similarities with adult
presentations,see Chapter8).
Epidemiology
• JIAaffects1in1000childrenandyoungpeopleupto16yearsofage,from
bestavailableUKestimatesandhassimilarprevalencetodiabetes(1in700).
Morerecentinternationalstudiesindicateahigherprevalenceof167–400per
100,000person-years.
• TheannualincidenceofJIAis~1in10,000children/youngpeople.
• A majority of patients with JIA have a phenotype distinct from adult
inflammatoryarthritiswhichincludesanassociationwithuveitis.
• The diagnosis of JIA requires the presence of arthritis for 6 weeks to
distinguish it from reactive arthritis etc.; however, the treatment of JIA and
referraltoophthalmologyshouldnotwait6weeks.
• In most forms of JIA, there is inflammation of the joint lining (synovium).

Circulating activated lymphocytes migrate into joints and the resulting

generationofpro-inflammatorycytokinesleadstoactivationofmacrophages

and joint stromal cells (e.g. fibroblasts) similar to that seen in adult RA. In

affectedjoints,thereisexcesscytokineproduction,ofTNFα,IL-6,andIL-17.

Classification

The classification of JIA was radically changed in 2001. For years, there was

confusion between North America and European conventions for naming the

differentformsofjuvenilearthritis.

• Classificationhasbeensubsequentlycomplicatedinpracticebytheevolving

understanding of the breadth of effects in the spondyloarthritis (SpA)

conditions.

• WeincludejuvenileSpAalsoin Chapter8.

Table9.1TheclassificationofJIAsubtypes

Diagnosis Peakage-

range(s)

Extra-articular

features

Oligo-

JIA

≤4joints 2–4yrs Uveitis

Poly-JIA

(RF or

ACPA

+ve)

>4joints >9yrs Nodules,malaise,

weightloss

Poly-JIA

(RF and

ACPA

−ve)

>4joints 2–4yrs

7–12yrs

Uveitis,poorgrowth

SoJIA Fever,rash,hepatomegaly

splenomegaly

4–7yrs Serositis,carditis,

coronaryectasia,MAS

ERA Enthesitis,asymmetricallarge

jointarthritisandSIJs

>6yrs Acuteuveitis

JPsA Psoriasis±in1st-degree

relative,nailpitting,dactylitis

9–11yrs Psoriasis,bone

oedema,panuveitis

InformationfromPettyREetal.InternationalLeagueofAssociationsforRheumatologyclassification

ofjuvenileidiopathicarthritis:secondrevision,Edmonton,2001.JRheumatol2004;31:390–2.

ManagementofJIA

Nationalguidelinestoaidmanagement

The following key documents promote best practice in JIA and paediatric

rheumatology:

• National service specification for paediatric rheumatology (E03/S/b):

http://www.england.nhs.uk/commissioning/spec-services/npc-crg/group-e/e03/

• NHS Commissioning Quality Dashboard:

http://www.england.nhs.uk/commissioning/spec-services/npc-crg/spec-

dashboards/

• British Society of Paediatric and Adolescent Rheumatology (BSPAR)

guidelines: http://www.bspar.org.uk/clinical-guidelines

• ArthritisandMusculoskeletalAlliance(ARMA)StandardsofCareforJIA:

http://www.arma.uk.net/resources/standards-of-care

• BSPARwebsitewww.bspar.org.uk

• InterimClinicalCommissioningPolicyStatement:BiologicTherapiesforthe

treatment of Juvenile Idiopathic Arthritis (JIA):

http://www.engage.england.nhs.uk/consultation/specialised-services-

policies/user_uploads/biolgcs-juvenl-idiop-arthrs-pol.pdf

• NICE—abatacept,adalimumab,etanercept,andtocilizumabfortreatingJIA:

http://www.nice.org.uk/guidance/TA373

Diagnosingarthritisinchildren

TherearenodiagnostictestsforJIA.Diagnosisrequiresathoroughhistoryand

examinationtodistinguishJIAfromothercausesofjointpainorswelling(Table

9.2).

• Inflammatory arthritis in children is characterized by prolonged morning

stiffness(typically>20min),swelling,restriction,andlossofjointfunction.

• JIAshouldbeconsideredwhen:

• joint swelling from presumed trauma (including knee and ankle) persists

beyond2weeks.

• thereisinvolvementofseveraljoints.

• aspiratedjointfluidisshowntobeaseptic.

• thereismorningstiffness.

• thereisjointrestrictionintheabsenceofamechanicallesion.

• Carefulexaminationaimstoconfirmswelling,whichmaybesubtle,identify

jointrestriction(typicalofactivelyinflamedjointsinchildren)andestablish

thedistributionofaffectedjoints.

• Quick and methodical assessment of other joints is achieved using pGALS

(see Chapter1,‘ThepaediatricGALSscreen’).

• The examination technique of specific joints uses a systematic approach

identifiedinpREMS( http://www.pmmonline.org).

• Abnormal signswhichmightrevealJIA summarizedfrom atypicaldetailed

regionalexaminationareshowninTable9.3.

• Involvement of multiple joints increases the likelihood that arthritis is JIA,

especiallyintheabsenceofsystemicsymptoms.

• Juxta-articularchangesinJIAincludemuscleatrophy,leglengthdiscrepancy

due to limb overgrowth from knee involvement, reduced limb length from

early closure of growth plates adjacent to inflammation during adolescence,

andsynovialcysts.

• SoJIApresentswithsystemicfeaturesandthedifferentialdiagnosisiswideso

abroadapproachtoassessmentandinvestigationsisessential(Table9.4).

Table9.2ThedifferentialdiagnosisofJIAconditions

Condition Examples Investigations

Monoarticular

disease

Septicarthritis,TB,PVNS,foreign-

bodysynovitis,sicklecelldisease,

haemophilia,leukaemia,non-bacterial

osteomyelitis

Bloodandsynovial

fluidculture,

Mantoux,IGRA,

US,MRI,synovial

biopsy,bloodfilm,

genetics,

coagulationfactor

assays

Arthritis

following

infection

Lymedisease,viralarthritis,post-

streptococcalarthritis,HSP,Kawasaki

disease

AIserology,ASOT,

anti-DNAseB,

throatswab,

transthoracicecho

Inflammatory

backpains

conditions

HLA-B27-associatedreactivearthritis,

ERA,IBD-associatedSpA,enthesitis

Biomechanical

and

orthopaedic

conditions

Trauma,haemarthrosis,NAI,

patellofemoralpain,osteochondroses,

osteochondritisdissecans,

osteonecrosis,osteoidosteoma,tarsal

coalition,biomecanicalimbalance

Radiographs,MRI

fromdeconditioning,muscletightness

andhypremobilityconditions

Painconditions Complexregionalpainsyndrome

(CRPS),chronicwidespreadpain

Differencesfromadultarthritis

• Arthritis in children directly affects limb growth and may have an overall

effectonheightandweightattainment.

• Joint restriction is often a more sensitive sign of inflammatoryjointdisease

activityinchildrenthanitisinadults.

• Witheffectivediseasecontrolandbeforepubertythereisalikelihoodofrepair

ofjointdamage.

• Medicationhastoaccountforbodysizeanddifferentpharmacodynamicsand

pharmacokinetics.

• Bloodmonitoringofmedicationsuseisfrequentlydifferent.

Table 9.3 Key signs compatible with a diagnosis of JIA, summarized from a (necessarily) detailed

regionalMSKexamination

Joint AbnormalsignstoidentifyinJIAconditions

Wrist Volardisplacement,reducedgripstrength,poorordifficultyin

handwriting

Fingers Dactylitis,nailpitting,nodules,handwriting(asforwrist)

Elbow Flexiondeformity,inabilitytotouchshoulder

Shoulder Lossofabduction,difficultydressing

Neck Lossofnormalcervicothoracicspinelordosis,reducedrotation

Spine Lossoflumbarspinelordosis,positiveSchöbertest,midlineor

sacralbonytenderness,reducedorasymmetriclowerlimbmuscle

length

Hips Apparentleglengthdiscrepancy,Trendelenburggait,lossofhip

swingongait,painatendofrangeof(passive)rotation,positive

FABERtest,positiveThomastest

Knees Lossofextension(especiallyifasymmetrical),synovial(including

popliteal)cysts,vastusmedialiswasting

Ankle

andfoot

Abnormal/antalgicgait:no/abnormalheelstrike,foot

pronation/inversion,calfmusclelengthasymmetry,midfoot

rigidity

TMJ Restrictedorasymmetricjawopening,TMJcrepitus

Investigations

Atpresentation,investigationshelpdistinguishdifferentialdiagnosessincethere

arenodiagnostictestsforJIA.

• ESRandCRPdonotcorrelatewellwiththeextentorseverityofinflammation

andmaybenormal.

• A particularly high ESR may indicate the presence of inflammatory bowel

disease(IBD)or(veryrarely)leukaemia.

• Alowhaemoglobinmayindicateanaemiaofchronicdiseaseratherthaniron

deficiency.

• ANApositivityoccursin 40–75%ofJIApatientsandindicatesanincreased

riskofeyedisease.Itisnotadiagnostictestorpredictiveofoutcome.

• Rheumatoid factor (RF) positivity is rare in JIA and difficult to interpret in

oligoarticularJIA.HightitreANAandRFmayindicateSLE.

• US is the radiological investigation of choice to corroborate arthritis and

evaluate tenosynovitis and joint damage. Its false-negative rate is higher in

footandanklediseasethanforotherjoints.

• Radiographs may show soft tissue swelling, periarticular osteopenia. and

erosionsinlong-standingarthritis.

• ArthroscopyshouldbeavoidedunlessabiopsyisrequiredasinPVNS.

• Synovial fluid aspiration, but not arthroscopy, is essential when considering

sepsisandTB.

• Tomonitordiseaseactivity,drugtherapyandtissuedamage:

• ESR and CRP frequently do not reflect the extent or severity of

inflammation.

• A falling ESR and haemoglobin with climbing ALT/AST may indicate

macrophageactivationsyndrome(see Chapter25)asmayaferritinlevel

>10,000ng/mL.

• USisusedtomonitorchangesinsynovialinflammationandjointdamage

butcontrast-enhancedMRImayprovidemoreusefulimagesincludingthe

presenceofboneoedema.

• MonitoringofdrugsideeffectsincludesthemeasurementofFBCandLFTs.

Table9.4ConditionsandinvestigationstoconsiderwhensuspectingSoJIA

Conditions Investigations

Acute

lymphoblastic

leukaemia

Bloodfilm,bonemarrowaspirate,whole-bodyMRI

(includingfat-suppressedsequence)

Neuroblastoma Urineorbloodadrenaline/noradrenaline

Lymphoma CXR,abdominalUS,whole-bodyMRIorCT

Sepsis,TB Bloodcultures,serology,PCR,Mantoux,IFNγrelease

assay,jointaspiration,MRI

SLE,APS Coagulation,complementC3andC4,autoantibodies,

urinalysis

JuvenileDM QuadricepsMRI,CK,LDH

Reactivearthritis,

rheumaticfever

Lyme,BartonellaandBrucellaserology,ASOT/anti-

DNAaseBandthroatswab,transthoracic

echocardiogram(TTE)

Vasculitides TTE,ECG,urinalysis,ANCA,detailedhistory,

angiography,biopsy

Viruses Serology(EBV,CMV,Parvovirus,Rubella)

Travel-associated

diseases

Testsaccordingtosuspicion

Periodicfever

conditionsand

porphyrias

Genotyping(see Chapter18),IgD,urinarymevalonic

acid,urinaryporphyrins

Inflammatory

boweldisease

Faecalcalprotectin,endoscopy,bariumswallow

Treatment

The overall approach to treatment in JIA is to gain early rapid control of

inflammation,minimizetheadverseeffectsoftreatment,andsupportthegeneral

physicalandmentalhealthofthepatient.Thispatient-centredholisticapproach

requires the participation of a full multidisciplinary team—each member with

dedicatedexperienceofJIA.

Treatmentoftheacuteswollenjoint

Themanagementoftheacuteswollenjointshouldprimarilyfocusonrulingout

sepsis(see Chapter25,pp.708–709).

• Ibuprofen,naproxen,diclofenac,orotherNSAIDS,shouldbeused,especially

whenwaitingforapaediatricrheumatologyreview.

• For an effective NSAID response (managing inflammation as opposed to

simplypain),therecommendeddosingfrequencyshouldbecontinuedfor>2

weeks+/–gastroprotection.

• IAglucocorticoids(GCs)canbeconsideredfor:

• limp,disability,jointrestriction,othercomplicationsofarthritis.

• persistentlymarkedjointswelling.

• a bridging strategy whilst awaiting long-term medication to become

effective.

• OralorIVGCsshouldbeusedtosupplement,orasanalternative,toIAGC,if

therearemanyjointsinvolvedor jointinjectionstherapyisnotimmediately

feasibleortheeffectofIAGCshasbeentriedandwaslimited.

Long-termmanagementofJIA

• Long-termmanagementofJIArequiresclosecollaborationbetweenmembers

oftheMDTwitheffectivecommunicationbothwithintheserviceandacross

theregionalnetwork.

• Members of the MDT include a clinical nurse specialist, physiotherapist,

occupational therapist, orthotist or podiatrist, ophthalmology colleagues,

musculoskeletalradiologist,psychologist,socialwork,anddieteticsupport.

• Medicationformsonlyapartofthelong-termmanagementofJIA.

• Fundamentalisthepromotionofphysicalactivitywhichencouragesareturn

of the strength and stamina lost from active arthritis, and correction of

muscularimbalancesthatresultinpain,injury,andlossofjointprotection.

• Provisionofinformationandeducationforparentsandpatientsisaconstant

requirement.Thisiscriticalfortheirparticipationinjointdecision-makingand

adherencetoagreedtreatmentplansandhelpsdissipatelingeringanxiety.

• Pain management frequently involves strategies other than the use of

medication.

• Vaccination advice is usually given at the outset and changes in national

guidelines (August 2017) indicate that it is safe to give live vaccines to

patients before treatment or whilst on low to moderate doses of GCs and

csDMARDs (

http://www.gov.uk/government/uploads/system/uploads/attachment_data/file/655225/Greenbook_chapter_6.pdf

• Inindividualcases,givinglivevaccinesevenifimmunosuppressionisbeing

taken far outweighs the risks. All routine non-live vaccines may be given

withoutcomplication.

• Effective liaison is required with schools, primary care, and community

services.

• Effectivetransition,whichincludesage-appropriateservicesforyoungpeople

frompubertyonwards,isalsoanessentialrequirementtooptimizethewell-

being and self-efficacy of this age group. This should continue well after

transfertoadultservices.

• Ahealthydietavoidssomeoftheproblemsofgrowthrestrictionordelayand

excessweightgainfromlowphysicalactivityorGCuse.

• Although close collaboration with orthopaedics ensures timely referral of

patientsandgoodmedicalmanagementoforthopaedicconditions,therateof

surgicalinterventioninJIAhasgreatlydiminished.

• Surgicalsynovectomy,softtissuerelease(tenotomiesandcapsulotomies)and

jointreplacementarenowrare.

Long-termmedicationinJIA

Theaimofmedicationinthelongtermistoreducethefrequencyandimpactof

flaresofarthritisanduveitis.

• Long-term medications in the form of (synthetic) disease-modifying

antirheumaticdrugs(sDMARDs)areusedfor:

• Persistentarthritisoruveitisrefractoryto,orincompletelycontrolledby,IA

orperiocularGCs.

• Presenceofchroniccomplicationsortissuedamage.

• Extensiontootherjointsoreye.

• Joint-specificeffectsonthewristandhandfunction,thehipandmobility,or

jaw.

• sDMARDtreatmentstypicallytakeafewweekstobecomeeffectiveandmay

requireabridgingcourseofGCseitherIA,orally,orIV.

• Given the extensive support and experience required, sDMARDs are best

institutedbyaspecialistserviceordelegatedresponsibilitytosecondarycare

withinaclinicalnetwork.

• There is now extensive experience of the valuable role of primary care in

monitoringtreatmentwiththeback-upofanaccessiblesecondaryortertiary

service.

• ThestandardsDMARDusedinJIAanduveitisismethotrexate(MTX).

• MTXinSCform,ratherthantabletsorliquidpreparations,istypicallyusedin

theyoungchildandwherethereisextensiveorsevereinflammation.

• AlternativesDMARDS forarthritisincludeleflunomide(LEF),sulfasalazine

(SSZ),andhydroxychloroquine(HCQ).

• Azathioprine (AZA) and ciclosporin may have a role in both arthritis and

uveitis, whereas mycophenolate and tacrolimus are considered to have a

specificroleinuveitis.

• ThevalueofsDMARDcombinationsisnotwellstudiedinJIAbutareused

withgoodeffectinsomepatientsandhavenotbeenshowntohaveincreased

levelsofadverseeffects.

• BiologicDMARD(bDMARD)therapiesincludinganti-TNFαtherapieshave

been shown in high-quality studies to be effective in JIA and are now a

standard treatment in the presence of refractory disease to or intolerance of

MTXorothersDMARDs:

• IntheUK,thereisNHS(NICE)approvalfortheuseofabatacept(afusion

protein of the extracellular domain of human cytotoxic T-lymphocyte-

associatedantigen4(CTLA-4)linkedtoamodifiedFcportionofIgG1),the

anti-TNFαtherapiesadalimumabandetanercept,andtocilizumab(ananti-

IL-6 receptor monoclonal bDMARD) in JIA. In England there is also an

agreement with NHSE to use anakinra, infliximab and rituximab under

certainconditions.

• bDMARD use in England is directed by NICE and NHSE (

http://www.england.nhs.uk/commissioning/wp-

content/uploads/sites/12/2015/10/e03pd-bio-therapies-jia-oct15.pdf).

• Supplementarymedicationsincludethoseforpain,gastritis,andnauseaandto

optimizebonedensityandstrengthinthepresenceofGCsorreducedphysical

activity.

Outcomeandprognosis

GiventheprogressinmanagementstrategiesandadventofbDMARDtherapies,

old published outcome data will no longer be applicable. Current paediatric

rheumatologist consensus is that there has been a marked improvement in

outcomeandmanypatients.

• Theincidenceofjointreplacementhasreducedconsiderablyfromreportsin

theearly2000swhen80%ofpatientswithRF-positiveJIAfollowedupovera

periodof20yearsrequiredarthroplasty.

• Thereisstrikinglylittlehigh-qualitydata measuringlong-termremission off

medication.

• About 50–75% of patients with persistent oligo-JIA will achieve long-term

remission by their early teens but may still experience flares at any time in

adulthood.

• About20–30%ofpatientswith(RFandACPA)seronegativepolyarticular-JIA

achievedrug-freelong-termremissionintoadulthood.

• The concept of minimal disease activity has only recentlybeenvalidatedin

JIA and may be a better outcome variable for those patients who do not

achievecompleteremission.

• Despitechangesintreatmentstrategiesandoutcome,suboptimaloutcomesdo

occurandareassociatedwith:

• delayeddiagnosis.

• delayedreferraltoaspecialistMDT.

• suboptimalcontrolofactivedisease.

• inadequateengagementandcollaborationwiththepatient,parent,orother

carers(seepsychologysupportlaterinthislist).

• presentationwithuveitisandoculardamage.

• ongoingdiseaseactivityinsystemic-onsetJIA(SoJIA)at6months.

• SoJIAinmales.

• youngageofonsetinoligoarticularandpolyarticulardisease.

• psoriaticarthritis.

• hipinvolvement.

• rapidearlyonsetofJIAinsmalljointsofhandsandfeet.

• inassociationwithearlyradiographicchanges.

• Psychologysupportimprovesoutcomeby:

• reducingtheimpactofMTX-associatednausea.

• reducingtheimpactoffearandanxietyarounddiagnosisandtreatment.

• identifying,managing,andreferringanymentalhealthconcerns.

• alleviatingfactorsthatadverselyimpactonqualityoflifeandengagement

withschool.

• addressingadversebodyimageconcerns.

• managing thefrustration ordisappointment ofpersistent orflaring disease

activityandsideeffectsfrommedication.

Transitionservices

‘Transition’ means, and hopes to achieve, the seamless and appropriate care

transfer from paediatric/adolescent services to a young-adult or adult service.

Thedevelopmentofage-appropriateclinicsisawell-regardedstrategytoreduce

thebarrierstoeffectivetreatment.

• Atransitionserviceisachievedthroughoptimizingengagementofadolescents

oryoungadults,promotionofself-efficacy,andenhancementofself-advocacy

andadherencetoagreedmanagementplans.

• Manycentresnowofferadolescentclinicsforpatientsagedfrom10–13years

to17–18yearsandyoungadultclinicsforthoseaged17–25years.

• Theimplementationandoptimizationofadolescentandyoungpersons’clinics

requires:

• closecollaborationbetweenpaediatricandadultclinicians.

• age-specificnursingexpertise.

• age-appropriateenvironmentandinformationresources.

• thatthepatientbeseen(first)withoutparentspresent.

• thepromotionofanunderstandingofconfidentialityandconsent(orassent).

• the promotion of effective health-related behaviours including joint

decision-making,self-advocacy,andself-efficacy.

• support for the attendance and performance at school, college, and

universityandwhenseekingemployment.

• theearlyidentificationofmentalhealthproblemsthatmaybe abarrierto

care.

• respectfordevelopingbodyawareness.

• assistancewithfamilyplanningandsexualhealth.

• earlyanticipationofanysurgicalneeds.

• GuidelinestosupportthedevelopmentofyoungpersonclinicsincludeYou’re

Welcome Quality Criteria (Department of Health) and Transition to Adult

Care:ReadySteadyGo(UniversityofSouthampton).

JIAsubtypesandtheirspecificfeatures

OligoarticularJIA(oligo-JIA)

• Oligo-JIA is the commonest subtype, accounting for 30–40% of JIA and is

characterizedbytheriskofuveitis.SeeTable9.1

• Itpredominantlyaffectsfemaleswithpeakagesofonsetbetween2to4years

and7to13years.

• About50%ofcasesaremonoarticularinpresentation.

• If>4jointsbecomeinvolvedafter6monthsofdiseaseactivitytheconditionis

reclassifiedasextendedoligo-JIA.

• Extension to polyarticular JIA is more likely in those with uveitis and rare

beyond5yearsfromdiagnosis.

• Thecommonestjointsinvolvedareelbow,knee,andankle.

• Jointoralimbdeformityisofgreatconcerninthegrowingpatient.

• Leglengthdiscrepancyismorecommonwhenarthritisofthekneebegins<3

yearsofage.Toaccommodatefortheexcesslength,thechildstandswiththe

kneeflexedresultinginaflexioncontracture.

• HipmonoarthritisorprimarycoxitiscanoccurespeciallyinperipubertalAsian

girls,butasearchtoruleoutothercausesisessential.Thefollowingshouldbe

considered: septic arthritis, leukaemia (e.g. in an at-risk population such as

Down’s syndrome), psoriatic arthritis, IBD-associated arthritis, and juvenile

SpA.

• Studies have shown that over 80% of patients have little or no disability or

jointdamageafter15yearsoffollow-up.

• TheHLAassociationswitholigo-JIAincludeHLA-DRB1*08withadditional

susceptibilityhaplotypesHLA-DRB*1103/1104.

• HLA-DRB1*0401,foundinRA,isprotectiveforselectedsubtypesofJIA.

PolyarticularJIA(poly-JIA)

• Poly-JIAisdiagnosedwhen>4jointsareinvolvedwithinthefirst6monthsof

disease activity (excluding psoriatic arthritis, IBD-associated arthritis, and

enthesitisrelatedarthritis).

• Pragmatically, decision-making for extended oligo-JIA is similar to that for

poly-JIAandlong-termdataindicatesasimilaroutcome.

• A polyarticular course occurs in 20–30% of JIA and is subdivided by the

presence or absence of RF, which should be checked (on latex) on two

occasionsatleast3monthsapart.

• RFpositiveJIAoccursin<5%ofJIA,ismostcommoninfemalesandhasa

phenotypeverysimilartoRAinadults.

Rheumatoidfactor-negativepolyarticularJIA

• InRF-negativepoly-JIAthereisoftenincompletecontrolofarthritisdespite

majoradvancesintreatment.

• RF-negativepoly-JIAisassociatedwithhigherlevelsofdisabilityespecially

duringflaresofthearthritis.

• Joint restriction often indicates disease activity and is commonly associated

withmuscleatrophy,disability,andjointdamage.

• Thereisapoly-JIAphenotypewithboggysynovitisthatisnotassociatedwith

muchpainordisabilityandjointsarecommonlywellpreserved.Tenosynovitis

cancoexistwithjointsynovitisandcanremainundisclosedunlesssuspected.

• Another poly-JIA subtype is characterized by predominantly foot and ankle

involvement, the consequences of which can be a reduction in generalized

mobility,tarsalfusion,tenosynovitis,andbursitis.

• TMJ involvement is often insidious in onset. It is unlikely to be missed if

pGALS (see  Chapter 1) is undertaken at each clinic visit. If left
undertreated, TMJ arthritis may result in micrognathia and dental
malocclusion.
• Neckinvolvementcancausemarkedirritabilityandbeparticularlydisabling
intheclassroom.Occupationaltherapyassessmentisadvisable.
Juvenilepsoriaticarthritis(JPsA)
• JPsA is considered as one of the juvenile spondyloarthritides (JSpA; see
Chapter8;andforILARdiagnosticcriteriasee Chapter8,p.318).
• FeaturesofJPsAaresimilartoadultPsA(see Chapter8,p.318).
• JPsAshouldbeconsideredevenifthereisnopsoriasisbutthereisahistoryof
psoriasisinafirst-degreerelative.
• Nail pitting, dactylitis, previous or concurrent acute panuveitis, and
inflammatorybackpainhistorymaybepresent.
• JPsAcanbeoligo-orpolyarticular.
• JPsAisfrequentlyresistanttoconventionaltreatmentstrategiesincludingGC
resistance.
Juvenilespondyloarthritis(JSpA)andenthesitis-relatedarthritis(ERA)
• See Chapter8foradditionaldetail.
• JSpA should only be considered in patients older than 6 years, especially
males,andwhenthereisasymmetriclargejointinvolvement.
• Enthesitis is the inflammation at the sites of bony insertion of tendons and
ligaments. In ERA, enthesitis can be very painful and disproportionate to
examinationfindings.
• HLA-B27 is found in 30–50% of ERA patients and is associated with an
increasedriskofdevelopingjuvenileankylosingspondylitis.
• ERA is generally associated with a low-grade grumbling disease persisting
intoadulthoodbutassociatedwithlittleerosivejointdisease.
• In a minority of patients with ERA there may be high levels of disability
responsivetoanti-TNFαtherapy.
Systemic-onsetJIA(SoJIA)
ThisformofJIA,presentingwithfeverandrash,affectsjust5–8%oftheJIA
population. A broad approach to diagnosis is essential—many conditions can
presentwithMSKpains,rash,andsystemicsymptoms.
• SoJIA is best considered as an umbrella term that covers several
autoinflammatory disorders (see  Chapter 18 and Table 18.1, p. 544) and
poly-JIAtriggeredbyorpresentingwithaviralinfection.
• Previouslyknownas‘Still’sdisease’,thistermisnowdiscouragedduetothe

confusionitmaycause.

• Incidence:M=F.SoJIAoccursatanyageincludinginfantswithpeakonset

between2and3yearsold.

• Typically:highlevelsofIL-1andIL-6inserumandsynovialfluid.

DiagnosisofSoJIA

• Nospecificdiagnostictestsexist.

• Thereisabroaddifferentialdiagnosisthatrequiresassessmentbyapaediatric

rheumatologist.

• Many of the characteristic features including fever, rash, polyarthritis,

lymphadenopathy,andhepatosplenomegalyoverlapwithotherconditions(see

Table9.4).

• Similarly, acute lymphoblastic leukaemia can present with fever, rash, and

joint/limbpains(attributabletomarrowinvasion).

• Neuroblastomashouldbeconsideredinpatients<5yearsold.

• Ahistoryoftravelandcontactwithanimalsorticsshouldbetaken.

• Truepersistentjointinflammationmaynotbefoundatdiagnosisorformany

months(upto9yearsold)afterdiagnosis.

• Thefever,ofupto39°C,istypicallyquotidian—occurringonceortwiceper

day in a diurnal distribution with return to a normal baseline between fever

spikes.

• TypicalbloodresultsincludehighESRandCRP,neutrophilia(oftheorderof

20×10

/L),thrombocytopenia(often>600×10

/L),andanaemiaofchronic

inflammation(often<80g/L).

TreatmentofSoJIA

The initial treatment of SoJIA focuses on the need to allow time for

investigationstoexcludeothercausesoffeverandmanagepainanddisability.

• AtrialofNSAIDsfor2weeksisusedinitially,thoughNSAIDsmayhaveno

effectonserositis,orfloridpolyarthropathy.

• SoJIAisaGC-responsivecondition,butthere’slittleevidencethatGCsalter

thelong-termoutcome.

• GCsmaybeusedonceotherconditionshavebeenruledout.Ashortorlimited

courseofGCsmaybeusedtotemporizepain,fatigue,anddisabilitytoseeif

inflammationofapost-infectiousoriginsettlesonitsown.

• GCs provide effective symptomatic relief while waiting for a sDMARD

(typicallyMTX)response.

• BiologicDMARDs(bDMARDs)areusedwhen:

• unabletoweanoffGCsdespiteuseofMTX.

• MASispersistent.

• when a flare of joint pains/disease occurs despite MTX being taken at a

therapeuticdosefor>3months.

• If SoJIA isunresponsive toanakinra (ananti-IL-1 bDMARD)after 4weeks

treatment,thentreatmentshouldbeswitchedtotocilizumab.

• TocilizumabisrecommendedintheUKbyNICE.

• Anti-TNFα therapy can be used for children with a polyarticular course of

SoJIAoncesystemicfeatureshavesettled.

• Other less routine treatments for SoJIA include ciclosporin, canakinumab,

IVIg,andstemcelltransplantationinseveredisease.

Macrophageactivationsyndrome

Macrophageactivationsyndrome(MAS)israrebutislife-threatening(mortality

is8–22%).MAScancomplicateotherdiseases.MASisalsotermedsecondary

haemophagocytic lymphohistiocytosis (HLH). For a summary see

http://www.the-rheumatologist.org/article/macrophage-activation-

syndrome/6/)ThereaderisreferredtoChapter25

Uveitis

This important association of JIA occurs in 10–20% of patients and within 7

yearsofarthritisonset.

• Visuallossoccursin~25%ofJIA-associateduveitisandirreversibleblindness

occurswithoutsymptomsorchangesineyeappearance.

• Irreversiblecomplicationsmayoccurafteronlyafewweeksofuncontrolled

uvealinflammation.

• However, abouthalfof children with anteriororintermediate uveitis do not

experiencevisuallossdespiteprolongedinflammation.

• Therearenumerouscausesofuveitis(Table9.5).

Table9.5Thedifferentialdiagnosisofcausesofpaediatricuveitis

Infectious Non-infectious

Toxoplasma

Varicella

Herpessimplex

CMV

Trauma (sympathetic

ophthalmia)

Inflammatoryboweldisease

Sarcoid

Borrelia(Lymedisease)

Bartonella

Other: toxocariasis, Ascaris, fungal,

histoplasmosis,Syphilis

Tubulointerstitialnephritis

Blausyndrome

Behçet’sdisease

Periodicfevers

Multiplesclerosis

Vogt–Koyanagi–Harada

Vasculitis (including

Kawasakidisease)

Uveitissurveillance(screening)programmes

Allpaediatricrheumatologyunits/physiciansshouldhaveanagreedmechanism

of systematically screening for, managing, and having emergency access to, a

suitably resourced ophthalmology team skilled in examining very young

children.

• UveitissurveillanceinJIAisessentialbecauseuveitis:

• issight-threatening.

• is rarely apparent from routine history and examination, especially in

children<8yearsofage.

• isnotpredictableandisunrelatedtotheseverityofarthritis.

• ispresentin40%casesatthetimeofthefirsteyescreen.

• complications,especiallycataract,occurinupto40%.

• ismostlikelytorespondwithaggressivetreatment.

• Other major ophthalmological concerns include glaucoma, macular oedema,

retinaldetachment,bandkeratopathy,andhypotony.

• There should be immediate access to advice and assessment should eye

symptomsdevelop.

• A uveitis screening interval schedule should be adopted (e.g. Table 9.6) to

avoidirreversibleeyedamage.

• Uveitissurveillanceschedulesshouldbeadaptedtotheriskofuveitis,andin

thecontextoftreatmentuse(e.g.whenstoppingMTX).

• Eyescreeningcontinuesuntil12yearsofagewhenapatientcanreliablyself-

reportfeaturesofinflammationsuchasfloatersandpain.

• Cessationofeyescreeningat12yearsolddoesnotindicatethatuveitismay

notoccur,buttheriskbeyondthisageissufficientlylowtomakeself-report

morereliable.

Table9.6Uveitissurveillance:recommendedfrequencyofslitlampexamination(summarisedfromthe

UKRoyalCollegeofOphthalmologyGuidelines)

Condition Frequency

SoJIA Yearly

Onsetof

JIA<7

yrsold

ANA+ve:every2monthsfor6months,thenevery3monthsfor

3.5 yrs, then 6 monthly for 3 yrs or until aged 12 yrs, then

yearly(ifpreviousuveitishasoccurred)

ANA−ve:every6monthsfor7yearsoruntilaged12yrs,then

yearly(ifpreviousuveitishasoccurred)

Onsetof

JIA≥7yrs

old

6monthlyfor4yrsthenyearly(ifpreviousuveitishasoccurred)

Managementofuveitis

Uveitismanagementaimstobalancelong-termriskofvisuallosswithshort-and

long-termrisksoftreatment.

• First-linetreatmentofanterioruveitis:topicalGCs(e.g.Maxidex

orPredsol

eyedrops)givenuptohourlydependingontheseverity.TopicalGCsareless

effectiveinintermediateorposterioruveitis.

• There is a dose-dependent increase in risk of cataract formation from using

steroideyedrops.Theriskfromonedropperdayis0.1%peryearandrises

withmorefrequentandprolongeduse.

• Othertopicalagentsincludemydriaticstoreducetheriskoftheirisstickingto

thelens(posteriorsynaechiae)andglaucomaagents.

• SystemicorperiocularGCsareusedinthepresenceofpanuveitisandfeatures

inadequatelyresponsivetoeyedrops.

• Aggressive or long-term treatment should be confined to those with a

significantriskofpermanentvisualloss.

• sDMARDsorbDMARDsareusedwhenrecurrentcoursesorprolongeduseof

steroideyedropsisrequiredtomaintaininflammationtolessthe0.5+activity

usingtheSUNcriteria.

• Poor outcome from uveitis is associated with presence of ocular damage at

presentation,whenuveitisprecedesarthritis,whenthereisdelayintreatment

initiation,andwithfailuretoachieveearlyremission.

Reference

3. ScottishUveitisNetwork(SUN).Guidelines. http://www.sun.scot.nhs.uk/guidelines.html

Chapter10
Systemiclupuserythematosus
Introduction
Pathophysiology
Clinicalfeaturesofsystemiclupuserythematosus(SLE)
AntiphospholipidsyndromeandSLE
PregnancyandSLE
Assessmentofdiseaseactivity
Drug-inducedSLE
ManagementofSLE
Prognosisandsurvival
JuvenileSLE
Neonatallupussyndrome
Introduction
Systemic lupus erythematosus (SLE/‘lupus’) is a multisystem autoimmune
disorderwithabroadspectrumofclinicalfeaturesinvolvingalmostallorgans
andtissues.
• SLEisachronicdiseasewhichremitsandrelapses.Apreclinicalphaseexists
characterized by autoantibodies common to other autoimmune diseases,
followedbyadisease-specificautoimmunephase.
• Variations exist in the incidence of clinical features between ethnic groups
necessitating a keen sense of awareness of a variety of multisystem
pathologiesandappreciationthatSLEhastakenonthemantleofsyphilisas
thegreatmimicofotherconditions.
Epidemiology
• Prevalencevariesworldwide,butintheUKitis97per100,000.
• SLEis10–20×morecommoninwomenthanmen,andmostlikelytodevelop
betweentheagesof15and40years.

• It is more common and often more severe in certain ethnic groups such as

thoseofAfrican-Caribbean,India,Hispanic,andChineseoriginlivinginthe

USAandEuropethaninwhiteCaucasians.

Classification

• TheAmericanCollegeofRheumatology(ACR)publisheditsrevisedcriteria

fortheclassificationofSLEin1997(Table10.1).

• Criteria are for the classification of SLE for epidemiological and research

purposes and not for diagnostic purposes. In practice, however, criteria

naturallytendtoformthecornerstoneforclinicaldiagnosis.Thecriteriawere

developedandvalidatedinpatientswithestablished,long-standingdiseaseand

thereforemayexcludepatientswithearlyorlimiteddisease.

• TheSystemicLupusInternationalCollaboratingClinic(SLICC)classification

criteria for SLE are similar to the ACR classification criteria. The main

differencesarethat,fortheSLICCclassification:

• Haematologicalabnormalitiesneedbepresentononlyoneoccasion.

• ThereisinclusionoflowC3,C4,andCH50levelsandapositiveCoombs

testintheabsenceofhaemolyticanaemia.

• The criteria also include non-scarring alopecia and a broader range of

cutaneousandneurologicalmanifestations.

Table 10.1 1997 update of the 1982 American College of Rheumatology revised criteria for the

classificationofSLE

1 Malarrash Fixederythemaflatorraisedovermalareminencestending

tosparethenasolabialfolds

2 Discoid

rash

Erythematousraisedpatcheswithadherentkeratoticscaling

andfollicularplugging;atrophicscarringmayoccurin

olderlesions

3 Photo-

sensitivity

Skinrashasaresultofanunusualreactiontosunlightby

patienthistoryorphysicianobservation

4 Oralulcers Oralornasopharyngealulceration,usuallypainless

observedbyphysician

5 Non-

erosivearthritis

Involving2ormoreperipheraljointscharacterizedby

tenderness,swelling,oreffusion

6 Serositis Pleuritis(historyofpleuriticpainorrubheardbyphysician

orevidenceofpleuraleffusion)orpericarditis(documented

byECGorruborpericardialeffusion)

7 Renal

disorder

Persistentproteinuria>0.5g/24hrsor>3+ifquantitation

notdoneorcellularcasts(redbloodcell,Hb,granular,

tubularormixed)

Neurological

disorder

Seizuresorpsychosisintheabsenceofoffendingdrugsor

knownmetabolicderangements,e.g.uraemia,ketoacidosis,

orelectrolyteimbalance

Haematological

disorder

Haemolyticanaemiawithreticulocytosisorleucopenia

<4.0×10

/Lon≥2occasionsorlymphopenia<1.5×109/L

on≥2occasionsorthrombocytopenia<100,000/mm

inthe

absenceofoffendingdrugs

Immunological

disorder

Anti-dsDNAantibodytonativeDNAinabnormaltitreor

anti-Smantibodyorantiphospholipid(APL)antibodies

(abnormallevelofIgMorIgGcardiolipinantibodiesor

positivelupusanticoagulantor‘false-positive’testresultfor

>6monthsconfirmedbyT.pallidumimmobilizationor

fluorescenttreponemalantibodyabsorptiontest)

11 Positive

ANA

AbnormalANAtitrebyimmunofluorescenceorequivalent

assay(anypointintimeandintheabsenceofdrugs)

SLEmaybediagnosedif4ormoreofthe11criteriaarepresenteitherseriallyorsimultaneously

ReproducedfromHochberg‘UpdatingtheAmericancollegeofrheumatologyrevisedcriteriaforthe

classificationofsystemiclupuserythematosus’(1997)Arthritis&Rheumatology40(9):1725with

permissionfromWiley.

Pathophysiology

ThecauseofSLEisincompletelyunderstoodbutgenetic,immunological,and

environmentalfactorsallplayanimportantrole.

Genetics

• There is a higher concordance in monozygotic twins and the disease is

stronglyassociatedwithpolymorphicvariantsattheHLAlocus.

• In a few cases, SLE is associated with inherited mutations in complement

componentsC1q,C2,andC4,andintheimmunoglobulinreceptorFcγRIIIbor

intheDNAexonucleaseTREX1.

• Genome-wide association studies have identified common polymorphisms

nearseveralothergenesthatpredisposetoSLE,mostofwhichareinvolvedin

regulatingimmunecellfunction.

Serologyandimmunecomplexes

ThecharacteristicfeatureofSLEisautoantibodyproduction.

• Autoantibodies have specificity for a wide range of targets, but many are

directedagainstantigensinthecellorwithinthenucleus.

• SLEmayoccurbecauseofdefectsinapoptosisorintheclearanceofapoptotic

cells,whichcausesinappropriateexposureofintracellularantigensonthecell

surface, leading to polyclonal B- and T-cell activation and autoantibody

production.

• Followingautoantibodyproduction,immunecomplexformationisthoughtto

beanimportantmechanismoftissuedamageinSLE,leadingtovasculitisand

organdamage.

Environmentalfactors

• Environmentalfactorscauseflaresoflupus.

• UVlightandinfectionsincreaseoxidativestressandcausecelldamage.

• StresscanaggravateSLE.

Clinicalfeaturesofsystemiclupuserythematosus

(SLE)

ThereisanextensivenumberofclinicalfeatureswhichcanoccurinSLE.Ofthe

severalnon-specificfeaturesthatarecommontomanychronicdiseases,lethargy

andfatigueareoftenthemostdisabling.

Mucocutaneous

Approximately half of patients diagnosed with SLE will have the classic UV-

sensitive‘butterfly’rashoverthenasalbridgeandmalarbones.Thecutaneous

manifestations of SLE include a combination of acute, subacute, chronic, and

otherrashes,listedinTable10.2.

Musculoskeletalfeatures

• Musculoskeletal immobility-related stiffness and polyarticular, symmetrical

arthralgiaorarthritisoccurin90%ofcases.

• In most cases, symptoms outweigh objective clinical signs, and overt joint

damagefromsynovitisisconfinedto<10%ofpatients.

• Reversiblesubluxationofjointswithouterosivedisease(Jaccoudarthropathy)

canalsooccur.

• Osteonecrosis occurs in 5–10% of patients; most cases are associated with

previous glucocorticoid (GC/‘steroid’) use or secondary to antiphospholipid

syndrome(APS).

• Raynaud’s disease, vasculitis, fat emboli, GCs, and APS can result in bone

ischaemia.

• Myalgiaiscommon,buttruemyositisisseenin<5%.

• Myopathymaybeaconsequenceofsteroidtreatment.

Cardiovasculardisease

• Pericardialdiseaseisthemostcommonmanifestation.

• Most cases of pericardial disease are asymptomatic. A mild pericarditis is

more common than a clinically significant pericardial effusion. On

echocardiography, pericardial thickening is seen more frequently than

pericardialeffusions.

• AlthoughSLEcanleadtolife-threateningpericardialeffusionsorconstrictive

pericarditis,thesemanifestationsarequiterare.

• Myocarditis,presentin8–25%ofpatients,isoftenasymptomatic.

• Clinicalmyocarditis(definedbycombinationsoftachycardia,dysrhythmias,a

prolongedPRintervalonECG,cardiomegaly,orcongestivecardiacfailure)is

considerablylesscommon.Bloodtestingoftenrevealsaraisedtroponinlevel

andN-terminalpro-BNP.DiagnosisisconfirmedbycardiacMRI.

• Valvular heart disease iscommon.Themost frequent abnormality is diffuse

thickening of the mitral and aortic valves followed by vegetations, valvular

regurgitation,andstenosis.Anyvalvevegetationsidentifiedinapatientwhois

febrile should raise the possibility of bacterial endocarditis. Libman-Sacks

endocarditis is characterised by immune-complex dominant vegetations

classically on the mitral or the aortic valves in patients with SLE. The

vegetations are associated with lupus duration, disease activity and

anticardiolipinantibodies,amongothers.

• SLE patients have increased morbidity and mortality from cardiovascular

disease. Patients are 5–10× more likely to have clinically evident coronary

arterydiseasethanthegeneralpopulation.

• Subclinical cardiovasculardiseaseis alsoseen,with increasedprevalenceof

carotidplaqueandfasterprogressionofplaqueformation.Thepathogenesisof

earlycardiovasculardiseaseismultifactorialincludingtraditionalriskfactors

(smoking, obesity, hypertension, diabetes mellitus, hyperlipidaemia, and

positivefamilyhistory),SLE-relatedriskfactors(diseaseactivityanddamage,

GC use, disease duration), and factors related to the inflammatory process

(raised C-reactive protein and pro-inflammatory cytokine levels, elevated

homocysteinelevels).

• Reducing cardiovascular morbidity and mortality requires management of

traditional risk factors, using antihypertensive agents and statins as

appropriate, as well as minimizing GC and NSAID use and achieving early

andprolongedcontrolofdiseaseactivity.

• GCs, althoughindicated forinflammatorycardiac disease,are anaddedrisk

factor for atherosclerosis given its propensity to induce hypertension,

hypercholesterolaemia,andobesity.

Table10.2MucocutaneousmanifestationsofSLE

Frequency Feature

Common(20–50%) Malarrash

Photosensitiverash

Chronicdiscoidlesions

Non-scarringalopecia

Lesscommon(5–20%) Mucosalulcers

Occasional(5%) Periorbitaloedema

Bullouslupus

Severescarringalopecia

Subacutecutaneouslupus

Legulcers

Panniculitis

Cutaneousvasculitis

Pulmonarydisease

• Because of the tendency for disease to be subclinical, CXR and pulmonary

function tests invariably indicate a greater degree of involvement than is

evidentclinically.

• Patients may present quitelatein the disease process following ahistoryof

slow-onsetnon-productivecoughandincreaseddyspnoea.

• Pulmonaryfunctionteststypicallyshowreducedtotallungcapacityandpeak

flowrates.

• Shrinking lung is associated with unexplained dyspnoea, initially exertional,

butthenatrestandonlyingflat,smalllungvolumesonCXR,diaphragmatic

elevation, and restrictive pulmonary function tests in the absence of

parenchymallungdisease.

• Pleuritic pain/pleuritis is present in up to 60% of cases, with a clinically

apparentpleuraleffusioninupto50%.

• Pleural effusions are a feature in one-third of patients, but they are usually

smallandclinicallyinsignificant.

• Interstitialfibrosis,pulmonaryvasculitis,andpneumonitisarefoundinupto

20%ofpatients.

• Pulmonaryhaemorrhageisrarebutpotentiallyacatastrophiccomplicationof

SLE.

• Pulmonary hypertension is found in ~10% of patients with SLE, and is

associatedwithRaynaud’sdisease,vasculitis,andAPLantibodies.

• Patientspresentingwithpleuriticpainand/orpulmonaryhypertensionshould

beinvestigatedforthepresenceofpulmonaryemboliandAPS(see Chapter

11).

Renaldisease

Assessment of blood pressure for hypertension, urine for protein, blood, and

casts,andtheserumcreatinine,urea,andalbuminisanessentialpartofregular

proactivemonitoring.

• Symptoms suggesting renal failure rarely become obvious until substantial

damagehasoccurred.

• If early disease is suspected, a spot urine protein:creatinine ratio(uPCR),is

moreaccuratethanurinedipstickandmoreconvenientthantheconventional

24-hoururinecollectionforproteinandcreatinine.

• Even low levels of proteinuria (<100 mg/mmol) may indicate renal

involvement.

• Theglomerularfiltrationrate(GFR)andrenalfunctionmayalsobeassessed

bynuclearmedicinetechniques.

• A uPCR of >50 mg/mmol should be investigated in a patient with SLE. A

uPCRof>300mg/mmolissuggestiveofnephroticrangeproteinuria.

• Renal biopsy should be considered if there is any evidence of new-onset

proteinuria,increasingproteinuria,haematuria,casts,oracutekidneyinjury.

• Biopsyshouldbedoneincentreswithahighdegreeofexperience.

• In2003,theInternationalSocietyofNephrology(ISN)andRenalPathology

Society (RPS) released a new classification of SLE (‘lupus’) nephritis

designedtostandardizedefinitions.The2003ISN/RPSclassificationoflupus

nephritis replaced the 1982 modified World Health Organization (WHO)

classification:

• ClassI:minimalmesangiallupusnephritis.

• ClassII:mesangialproliferativelupusnephritis.

• ClassIII:focallupusnephritis(<50%ofglomeruli).

• ClassIII(A):activelesions.

• ClassIII(A/C):activeandchroniclesions.

• ClassIII(C):chronicinactivelesions.

• Class IV: diffuse lupus nephritis (50% glomeruli), divided into diffuse

segmental(IV-S)orglobal(IV-G)lupusnephritis.

• ClassIV-(A):activelesions.

• ClassIV-(A/C):activeandchroniclesions.

• ClassIV-(C):chronicinactivelesions.

• ClassV:membranouslupusnephritis.

• Class VI: advanced sclerosing lupus nephritis (90% globally sclerosed

glomeruliwithoutevidenceofactivity).

• Chronicinactivelesions(glomerulosclerosis)areapoorprognosticfeature.

• Arepeatrenalbiopsymaybeconsideredwhenthereisincreasingproteinuria

orprogressiverenalfailureintheabsenceofanalternativecause(i.e.poorly

controlled blood pressure, intercurrent infection, or non-compliance with

medication).

• Active lupus nephritis may be present in otherwise clinically quiescent

disease.

• Patientswithlupusnephritisshouldhavegoodbloodpressurecontrolwitha

targetof≤130/80mmHg.

Haematologicalfeatures

• A microcytic anaemia may be due to anaemia of chronic disease, NSAID-

relatedpepticulcerdisease,dietarydeficiencyofiron, gastrointestinalblood

loss,haemoglobinopathy,ormenorrhagia.

• A normocytic anaemia can be due to myelosuppression from

immunosuppressants, chronic kidney disease due to nephritis, macrophage

activationsyndrome(MAS),orrarelyacutebleedinginalveolarhaemorrhage

orinthecontextofautoimmunethrombocytopenia.

• Macrocytosiscanbecausedbyimmunosuppression(e.g.azathioprine(AZA)

or methotrexate (MTX)) or as a consequence of hypothyroidism, alcohol

excess,vitaminB12,orfolatedeficiencyoroccasionallywithareticulocytosis

afterhaemolysis.

• Autoimmune haemolytic anaemia causes fragments on blood film, an

increased reticulocyte count, low haptoglobin, raised lactate dehydrogenase

(LDH)andbilirubin,andapositiveCoombstest(directantiglobulintest).

• Leucopeniaandlymphopeniaarecommonabnormalities,in50%and80%of

patients,respectively.

• Aleucocytosisisrare,suggestinginfectionorGCtherapy.

• Thereareseveralformsofclinicalthrombocytopenia.Chronic,indolent,and

uncomplicated thrombocytopenia (<100 × 10

/L) is present in up to 20% of

patients,particularly amongpatientswith APL antibodies.A rareracute and

life-threatening severe thrombocytopenia is also recognized, as well as

thromboticthrombocytopenicpurpura(TTP).

• Some patients may also present with immune thrombocytopenia, later

followedbyothermanifestationsofSLE.

• ThrombocytopeniaalsooccursinthecontextofMAS.This‘cytokinestorm’

requiresurgenttreatmentwithhigh-doseGCs(see Chapter9and 25).

Neurologicaldisease

Featuresofneurologicaldiseaserangefromcognitiveimpairment(inupto50%

ofpatients)topsychosesandseizures(in5–10%ofpatientsoverthecourseof

theirdisease).

• About 10% of patients develop a sensory (or, less often, sensorimotor)

peripheralneuropathy.

• Cranialnerveinvolvementisnotcommon.

• Upto70%prevalenceofpsychiatricillnesshasbeenquotedintheliterature

(includesanxietyanddepression).

• WhileitisacceptedthatGCscaninducepsychiatricsymptoms,ingeneralitis

felt the drugs given in SLE are not responsible for most of the psychiatric

manifestationsobserved.

• ExaminationofCSFinneuropsychiatricdiseaseshouldbedoneaspartofthe

initialevaluation—itmayrevealaraisedproteinand/orwhitecellcount,and

glucosemaybelow.CSFcanalsobenormal,makingdiagnosischallenging.

• Electroencephalographyisoftennon-specific.

• MRI with contrast is more sensitive than CT in detecting small vessel

vasculopathyassociatedwithSLE.

• Brain biopsy can be used to exclude opportunistic infection or neoplastic

diseasebutisoftennotrequired.Thepathologicalfindingsinlupuscerebritis

areofasmallvesselvasculopathy.

Otherclinicalfeaturesandimportantcomorbidities

OtherclinicalfeaturesarelistedinTable10.3.

VitaminDdeficiency

Thismaybeassociatedwithlossofimmunetolerance.MostpatientswithSLE

haveinsufficientlevelsofvitaminD,andtheeffectofreplacementondisease

activityremainsuncertain.

Osteoporosisandosteopenia

There is a high prevalence of fractures in young patients with SLE, due to a

reductioninbonedensity.

• Factors that contribute to osteopenia and osteoporosis include GCs, renal

osteodystrophy, low vitamin D levels due to sun avoidance, premature

menopause,orcyclophosphamide(CYC)treatment.

Malignancy

There is a 7× increased risk of non-Hodgkin lymphoma with SLE. There is

increasedincidenceofcervicalcancerduetohumanpapillomavirusinSLE.

Table10.3OtherclinicalfeaturesofSLE

Vascular Raynaud’sdisease

Cutaneousvasculitis

Digitalulcersandgangrene

Gastrointestinal

Hepatomegaly(25%)

Abdominalserositis(10–20%)

Splenomegaly(10%)

Mesentericvasculitis(rare)

Pancreatitis(rare)

Immunological Hypergammaglobulinaemia(60%)

Ocular Keratoconjunctivitissicca

Episcleritis

Scleritis

Anterioruveitis

Retinalvasculitis

Retinalvesselocclusion

Investigations

• ImportantinitialinvestigationsareshowninBox10.1.

• There are a variety of circulating autoantibodies to a range of nuclear,

cytoplasmic,andplasmamembraneantigens(Table10.4).

• Most patients (≥98%) will have antinuclear antibodies (ANAs). ~60% have

double-strandedDNA(dsDNA)antibodies (detectedbyimmunofluorescence

oncrithidialucillaeorbyELISAorradioimmunoassay).

• Somepatientshavevaryingcombinationsofantibodiesthatmaychangeover

thecourseofthedisease.

• SLE is associated with deficiencies of the early classical pathway of

complement(e.g.C1q,C1r,C1s,andC2).

• ReducedlevelsofcomplementC3andC4arecommoninSLE,particularlyat

thetimeofadiseaseflare.

• A subset of patients will be ‘serologically active but clinically quiescent’,

meaning they will have low complement levels and raised dsDNA antibody

titre,butnosignsofactivedisease.

• Patientsshouldalwaysbetreatedonthebasisofsymptomsratherthanblood

tests alone, but should be closely monitored for a flare in the context of a

risinganti-dsDNAantibodylevelandfallingC3.

• Some individuals may have high levels of RF and features of RA (thus an

‘overlap’syndrometermed‘rhupus’).

Box10.1Initialinvestigationsinpatientswhohave,oraresuspectedof

having,SLE

• Fullbloodcount

• Ureaandelectrolytes

• ESRandCRP

• Liverfunctiontests

• Urinalysis

• Urinemicroscopy

• Bloodpressure

• Urinaryprotein:creatinineratio

• ANAandextractablenuclearantigens(ENAs)

• ComplementC3andC4

• Anti-dsDNAantibodytitre(ELISA)

• Directantiglobulintest(Coombstest)

• Anticardiolipinantibodies

• Lupusanticoagulant(diluteRussellvipervenomtest)

• Rheumatoidfactor

Table10.4AutoantibodiesinSLE

Autoantibodyspecificity Prevalencein

SLEpatients

Associations

Intracellular: dsDNA 40–90% Renaldisease

Histone 30–80% Drug-inducedSLE

Sm 30% (Afro-

Caribbeans)

10%

(Caucasians)

Renalorneurologicaldisease

U1RNP 20–30% Mixedconnectivetissuedisease

Ro/SS-A 25–40% Sjögren’ssyndrome,cutaneous

SLE,congenitalheartblock

La/SS-B 10–15% AsforRo/SS-A(seeabovein

table)

Cell

membrane

Cardiolipin 20–40% Pregnancyloss,thrombosis

Redcell <10% Haemolyticanaemia

Platelet <10% Immunethrombocytopenia

Extracellular RF 25%

C1q 50%

AntiphospholipidsyndromeandSLE

(See also  Chapter 11.) Abnormal procoagulant factors occurring in SLE

patientsincludeapositivelupusanticoagulanttest,anticardiolipinandanti-β

glycoprotein-1(GP1)antibodies.

• Antiphospholipid(APL)antibodiesoccurinupto33%ofSLEpatients.

• Although the presence of APL antibodies alone is not sufficient to make a

diagnosis of APS, 50% of SLE patients with positive APL antibodies will

develophypercoagulopathy.

• The manifestations of SLE-associated APS include venous and arterial

thrombosis, thrombocytopenia, cerebral disease, recurrent fetal loss,

pulmonaryhypertension,andlivedoreticularis.

• Some patients with APL antibodies develop renal impairment (e.g.

hypertensionorproteinuria)duetomultiplesmallthrombi.

PregnancyandSLE

• Thereisdebateaboutwhetherpregnancyisassociatedwithanincreasedrisk

of SLE flare. However, pregnancy does not appear to worsen the long-term

outcomeofSLE.

• A USA study

 has shown that SLE patients suffer more from gestational

diabetes mellitus, hypertension, pulmonary hypertension, renal failure, and

thromboticepisodesinpregnancy.

• Incidenceofintrauterinegrowthretardation,pre-termdelivery,andincidence

ofcaesareansectionsarealsoincreased.

• Activediseaseincreasestheriskofmiscarriageandpretermbirth.

• A major complication is pre-eclampsia—it occurs in 22.5% of women with

SLE.Pre-existingrenaldiseaseisanimportantriskfactor.

• SLEisassociatedwithanincreasedrateoffetaldeathlateinpregnancy.~10%

ofSLEpregnanciesresultinfetalloss.

• APS-associatedcomplicationsarediscussedin Chapter11.

• Anti-Roassociateswithfetalheartblockandneonatallupus.

• Women who wish to conceive should receive appropriate counselling to

discussdiscontinuationofteratogenicdrugs.

• Features of a high-risk pregnancy include increasing age, significant organ

impairment/damage, lupus nephritis, active disease, high-dose GCs, and

presenceofAPL/Ro/Laantibodies.

• Womenathighriskshouldbemanagedinacombinedmedical-obstetricclinic,

and care should continue into the postpartum period, when flares and

thromboemboliceventscanoccur.

Reference

1. ClowseMEB,JamisonM,MyersE,etal.Anationalstudyofthecomplicationsoflupusinpregnancy.

AmJObstetGynecol2008;199:127.e1–127.

Assessmentofdiseaseactivity

Assessmentof changesinSLEactivityis anessentialpartofdecision-making

anddrugtreatment.

• Severalglobalactivityindiceshavebeenproducedthatcorrelatewellandare

reliable.

• Global scoring systems such as the Systemic Lupus Erythematosus Disease

Activity Index (SLEDAI) and the British Isles Lupus Assessment Group

(BILAG)activityindexareofsomevalue,bothinthecontextofclinicaltrials

andlong-termfollow-upofpatients.

• Equally constructive is the concept of an index of damage as distinct from

diseaseactivity.Forexample,apatientwithdyspnoeamayhaveanactivebut

reversiblepneumonitisorirreversiblefibrosis.

• The distinction between disease activity and damage is important since

treatments/managementforeachsituationaredifferent.

• The SLICC damage index has been developed as a method of recording

damageinpatientswithSLE.

2,3

References

2. Gladman DD, Goldsmith CH, Urowitz MB, et al. Sensitivity to change of 3 Systemic Lupus

ErythematosusDiseaseActivityIndices:internationalvalidation.JRheumatol1994;21:1468–71.

3. GladmanDD,GinzlerE,GoldsmithC,etal.ThedevelopmentandinitialvalidationoftheSystemic

Lupus International Collaborating Clinics/American College of Rheumatology damage index for

systemiclupuserythematosus.ArthritisRheum1996;39:363–9.

Drug-inducedSLE

Drug-inducedlupuserythematosus(DILE)shouldbesuspectedinpatientswith

nohistoryofSLE,whodevelopapositiveANAandatleastoneclinicalfeature

ofSLEafteranappropriatedurationofdrugexposure.

• DrugsmostcommonlyassociatedwithDILEare:

• minocycline.

• hydralazine.

• procainamide.

• isoniazid.

• quinidine.

• methyldopa.

• chlorpromazine.

• sulfasalazine(SSZ).

• anti-TNFαdrugs.

• Hydralazine-associated DILE is considered to be dose dependent, and

procainamide,timedependent.

• Upto90%ofpatientstakingprocainamidedevelopapositiveANAand30%

ofthesedevelopDILE.

• Renal, central nervous system, and skin features of SLE are rare in DILE.

OtherfeaturesofSLEsuchasmusculoskeletal,pulmonary,andserosaldisease

arecommon.

• Inthemajorityofcases,theconditionsubsidesonwithdrawingthedrug.

ManagementofSLE

Generalmeasures

• ItisimportanttoavoidoverexposuretoUV/sunlight.

• Sunblock should be SPF30orgreater, and shouldprotectagainst both UVA

andUVB.

• Advice should include supplement intake of vitamin D and in some cases

calcium to maintain adequate vitamin D levels (>50 nmol/L 25-

hydroxyvitaminD(25OHD)).

• Postmenopausalwomenandmen>50yearsoldonlong-termGCsshouldbe

offered a bisphosphonate as prevention against GC-induced osteoporosis

(GIO).

• In premenopausal women and men <50 years old, a DXA scan should be

obtained, and FRAX assessment done, and fracture risk—and need for

bisphosphonates—assessedaccordingly.

• Livevaccines(e.g.yellowfever,polio)arecontraindicatedinpatientstaking

immunosuppressants. Other vaccinations are not contraindicated though the

degreeofresponsetoavaccinemaydifferfromthehealthyindividual.

• Oestrogen-containing contraceptives should beavoidedideally. Progesterone

only contraceptives or other methods of contraception are advised in

preference.

• AlloralcontraceptivesshouldbeavoidedbywomenwithSLEwhohaveAPL

antibodies(orpositivelupusanticoagulant).

• Manypatientstoleratehormonereplacementtherapy(HRT)butuseofHRTin

themenopauseiscontroversial.Thereis,forexample,a20%increaseinSLE

flaresamongwomentakingHRT.

Reductionofcardiovasculardiseaseriskfactors

Thereisanexcessincidenceofcardiovascular disease(CVD) inSLE patients

comparedwithnon-SLEgeneralpopulation.

• ManagementofbasicCVDrisksisessential(smoking,hypertension,diabetes,

obesity).

• Considerstatinsforhypercholesterolaemia.

• AspirinorformalanticoagulationinthepresenceofAPSorifAPLantibodies

arepresent(butseealso Chapter11).

• TightcontrolofSLEdiseasemayreducerisk(seeTable10.5)

Table10.5RecommendationsfordruguseinSLE

Symptom Drug Regimen

Arthralgia/fever NSAIDs(caution

withrenaldisease)

Nospecial

recommendation

Arthralgia/myalgia/lethargy Hydroxychloroquine 200–400mgdaily

Malar/discoidrash Prednisolone,

hydroxychloroquine,

sunscreen,topical

steroid,or

tacrolimus

Arthritis/serositis/myositis Prednisolone,MTX,

AZA

20–40mgof

prednisolonedailyfor2–

4weeks,thenreducing

dosein5mgstepseach

week.Requiresbone

prophylaxisagainst

osteoporosisifdose

treatmentlastsfor>3

months

Autoimmuneanaemiaor

thrombocytopenia(ITP)

Prednisolone,IVIg,

AZA,rituximab

(RTX)

IVmethylprednisolone

followedby60–80mg

prednisolonedailyfor2

weeks,reducingin10

mgstepsperweek,

dependingonresponse.

ITPoftenrequires

immunoglobulin.

Refractorycasesmaybe

treatedwithRTX,AZA,

orsplenectomy

Renal Prednisolone,AZA,

CYC,

mycophenolate

mofetil(MMF),

RTX,tacrolimus

Control BP with ACE

inhibitororangiotensin

receptorblocker:

BP target <130/80

mmHg

Centralnervoussystem Prednisolone,AZA,

MMF,CYC,RTX

Raynaud’sdisease Calciumchannel

blockers,losartan

Immunosuppression

(SeeFig.10.1.)

Glucocorticoids(GCs)

• Prednisolone is frequently used with immunosuppressive drugs to rapidly

reduceSLEdiseaseactivity.

• DosingofGCsvarieswidelydependingontheseverityofdiseaseactivity,and

isgraduallytapered.

• Intravenous‘pulsed’methylprednisolone0.25–1guseddailyfor3consecutive

daysispreferredinseriousorganorlife-threateningdisease.

Antimalarialdrugs

• Hydroxychloroquine (HCQ) 200–400 mg/day is an initial treatment for

patientswithmildSLEsymptoms.

• HCQreducesthefrequencyofflaressoisnormallycontinuedinallpatients,

evenwhentheyrequireadditionalimmunosuppression.

• Patientsshouldbeadvisedabouttheneedforannualeyetesting,andafter5

yearsofusetheyshouldbereferredtoanophthalmologisttoassessforretinal

toxicity.

• Eyeexaminationshouldincludeexaminationofcentralvisualfield,visualand

readingacuity,slitlampofthecornea,andstereoscopicslitlampoftheretina.

• For patients intolerant of HCQ, chloroquine phosphate 250 mg daily is a

usefulalternative.

• MepacrineisanantimalarialeffectiveintreatingSLEskinrashes,butdoesnot

treatothermanifestationsofthedisease.

Azathioprine,mycophenolatemofetil(MMF),andmethotrexate

• Azathioprine (AZA) 2–3 mg/kg/day or mycophenolate mofetil (MMF) 0.5–

3g/dayareusedinmoderatetoseveredisease.

• MMF is often preferred to AZA for lupus nephritis after the ALMS trial

demonstrated superiority as a maintenance treatment with significantly less

timetotreatmentfailure(andequivalenceofMMFtoIVCYCasaninduction

agent

• TrialdatashowMMFisusefulintreatingnon-renalmanifestations.

• MTX isusedwhen arthritisisthe mainclinicalmanifestation ofSLE,or in

overlapsyndromeswithRA.

• A recent systematicreviewfound MTX is alsoassociatedwith a significant

reductioninSLEDAI.

Rituximab

RTXdepletescirculatingBcellsthroughtargetinganti-CD20.Itisamonoclonal

antibody that was first used effectively in 2002 in patients with active SLE

whichhadfailed,oronlyhadpartiallyrespondedto,conventionaltreatments.

• Open-label studies using pulse IV infusions of RTX confirmed the efficacy,

withbenefitsextendingto6months.

• However, a major RCT failed to demonstrate that RTX was beneficial to

patientswithmoderate-to-severeSLE.

• In NHS England healthcare,RTX is allowed forusein SLE, as long asthe

patient has one BILAG A and/or 2B scores or SLEDAI-2K score >6, in

additiontohavingfailedatleasttwoimmunosuppressivedrugs(atleastoneof

thesemustbeMMForCYC).

• B-celldepletioncanbetestedbymonitoringtheCD19count.

• Significantsideeffectsincludeinfusion-relatedreactionsandinfection.Rarely,

progressive multifocal leucoencephalopathy (PML) has been reported in

associationwithRTX,butPMLisalsoseeninSLEpatientswhohavenever

receivedRTX.

• Low IgG levels can occur with successive cycles, with very low levels

occasionally preventing further treatment, or necessitating the use of

maintenanceimmunoglobulin.

Cyclophosphamide(CYC)

• IV‘pulsed’CYCiscommonlyusedformanyoftheseveremanifestationsof

SLE, and has been demonstrated to be particularly effective for renal and

neurologicaldisease.

• The ‘Euro-Lupus’ regimen (low-dose IV CYC) is often used with clinical

outcomessimilartothehigher-doseregimens.

• As an alkylating agent with a broad effect on different cells, CYC depletes

bothBandTcells.

• Major side effects include infection, hair fall, premature menopause, and

bladdertoxicity(nowrareduetoco-treatmentwithmesna).

• ThereissomeevidencethatusingGnRHagonistsgivenpriortoeachdoseof

CYC may prevent premature menopause and preserve fertility following

treatment.

Belimumab

• Belimumabisa fully-humanizedantibodythatneutralizesthe activityofthe

soluble B-lymphocyte stimulator (BLyS)/B-cell activating factor (BAFF).

BLyS/BAFF is also known as TALL-1, and THANK, and is a TNF

superfamilymember(TNFSF13B)bestknownforitsroleinthesurvivaland

maturationofBcells.

• It is the first drugtobelicensed for SLE in approximately50years, and is

currentlyapprovedbyNICEintheUK.

• GivenIV,belimumabhasprincipallydemonstratedapositiveeffectinMSK

andmucocutaneousdisease,aswellasreductionindiseaseactivityandflares.

• ItsefficacyinneurologicalandrenalSLEremainsuncertain.

Plasmaexchange(PE)

• PE is a treatment option for severe manifestations of SLE such as alveolar

haemorrhage,refractorynephritis,orassociatedcatastrophicAPS,thoughthe

limitedtrialdataforitsuseareconflicting.

Stemcelltransplantation

• Haemopoieticstemcelltransplantation(HSCT)isusedtotreathaematological

disease,buthasalsobeenusedinpatientswithsevererefractorySLE.

• HSCTiseffectiveininducingremissionbutiscurativeonlyin<50%.

• Mortalityishighandlong-termeffectsareunknown.

• NewautoimmuneconditionshavebeenreportedafterHSCT.

• Itiscurrentlyusedonlyinthosewithlife-threateningSLE.

• Mesenchymalstemcelltransplantationhasrecentlyemergedasanalternative

treatment.It significantlyreducesSLEactivityandmayinduce remissionin

upto50%ofpatients.

Otheragents

• Tocilizumab hasbeenshown to improve diseaseactivity scores and dsDNA

antibodytitresinopen-labelstudies.

• Epratuzumab,ananti-CD22monoclonalantibody,reducesdiseaseactivityand

seemstodepleteamore‘lupus-specific’setofB-cellsthanRTX.Itiscurrently

undergoingphaseIIItrials.

• Ofatumumabisafullyhumanizedanti-CD20monoclonalantibodythatmay

be usefulinSLE as an alternative toRTX when there hasbeenan infusion

reaction.

• Eculizumab,afullyhumanizedmonoclonalantibodyagainstcomplementC5

haspassedphaseItrialsinSLE.Therearecasereportsofitsbenefit.

• Atacicept is a recombinant fusion protein that acts on B cells inhibiting

BAFF/BlySandaproliferation-inducingligand(APRIL).Inrecentstudies,it

significantlyreducedtheSLEflarerate.PhaseIIbtrialsareongoing.

• Tacrolimus,acalcineurininhibitor,may beusedinlupusnephritis.A recent

RCT suggests it may be non-inferior to MMF when used as an induction

agent.

• Pooled immunoglobulin (IVIg) may be of use in severely ill patients not

respondingtoothertherapies,andespeciallyinsituationswheresepsisisthe

triggerandlife-threatening.

• IVIg may have a role in drug-resistant membranous and

membranoproliferative nephritis, and has been used in severe immune

thrombocytopeniaandhaemolyticanaemiawithgoodeffect.

For additional detail on all drug therapies used for rheumatic disease,

includingimmunosuppressants,seeChapter23.

Fig.10.1Managementoflupusnephritis.DatafromBertsiasGK,TektonidouM,AmouraZ,etal.Joint

EuropeanLeagueAgainstRheumatismandEuropeanRenalAssociation–EuropeanDialysisandTransplant

Association(EULAR/ERA-EDTA)recommendationsforthemanagementofadultandpaediatriclupus

nephritis.AnnRheumDis2012;71:1771–82.

References

4. Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus AZA as a maintenance therapy for

lupusnephritis.NEnglJMed2011;365:1886–95.

5. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for

inductiontreatmentoflupusnephritis.JAmSocNephrol2009;20:1103–12.

Prognosisandsurvival

Many studies of the duration of disease and survival rates are confounded by

inadequateattentionpaidtotheethnicgroup,ageofonset,andsocioeconomic

status of individual patients. The number of patients lost to follow-up is also

high.

• In relevant studies, with the division of patients into those with or without

overtnephritis,thereisa5-yearsurvivalinSLEof90%.

• At 15 years, only 60% of those with nephritis will be alive compared with

85%ofthosepatientswithoutrenaldisease.

• Abi-modal mortalitycurveis consideredtoexist.Patients whodiewithin5

years usually have very active disease, requiring high doses of

immunosuppressivedrugs.

• Patientsdyingafter5yearstendtodoso fromcardiovasculardisease,renal

disease,andpossiblyinfection.

• Thecombinedeffectofthediseaseanditstreatmentistoincreasetheriskof

infectionmarkedly.Thepossibilityofinfectionmustalwaysbeconsideredand

treatedaggressivelyasoutcomesfromsepsiscanbeverypoor.

• SLEincreasestheriskofallmalignanciescomparedtothegeneralpopulation,

particularlynon-Hodgkin’slymphoma.

• CervicaldysplasiaisincreasedinSLEpatientsandregularmonitoringshould

beemphasized.

• The exact contribution of disease activity, duration, and immunosuppressive

drugexposuretotheriskofdevelopingamalignancyrequiresfurtherresearch.

Cliniciansshouldbeawareofthisincreasedriskandbealerttoinvestigating

worryingsymptomspromptly.

JuvenileSLE

Epidemiology

Approximately 20% of patients with SLE present before 18 years of age,

commonlybetween12and14years.

• Increasedincidenceofrenal,haematological,andneuropsychiatricdiseaseis

seeninjuvenileSLE(JSLE).

• TheoverallincidenceofJSLEis0.4–0.6per100,000,butismuchhigherin

Afro-CaribbeanandAsianpopulations.

• F:Mratioislesspronouncedthaninadultsandis3:1prepubertybutincreases

to9:1postpuberty.

Clinicalfeatures

TheclinicalfeaturesofJSLEareextremelyvariable,rangingfromamildillness

with rash, fatigue, and joint involvement to severe life-threatening organ

involvement.

• JSLE tends to be a more severe phenotype than adult disease, accruing a

greaterburdenoforgandamage.

• JSLE has a similar presentation to adult disease and follows a

relapsing/remittingcourse.

• Otherdifferencesfromadultdiseaseinclude:

• Raynaud’sdiseaseislesscommon(10–20%ofpatients).

• AvascularnecrosisofthehipismorecommoninJSLE.

• InJSLE,thediseaseitselfanditstreatmentshavesignificantconsequences

ongrowthandphysicaldevelopment.

• Malarrashoccursin30%ofcasesatdiagnosis.

• Prevalenceofrenaldiseaseishighatdiagnosis,upto60%ofcases.

• Neuropsychiatricdiseaseispresentinupto40%ofcases.

Diagnosisandinvestigations

• Similar to adult SLE, diagnosis is based on both clinical and laboratory

features.

• The ACR revised classification criteria for SLE have alsobeenvalidatedin

JSLE.

• Of the ACR criteria features, the commonest found in JSLE include ANA

positivity, arthritis, haematological disorders, malar rash, renal and

neuropsychiatricinvolvement.

• Assessment of JSLE includes history, examination, and disease activity

assessmentusingtoolsusedinadultSLE,includingBILAGandSLEDAI.

Initialassessmentinvestigations

• ANA(+vein>95%),dsDNA(+vein60%),ENAs—mostcommonlyinclude

anti-RoandLa,anti-Smantibodies.

• Lupusanticoagulant(LA),ACLIgGandIgM,β

GP1antibodies.

• Clottingscreen—prolongedinAPLSandMAS.

• Fibrinogen—increasedininflammation,lowinMAS.

• Coombstest/DAT—positiveinautoimmunehaemolyticanaemia.

• ImmunitystatustomeaslesandvaricellaIgG.

Ateachreview

• FBC (Hb low in anaemia of chronic disease or autoimmune anaemia,

leucocytecountincreasedininfectionandserositis,lowplateletsoften).

• IfpancytopeniaonFBCinunwellpatient—considerMAS.

• ESRtypicallyincreasedinflares,lowinMAS.

• CRP—ifincreasedconsiderinfection,serositis,polyarthritis.

• Complement:lowC3andC4levelscancorrelatewithdiseaseactivitybutwith

lowsensitivity.

• Urinalysis for blood and protein to check for renal involvement. If protein

present,quantificationisneededwithuPCR.

ManagementofJSLE

Early and aggressive therapy is key to improve outcome and prevent organ

damage.Thisincludesinductionandmaintenancetherapies.

• Management is similar to adult SLE (see  ‘Management of SLE’, pp.

360–365).

• ThecurrenttreatmentparadigmistotreatallchildrenwithHCQtominimize

flares,skindisease,andlimitatherogenicandthromboticrisksassociatedwith

JSLE.

• ProvideadviceregardingsunandUVavoidanceanduseofsunblock(SPF50)

toreduceflaresandphotosensitiverashes.

• Induction therapy typically includes use of IV GCs (e.g. IV

methylprednisolone on 3 consecutive days), followed by a dose reduction

regimenoforalprednisolone(from1–2mg/kg/day)togetherwithasDMARD.

• TheroleofIVCYCininductionislessclearandMMFistypicallypreferred

inJSLEnephritis.

• CYC isstill usedinneurological disease,systemic vasculitis,andrefractory

JSLEnephritis.

• MildtomoderatediseaseatpresentationistreatedwithGCs,MMF,orAZA.

MTX is used when arthritis or cutaneous manifestations (including discoid

lupus)predominate.

• MaintenancetreatmentiswithAZA,MMF,orMTX—similartoadultdisease.

• RTX is effective in JSLE and can be used in disease refractory to first-line

induction therapy or in patients experiencing unwanted adverse effects of

alternativetreatments.

• Anticoagulants(heparinand/orwarfarin)shouldbeconsideredinAPLS,and

low-dose aspirin in cases of positive LA or ACL antibodies. Optimum

anticoagulationregimens,arenotknown,however.

• Hypertension and proteinuria should be aggressively managed with ACE

inhibitorsandcalciumchannelblockerstopreventorgandamage.

• Closesurveillanceofpatientsatintervalsof1–3monthsisnecessarytoensure

therearenounexpectedcomplicationsofJSLEoritstreatment.

Prognosisandsurvival

• TheprognosisofJSLEisoftendeterminedbytheseverity,management,and

outcomeofrenaldisease.

• Risk factors for poor outcome include severe JSLE flares, infection,

neuropsychiatricmanifestations,andsomefeatures,seennotablyinblackand

Hispanic populations, such as persistent anaemia, high creatinine,

hypertensionandpersistentlylowC3.

• JSLE continues to have a 2× higher mortality than adult SLE, although

outcomehasimprovedinrecentyears.

• 5-yearsurvivalofJSLEnowexceeds90%.

Furtherreading

BrunnerHI,HugginsJ,Klein-GitelmanMS.PaediatricSLE–towardsacomprehensivemanagementplan.

NatRevRheumatol2011;7:225–33.

MidgleyA,WatsonL,BeresfordMW. New insightsintothepathogenesisandmanagementoflupusin

children.ArchDisChild2014;99:563–7.

Thorbinson C, Oni L, Smith E, Pharmacological management of childhood-onset systemic lupus

erythematosus.PediatrDrugs2016;18:181–95.

Neonatallupussyndrome

Neonatallupuserythematosus(NLE)isanautoimmuneconditionattributableto

transfer of maternal autoantibodies across the placenta, such as anti-SSA/Ro

and/oranti-SSB/Laantibodies.

• Theconditioncanpresentinuteroorpostnatally.

•  ~50% of mothers of babies with NLE are healthy at childbirth with no

recognizedsymptomsofAICTD.

• Only1–2%ofautoantibody-positivemotherswillhaveaninfantwhodevelops

NLE,althoughsubsequentriskincreasesto10–25%forfuturepregnancies.

• NLE is transient in cases other than those with heart block. Skin and

haematologicalmanifestationsresolveasmaternalantibodiesdisappearat3–6

monthspostbirth.

• Severe hepatitiscanbe life-threateningandmortality incardiacNLE is20–

30%.

Clinicalfeatures

There should be suspicion of the presence of NLE where there is a persistent

bradycardia or a combination of non-scarring rash, transaminitis, and

cytopeniainababy0–6monthsold.

Skin

• Rashesoccurin70%ofNLEbabies—typicallypresentatbirth.

• Typical lesions are transient and similar to subacute cutaneous LE with

annularpinkscalyplaques.

• Lesionsmaybecrustedandmayaffectheadandneckaselsewhere.

• Telangiectasiaandpetechiaearealsocommonandmayoccuralone.

Cardiacmanifestations

• Cardiaclesionsoccurin65%ofNLEbabies.

• Athirdofaffectedbabieshavecongenitalcompleteheartblock,whichusually

developsbetween18and20weeksofgestation.

• Other problems include bradycardia, prolonged QT interval, ventricular

tachycardias,valvedisease,cardiomyopathy,andheartfailure.

Othermanifestations

• Haematological effects usually appear during the second week of life and

includethrombocytopenia,haemolyticanaemia,andneutropenia.

• Liver involvement includes transaminitis in half of patients and conjugated

jaundice.

• OthereffectsofNLEcanincludetransientneurologicalandlunginvolvement.

Theformermaybemanifestbyasymptomaticneuroimagingabnormalities.

Investigations

• AllwomenofchildbearingagewithanAICTDshouldbetestedforanti-Ro

andanti-Laantibodiesearlyintheirpregnancy.

• Women testing positive for anti-Ro and/or anti-La antibodies should be

referred to a specialist obstetric unit for weekly fetal US-echocardiography

from16weeks’gestationonwards.

• ThefrequencyofUS-echomaybereducedinabsenceofcompleteheartblock

afterweek26.

• Diagnosis is made on the basis of clinical features and in the presence of

positiveautoantibodiesinneonatalormaternalserum.

ManagementofNLE

• Incompleteheartblock,64%oflivebirthsrequireapacemaker,almostallin

thefirstyearoflife.About60%ofcasesrequireapacemakerduringthefirst

10daysafterbirth.

• GCs, HCQ, and IVIg may reduce the risk of NLE-related cardiac lesions

overall.

• Skin lesions can be managed with UV avoidance, sun block, and topical

steroids(±HCQ).

Prognosis

• Affectedbabiesmaybeatincreasedriskoffutureautoimmuneconditionsbut

developmentofJSLEisrare.

• Otherinflammatoryconditionsininfantsthatmaysubsequentlyoccurinclude

autoinflammatoryconditionssuchasCINCA/NOMID,Kawasakidisease,and

systemic-onsetJIA.

Furtherreading

Brito-ZerónP,IzmirlyPM,Ramos-CasalsM,etal.Theclinicalspectrumofautoimmunecongenitalheart

block.NatRevRheumatol2015;11:301–12.

JohnsonB.Overviewofneonatallupus.JPaediatHealthCare2014;28:331–41

Saxena A, Izmirly PM, Mendez B, et al. Prevention and treatment in utero of autoimmune associate

congenitalheartblock.CardiolRev2014;22:263–7.

Chapter11

Antiphospholipidsyndrome

Catastrophicantiphospholipidsyndrome

Antiphospholipidsyndrome

Classification

Antiphospholipid syndrome (APS) is a systemic autoimmune disease

characterizedbyrecurrentarterialorvenousthrombosis.APScanbeprimaryor

secondary to an underlying autoimmune disease—commonly SLE (see

Chapter10).

• Patients may be classified in terms of the antibody present. Anticardiolipin

(ACL) and anti-β

 glycoprotein 1 (β

GP1) are detected by quantitative

enzyme-linkedimmunosorbentassays(ELISA).SeeTable11.1.

• Lupus anticoagulant (LA) is a functional test that quantifies coagulation in

vitro.

Table11.1Classificationcriteriaforantiphospholipidsyndrome

Clinicalcriteria

Vascular

thrombosis

Oneormoreclinicalepisodesofarterial,venous,orsmall

vesselthrombosisinanytissueororgan,confirmedby

objectivecriteria.Histopathologyshouldshowthrombosis

withoutsignificantinflammationinthevesselwall

Pregnancy

morbidity

Oneormoreunexplaineddeathofamorphologicallynormal

fetusatorbeyond10weeks’gestation

Oneormoreprematurebirthofamorphologicallynormal

neonateatorbefore34weeks’gestationduetopre-eclampsia,

eclampsia,orplacentalinsufficiency

Threeormoreunexplained,consecutive,spontaneous

abortionsbefore10weeks’gestation,excludingmaternal

anatomicalorhormonalabnormalities,andexcludingmaternal

andpaternalchromosomalcauses

Laboratorycriteria

ACL

antibodies

Medium/hightitreofIgGand/orIgMisotypeanticardiolipin

antibodyinbloodon2ormoreoccasionsatleast12weeks

apartusingstandardassays

Anti-β

glycoprotein

1antibodies

Anti-β

glycoprotein1IgGorIgMinbloodon2ormore

occasionsatleast12weeksapartusingstandardassays

Lupus

anticoagulant

(LA)

LApresentinplasmaon≥2occasions>12weeksapart

AdiagnosisofAPSrequiresthepresenceofonepositiveclinicalcriterionmanifestedbythrombosisor

pregnancyloss,plusonepositivelaboratorycriterion(anyoneofthethreeantibodies)ontwodifferent

occasionsseparatedby12weeks.

AdaptedfromMiyakisSetal.Internationalconsensusstatementonanupdateoftheclassification

criteriafordefiniteantiphospholipidsyndrome(APS).JThrombHaemostasis2006;4:295–306with

permissionfromWiley.

Epidemiology

• Case–controlstudiesestimatetheprevalenceofACLantibodiesinthenormal

populationtobe1–4%.

• Prevalence of ACL antibodies in people >65 years increases to 12–50%

dependingonthestudy.

• Age-dependentreferencerangesdonotexistbuthavebeensuggestedbysome

authors.

• PrevalenceofACLantibodiesandLAinSLEpatientsisestimatedat20–40%

and10–20%,respectively.Thesedifferencesariseduetotreatmenthistoryand

thelackofuniformityofassaymethods.

Pathophysiology

• APL antibodies are directed against phosphorus-fat components of cell

membranescalledphospholipids.

• Certain blood proteins will bind with phospholipids to form complexes to

whichantibodiesmayoccur.

• ACL antibodies are a family of the immunoglobulins IgG, IgM, IgA, or a

combinationoftheseisotopes.TheIgGsubtypeshaveastrongerassociation

withclinicalcomplicationscomparedwithIgM.

• HighlevelsoftheIgMisotypecanbeassociatedwithautoimmunehaemolytic

anaemia.

• TheclinicalconsequencesofIgAACLantibodiesareunclear.

• β

GPIisaplasmaglycoproteinco-factortowhichACLbinds.Anti-β

GPIis

morespecificthanACLantibodyinpredictingthrombosis,andcanoccurin

~10%ofAPSpatientsastheonlypositivetest.

• LA is a functional measurement of the capacity of heterogeneous APL

antibodies that interferes with phospholipid-dependent stages of blood

coagulationinvitro,inhibitingboththeintrinsicandextrinsicpathways.

• Hence, in vitro, LA exhibits anticoagulant properties, whereas in vivo it

functions as a procoagulant. APL antibodies are therefore paradoxically

associatedwiththrombosis,ratherthanhaemorrhage.

• Apart from clinical suspicion, a clue to the presence of APS is prolonged

clottingtimeinassaysforthe‘internalpathway’clottingcascade.Around50%

of patients with positive LA antibodies have a prolonged activated partial

thromboplastintime(APTT).

Differentialdiagnosis

The most characteristic feature of APS is thrombosis in the presence of

thrombocytopenia.

• The main differential diagnosis to consider is thrombotic thrombocytopenic

purpura(TTP).

• TTPisamicrovasculardisorder,oftenassociatedwithneurologicalfeaturesof

confusion,seizures,andalteredconsciousness.

• Thedifferentialdiagnosisofunexplainedthrombosisincludesgeneticcauses

(e.g.proteinCandS,andantithrombinIIIdeficiencies)anddrugs(including

oestrogen,thalidomide,IVIg).Thereforeafullthrombophiliascreenshouldbe

carriedoutinpatientswithrecurrentvenousthrombosis.

Clinicalfeatures

(SeealsoTable11.2.)

Thrombosis

• Vesselsofallsizes,venousorarterial,maybeaffectedwithoutevidenceofan

inflammatoryinfiltrate,hencetherangeofclinicalfeaturesiswide.

• Unlike in most clotting disorders, arterial thrombosis is a major feature of

APS.

• Thrombosis can be present with or without a history of relevant pathology

associatedwithpregnancy.

• Occlusion of the intracranial arteries is the most common arterial

manifestation,withthemajorityofpatientspresentingwithstroke.

• APL antibodies should be sought in the younger stroke patient, where they

mayaccountforupto20%ofcases.

Catastrophicantiphospholipidsyndrome

• Widespread thrombosis is the feature of life-threatening ‘catastrophic

antiphospholipidsyndrome’(cAPS).

• cAPSmaypresentwithacutecollapse,severethrombocytopenia,multiorgan

failure (notably cerebral and renal), and adult respiratory distress syndrome

(ARDS).

Fetalloss

• Recurrent spontaneous pregnancy loss is a common manifestation of APS,

whichoccursaseitherrecurrentearlymiscarriageorintrauterinefetaldemise.

• ScreeningforAPLantibodiesinthecontextofpreviouspregnancyhistoryis

ofimportanceindeterminingthesignificanceofpositiveAPLantibodies.

• InAPLantibody-positivepregnanciesthatdonotendinmiscarriage,thereisa

high incidence of early onset pre-eclampsia, intrauterine growth restriction,

placentalabruption,andprematuredelivery.

Skinlesions

• Themostfrequentmanifestationsarelivedoreticularisandskinulcers.

• Livedo reticularis is characterized by a mottled purple reticular pattern.

Appearances look similar to a fishnet pattern and in APS is usually

disseminated.Livedoisamarkerofpoorprognosisanddiseaseseverity.

• Skinulcerscanbefoundintheextremities,andextensivecutaneousnecrosis

hasbeenreported.Digitalgangrenehasalsobeendescribed.

• Subungual splinter haemorrhages are seen in ~5%, and may suggest the

occurrenceofotherthromboticevents.

• Other cutaneous lesions also described include purpura, tender nodules,

papules,palmar–plantarerythema,andanetoderma.

Liverandgastrointestinaltract

• LiverabnormalitiesarecommoninAPS,possiblyduetovascularsludgingor

smallvesselthrombosis.

• Budd–ChiarisyndromewasafeatureoftheoriginaldescriptionofAPS.Itis

causedbythrombosisofthehepaticveins,presentingasatriadofabdominal

pain, ascites, and liver enlargement. It may be fulminant, acute, chronic, or

asymptomatic.

• Intestinal ischaemia and perforation due to thrombosis and coeliac artery

stenosishavealsobeendescribed.

Musculoskeletal

• OsteonecrosisisacomplicationofAPS.Itismostcommonlyofthefemoral

headbutcanaffectotherbonessuchasthenavicular.

• Non-specificarthralgiamayoccur.Jointpainsandstiffnessaremorecommon

inAPSassociatedwithSLEandotherautoimmunerheumaticandconnective

tissuediseases.

• Metatarsal fractures and other spontaneous vertebral and rib fractures have

alsobeenreported.

Endocrine

• Adrenalinsufficiencyisthemostcommonendocrinologicalmanifestation,and

canbethepresentingfeatureofAPS.

• Afewcasesofhypopituitarismandovarian/testicularinvolvementhavebeen

reported.

Kidney

• ThekidneyisamajortargetorganinAPS.

• Renalarteryocclusionandrenal arterystenosishavebeendescribed inAPS

patientswithhypertension,andmayresultinrenalinfarction.

• Thrombosis of the renal veins and thrombotic microangiography has been

described.

• DistinguishingbetweenSLEnephritis(immunecomplexmediated)andAPS

nephritis(thromboticdisease)canonlybeestablishedbyrenalbiopsy.

Lungs

• Pulmonaryembolismandinfarctionisthemostcommonlungmanifestationof

APS.

• Pulmonaryhypertensionisfoundinaround2%ofAPSpatients.

• ARDSisrarewithhighmortalityof~50%,usuallyseenincAPS.

Centralnervoussystem

• Cerebral ischaemia associated with APL antibodies is the most common

arterialthromboticmanifestation.Lesscommonlyassociatedissagittalvenous

sinusthrombosis.

• Migraineisacommoncomplaint,andcognitivedeficitscanoccur.

• APSpatientsmayexhibitfeaturesseenwithmultiplesclerosis,andMRIsmay

failtodifferentiate.

• Seizures can occur, thought to be secondary to the interaction of APL

antibodiesandneuronaltissue.

• Transverse myelopathy, though rare, has a strong association with APL

antibodies.

• Other lessfrequentmanifestations include chorea,Guillain–Barré syndrome,

sensorineuralhearingloss,andretinalischaemia.

Cardiacfeatures

• APSmaybeassociatedwithmultiplecardiovascularcomplicationsincluding

acceleratedatherosclerosis,valvularheartdisease,andintracardiacthrombi.

• CardiacmanifestationsofAPSresultinsignificantmorbidityinaround5%of

patients.

• InaEuropeancohort,myocardialinfarctionwasapresentingfeatureofAPS

in3%ofpatients,andwasseenduringfollow-upin5.5%.

• The prevalence of APL antibodies in patients with myocardial infarction is

estimatedat5–15%,butscreeningisnotindicated,exceptinyoungerpatients,

patients with other symptoms and signs of APS, and those with a family

historyofautoimmunedisease.

• Mitral and aortic valve thickening and dysfunction is commonly seen on

echocardiography,butsignificantmorbidityisuncommon.

• IntracardiacthrombusisararemanifestationofAPS.

Laboratoryfeatures

Thrombocytopenia

• Thrombocytopenia is common, seen in ~25%. It is rarely severe enough to

causebleeding.

• ACLantibodieshavebeenfoundinupto30%ofpresumedcasesofimmune

thrombocytopenicpurpura.

• Haemolyticanaemiawithapositivedirectantiglobulintestmayco-existwith

thrombocytopenia(Evanssyndrome).

Generalaspects

• Given an association with all AICTDs, extensive autoantibody screening

shouldbeconsidered:ANA,RF,anti-CCPantibodies.

• C3, C4, Coombs test/DAT, bilirubin, LFTs, FBC, ESR, CRP, and organ

functiontestsshouldbechecked.

Table11.2Clinicalfeaturesofantiphospholipidsyndrome

Feature Subgroup Frequency(%)

Thrombosis Deepveinthrombosis 39

Pulmonaryembolism 14

Arterialthrombosis,legs 4

Arterialthrombosis,arms 3

Stroke 20

Transientischaemicattack 11

Valvethickening/dysfunction 12

Livedoreticularis 24

Pregnancy

manifestations

Earlyloss(<10weeks) 35

Lateloss(≥10weeks) 17

Livebirth 48

Prematurebirth 11

Thrombocytopenia 30

Associated

features

Skinulcers,livedoreticularis,thrombophlebitis

Heartvalvelesionsandmyocardialinfarction

BuddChiari,transverse myelitis,chorea, cognitivedeficits,

pulmonaryhypertension

Lesscommon

features

Splinterhaemorrhages,digitalgangrene,amaurosisfugax,

retinalarteryandveinocclusion,renalartery

stenosis/thrombosis,osteonecrosis,Addison’sdisease,ARDS

ReproducedfromCerveraRetal.Antiphospholipidsyndrome:clinicalandimmunologicmanifestations

andpatternsofdiseaseexpressioninacohortof1000patients.ArthritisRheum2002;46:1019–27with

permissionfromWiley.

TreatmentofAPS

There is no evidence for the role of warfarin in primary prevention (‘primary

prevention’definedbypreventionbeforediagnosedthrombosis).Modifiablerisk

factors for thrombosis and cardiovascular lesions should be addressed (e.g.

smoking, high cholesterol, increased blood pressure, systemic inflammation,

oestrogenuse).

• Hydroxychloroquine has antiplatelet, anti-inflammatory, and anticoagulant

properties,andisrecommendedinSLEpatientswithpositiveAPLantibodies

(Table11.3andTable11.4).IthasalsobeenshowntoreduceAPLantibody

titres.

• HMG CoA reductase inhibitors lower cholesterol levels and have anti-

inflammatory,immunoregulatory,andantithromboticeffects.

• Studieshaveshown thatfluvastatinmaypreventthrombosisinpatientswith

APSbyinhibitingtissuefactorandothermonocytemarkersthatcontributeto

activation of the coagulation pathway, in addition to reducing thrombus

formationbiomarkers.

• Rituximab (RTX), an anti-CD20 monoclonal antibody that depletes CD20-

positiveB-cellpopulations,hasbeenusedinAPS-relatedthrombocytopenia,

haemolytic anaemia, venous and arterial thrombosis, ischaemic cardiac and

bowel events, cutaneous lesions, diffuse alveolar haemorrhage, nephropathy,

andcAPS.

• RTXmaybeusedinrefractorycasesofAPSafterfailureofanticoagulation.

• Glucocorticoids (GCs), immunosuppressive drugs, IVIg, or plasmapheresis

have been used in the treatment of APS with thrombosis, but the latter are

morejustifiedincAPS.

• Over the last 4 years, successful treatment with eculizumab (a complement

inhibitor) has been reported in a few cases, showing benefit in preventing

recurrenceofAPSamongtransplantrecipients,andinrefractorycAPS.

Anticoagulationinprimarythromboprophylaxis(APLantibodypositive

withoutpreviousthromboticevent)

• RecommendationsforprimarythromboprophylaxisinAPSsupporttheuseof

low-doseaspirin(75–100mg/day).

Anticoagulationinsecondarythromboprophylaxis(APS—afterfirstvenousor

arterialevent)

• After the first thrombotic event (either arterial or venous), recurrence of

thrombosisiscommon,butcanbepreventedbytreatmentwithwarfarin.

• Patients <50 years of age with cerebrovascular events and positive APL

antibodies,havea5×increasedriskoffurtherischaemicstroke.

• Invenousthrombosiswithtransientorreversibleriskfactorsorlow-riskAPL

antibody profile, 3–6 months of treatment may be adequate, aiming for an

internationalnormalizedratio(INR)of2–3.

• High-intensity anticoagulation (an INR of 3–4) is associated with increased

bleedingriskcomparedtostandardintensitytreatment(INRof2–3)withno

clearreductioninthromboticeventsaccordingtostudies.

• Hence, high-intensity anticoagulation is not recommended, but could be

considered in complicated cases where thrombosis occurs despite

warfarinizingwithanINRof2–3.

• Forpatientswithrefractorythrombosis,fluctuatingINRlevels,orhighriskof

major bleeding, alternative therapeutic options to warfarin should be

considered, such as long-term low-molecular-weight heparin (LMWH),

hydroxychloroquine,orstatins.

• Table 11.4 summarizes APS treatments in patients refractory to

anticoagulationorwhoareunabletotakewarfarin.

• Mild thrombocytopenia need not be treated but severe cases (<50 × 10

/L)

should be treated with oral GCs in the first instance. In those failing to

respond,IVIg,danazol,andsplenectomyhavebeenusedwithvaryingsuccess.

AnticoagulationinobstetricAPS

SeeTable11.5.

Noveloralanticoagulants(NOACs)

• Anticoagulation with warfarin is limited by drug and food interactions,

teratogenicity, high variability in response and necessity of frequent blood

monitoring.

• NOACsdirectlyinhibitasingleenzymeofthecoagulationcascade,andseem

tobepromisinginthepreventionofthrombosisinAPS(butnoAPStrials).

• Minimaldrugandfoodinteractionsandfixeddrugdosingwithouttheneedfor

laboratory monitoring contribute to the advantage of NOACs compared to

warfarin. However, the lack of antidotes remains a limitation. Some studies

reportariskofmajorbleedingofupto10%ofcasesperyear.

• NOACsincludedirectthrombininhibitorssuchasdabigatran,anddirectanti-

Xainhibitorssuchasrivaroxaban,apixaban,andedoxaban.TheRivaroxaban

forAntiphospholipidAntibodySyndrome(RAPS)studyiscurrentlyunderway

comparing the effects of warfarin versus rivaroxaban in thrombotic APS

patients.

Table11.3ThetreatmentofAPSandclinicalscenariosinvolvingAPLantibodies/positiveLA:summary

Clinicalsituation Treatment

Non-SLE

patientswith

high-riskAPS

profile

Noprevious

thrombosis

Low-doseaspirin75–150mg/day

(LDA)

SLEpatients

withLA/APL

antibodiesat

hightitres

Noprevious

thrombosis

Hydroxychloroquine200–400

mg/day±LDA

DefiniteAPS

withthrombosis

After1stvenous

event

Lifelongwarfarin(INR2–3)or3–

6monthswarfarin(INR2–3)if

low-riskAPLprofileorother

transient/reversibleriskfactorsat

timeofthrombosis

After1starterial

thrombosis

* Lifelong warfarin (INR 3–4) or

combined warfarin (INR 2–3)

withantiaggregantanticoagulant

therapy

*Assessbleedingrisk

After1stnon-cardio-

emboliccerebral

arterialeventwith

lowAPLprofile±

reversiblefactors

Considerantiplateletagents

CatastrophicAPS IVheparin

IVmethylprednisoloneplus

plasmapheresisorIVIg

DefiniteAPS

withpregnancy

Recurrent

miscarriage(<10

weeks’gestation)or

latecomplications

(>10weeks’

gestation)

Low-dose aspirin plus

unfractionated LMWH at

thrombo-prophylacticdoses

ConsiderLDAalonefor

selectedcaseswithin

1sttrimester

Pregnancyand

previousthrombosis

LDAplusLMWHattherapeutic

doses

Repeatfetalloss

despiteheparinand

aspirin

Unknown

DefiniteAPS

with

thrombocytopenia

Mild

(100–150×10

/L)

Observe

Moderate(50–100×

/L)

Observe

Severe(<50×10

/L) GCs(asITP),IVIg,

immunosuppression(e.g.RTX)

Table 11.4 Summary of the recommendations for refractory/difficult APL cases from the 14th

InternationalCongressonAPStreatmenttaskforce

Noveloral

anticoagulant

(NOAC)

Considerinafirstorrecurrentvenous

thromboembolismifwarfarinallergy/intoleranceor

pooranticoagulantcontrol

Oldernon-

heparin/warfarin

anticoagulants

Danaparoid,fondaparinux,andargatrobancanbeused

inheparin-inducedthrombocytopenia

Hydroxychloroquine RecommendedinSLEpatientswithAPLantibodies.

Considerinrefractorycases(adjuvanttreatment).No

evidenceforuseinprimaryAPS

Statins Maybeofbenefitinpatientswithrecurrenthistoryof

thromboembolismdespiteadequateanticoagulation

B-cellinhibition RecommendedforrefractorycasesofAPSpossiblyin

patientswithhaematologicalandmicro-angiopathic

manifestations

Complement

inhibition

monoclonalantibody

therapy

Notrecommendedyet.Dataonlyfromanimalstudies.

Mayhavearoleasadjuvantormaintherapyfor

patientsrefractorytoanticoagulation

Table11.5SummaryoftreatmentofobstetricAPLsyndrome

Recurrentearly

miscarriage(<10weeks’

gestation)

Latecomplications

(>10weeks’gestation)

Pregnantpatients

withprevious

thrombosis

Low-doseaspirin0.75–150

mg/day(LDA)plus

unfractionated/LMWH

combinationat

thromboprophylacticdoses

LDAplus

unfractionated/LMWH

combinationat

thromboprophylactic

doses

LDAplus

unfractionated/LMWH

combinationat

therapeuticdoses,then

warfarin(INR2–3)

postpartum

LDAaloneinselectedcases

Catastrophicantiphospholipidsyndrome

Introduction

ThisrarevariantofAPS(<1%cases)affectssmallvesselsandvisceralorgans

andwasfirstdescribedin1992.

• Catastrophic antiphospholipid syndrome (cAPS) is an important and serious

conditionthatcanpresentinpreviouslyasymptomaticpatients.

• Thetriggerisaninfectionin20%ofcases.Otherprecipitatingfactorsinclude

trauma/surgery, malignancy, warfarin withdrawal in a patient with APS,

pregnancy,andoralcontraceptives.However,itisestimatedthat45%ofcAPS

caseshavenoknowntrigger.

• cAPS is associated with other autoimmune conditions such as SLE (see

Chapter10),RA(see Chapter5),andSScl(see Chapter13).

• Mortalityishighat50%,andmostpatientsrequirecareinanintensivecare

unit.

Clinicalfeatures

• Diffuseperipheralandcentralthrombosisoccursleadingto:

• limbarterialandvenousocclusion.

• intra-abdominalorganinfarctionincludingrenalfailure.

• pulmonaryemboliandARDS.

• smallvesselcerebrovasculardisease.

• aorticandmitralvalvedefects,andmyocardialinfarction.

• other thrombotic complications, such as ovarian, testicular, and retinal

vesselocclusion.

• Livedoreticularis, gangrene,andpurpura arevisiblemarkersofthedisorder

ontheskin.

• Bonemarrowinfarctionhasalsobeenreported.

• Followingtheproductionofclassificationcriteria,datafrom300patientsina

cAPS registry have shown the majority are female (72%), almost half had

primaryAPS(46%),andaprecipitatingfactorwasfoundin53%.

• Data from the cAPS registry also show the most common sites are renal

(71%),pulmonary(64%),cerebral(62%),andcardiac(51%).

• The presence of systemic immune response syndrome, in which pro-

inflammatorycytokines arereleasedfromaffectedtissues,isalsothought to

contributetomorbidityandmortality.

Laboratoryfeatures

• Moderate-to-severethrombocytopenia.

• Haemolysiswithschistocytes.

• Disseminatedintravascularcoagulation.

• HighlevelsofIgGACLantibodiesorpresenceofaLA.

Differentialdiagnosis

• Theclinicianshouldconsiderthefollowingconditions:

• Thromboticthrombocytopenicpurpura(redcellfragmentsmorenumerous

thanincAPS).

• HELLPsyndrome(haemolysis,elevatedliverenzymesandlowplatelets).

• Haemolytic–uraemicsyndrome.

• Cryoglobulinaemia.

• Vasculitis.

Treatmentandprognosis

• Apartfromtechniquesandtherapiesusedintheintensivesupportofmultiple

organfailure,IVheparin,GCs,plasmaexchange,andIVIg(for4–5daysata

doseof0.4g/kg/day)canbeused.

• Case reports exist in single patients describing the use of epoprostenol,

defibrotide(notlicensedintheUK),andfibrinolytics.

• RTXcanbeusedinrefractorycasesorinthepresenceofmicro-angiopathic

haemolyticanaemia.

• CYChasbeenshowntobebeneficialincAPSwiththepresenceofsecondary

autoimmunediseasesuchasSLE.

• ARCTonbelimumab(aB-cellactivatingfactorinhibitor)inSLEpatientshas

shownadecreaseinACLIgA.

• Mortality remains >50% and 25% of survivors will develop further APS-

relatedevents.

• RecurrenceofcAPSisveryrare.

References

1. Merashli M, NoureldineMH,UthmanI,et al. Antiphophopholipid syndrome: anupdate.Eur J Clin

Invest2015;45:653–62.

2. CereveraR.Catastrophicantiphospholipidsyndrome(cAPS):updatefromthe‘cAPSRegistry’.Lupus

2010;19:412–18.

Chapter12
Sjögren’ssyndrome
Epidemiologyandpathophysiology
Clinicalmanifestationsandclassificationcriteria
Investigations
Treatment
Prognosis
Epidemiologyandpathophysiology
Sjögren’ssyndrome(SS)isachronicautoimmunediseaseofunknownaetiology,
characterizedbylymphocyteinfiltrationofexocrineglandsresultingindryness
ofmucosalsurfacesincludingmouth(xerostomia),eyes(xerophthalmia),nose,
pharynx,larynx,andvagina.
• SSmaybeprimary,associatedwithspecificextraglandular(systemic)disease,
or secondary, in association with a number of other autoimmune diseases
including RA (see  Chapter 5), SLE (see  Chapter 10), thyroid disease,
coeliacdisease,andprimarybiliarycirrhosis(PBC).
• SSis(rarely)associatedwithprogressiontolymphoidmalignancy.
• SShasaF:Mratioof14–24:1inthelargestreportedseries,andiscommon
between40and60yearsofage.
• Populationprevalenceisestimatedat1%,similartothatofRA.
• EBVandretroviruseshavebeenimplicatedinpathogenesis.
• AntibodiestonuclearproteinsRo/SSAandLa/SSBmaybeformedwhenRo
andLaareexposedonthesurfaceofapoptoticcells.
• Rheumatoid factor (RF) and a positive ANA are also common and patients
maybeerroneouslydiagnosedwithRA.
• HLA-DR3isstronglyassociatedwithSS.
Table 12.1 Classification criteria for primary Sjögren’s syndrome for use in the context of sicca

symptoms

Criteria Comment Score

PositiveSchirmertest <5mm/5min 1

Lowunstimulatedsalivaryflow <0.1mL/min 1

Anti-Roantibodypositive 3

Abnormallipbiopsy ≥1foci/4mm

Abnormalocularstainingscore ≥5 1

Individualswithsignsand/orsymptomssuggestiveofSSwhohaveatotalscoreof≥4fortheabove-

listeditemsmeetthecriteriaforprimarySS.

DataadaptedfromShiboskiCH,ShiboskiSC,SerorR,etal.2016AmericanCollegeof

Rheumatology/EuropeanLeagueAgainstRheumatismclassificationcriteriaforprimarySjögren’s

syndrome:aconsensusanddata-drivenmethodologyinvolvingthreeinternationalpatientcohorts.Ann

RheumDis2017;76:9–16.

Clinicalmanifestationsandclassificationcriteria

The classification criteria for primary SS are listed in Table 12.1. These

representanupdateofthe1993EuropeanCommunityCriteriaforclassifyingSS

and have been adopted by the scientific community worldwide. They have a

sensitivityandspecificityofaround94%.

• Exclusionsincludeheadandneckirradiation,hepatitisC,AIDS,pre-existing

lymphoma,sarcoidosis,graftvshostdiseaseandanticholinergicdruguse.

• Extraglandular diseaseis seenin one-thirdof patientswithprimarySS.The

main symptoms are fatigue, low-grade fever, myalgia, and arthralgia (Table

12.2).

Glandulardisease

• The initial manifestations can be non-specific and 8–10 years can elapse

beforethediagnosisisestablished.

• Typicalinitialfeaturesof‘sicca’syndromeincludedryeyes(xerophthalmia)in

>50% at presentation, dry mouth (xerostomia) in 40%, and parotid/salivary

gland enlargement in 25%. The prevalence of these manifestations increase

withthedurationofdisease.

• Concurrentcornealandconjunctivaldamage(keratoconjunctivitissicca),and

dentalcariesfrompoortearandsalivaryflowrespectively,canoccur.

• Lackofsecretionsmayalsoaffecttherespiratorytract(nasaldryness,cough,

orhoarsevoice),oesophagusandpharynx(dysphagia)orvagina(dyspareunia

andpruritus).

• Anumberofconditionscancausexerostomiaandother‘dryness’symptoms

andalsoparotid/salivaryglandswelling(seeTable12.3).

Joints

Joint disease needs careful assessment. Associated (‘overlap’) RA can occur

(ACPA positive and typical RA erosions on radiographs) and generalized

inflammatory osteoarthritis (OA) is common in the same age/gender

demography as primary SS. Whether a true SS-associated arthritis or (or)

whether(thereis)thereisasignificantassociationbetweengeneralizedOAand

PSS,isdebatedbutessentiallyisnotknown.

• Non-erosivearthritisismorefrequentinpatientswithRaynaud’sphenomenon,

andthelattercanpre-dateSSbymanyyears.

• AmilderformofSShasbeenlinkedtogeneralizedOAandhasbeentermed

‘SOXsyndrome’(sialadenitis,osteoarthritis,xerostomia).

Table12.2ThefrequencyofextraglandularmanifestationsofprimarySjögren’ssyndrome

Condition Frequency(%)

Arthralgia/arthritis 37

Raynaud’sdisease 16

Cutaneousvasculitis 12

Pulmonarydisease 9

Lymphadenopathy 7

Peripheralneuropathy 7

Renaldisease 6

Autoimmunehepatitis 2

Lymphoproliferativedisease 2

Myositis 1

Table12.3ThedifferentialdiagnosisoftheglandularfeaturesofSjögren’ssyndrome

Feature Differentialdiagnosis

Parotidandothersalivary

glandenlargement

Neoplasia

Infections(e.g.EBV,mumps,HIV,CMV)

Granulomatousdiseases(sarcoid,TB)

Endocrinecauses(diabetes,hypothyroidism,

acromegaly)

Chronicrecurrentidiopathicparotitis

Calculi

Amyloidosis

IgG4-relateddisease

Xerostomiaandxerophthalmia

(‘dryness’)

Age/elderly

Drugs(diuretics,antihypertensive,

parasympathetic,psychotropic)

Dehydration

Psychogenic

Irradiationdamage

SOXsyndrome

Congenital

Graftvshostdisease

HepatitisC

IgG4-relateddisease

Skin

• Itchy annular erythema, alopecia, and hyper/hypopigmentation can occur. A

hypersensitivityvasculitismayalsodevelop.

• Vascular involvement in SS affects small- and medium-sized vessels. The

most common manifestations are cutaneous purpura, urticaria, and skin

ulceration.

• SkinvasculitisinSSisbenignandtreatmentwithglucocorticoids(GCs)not

alwaysneeded.

• Cryoglobulins are present in 10–20% of patients with skin vasculitis in SS

(andmaybeassociatedwithhepatitisCpositivity).

• IncontrasttoSScl(see Chapter13),Raynaud’sdiseaseinSSisnottypically

associatedwithdigitalulcerationandinfarcts.

Pulmonarydisease

Pulmonarydiseaseiscommon.

• Pulmonaryfunctionabnormalitiesareseenin25%ofpatients,althoughthey

arenotusuallyclinicallysignificant.

• Rarely a lymphocytic interstitial pneumonitis (LIP) may occur, causing

pyrexia,cough,anddyspnoea.

• In LIP, lymphocytic infiltration occurs around bronchioles, leading to

cryptogenicorganizingpneumonia.ThisrespondswelltoGCs.

Renaldisease

Overtrenaldiseaseisfoundin10%ofpatientswithprimarySS.

• A renal tubular acidosis (RTA) may occur, causing a normal anion gap

metabolicacidosis,aurinepHof>5.5,andhypokalaemia.

• RTAistypicallytype1distaltubulepredominantinSS.

• Long-termRTAcanresultinnephrocalcinosisornephrolithiasis.

• GlomerulonephritisisrareandseenmainlyinthosewithSS/SLEoverlap.In

many cases, a consistent finding is cryoglobulinaemia and

hypocomplementaemia.

Gastrointestinalandhepatobiliarydisease

• Dysphagiaduetodrynessofthepharynxandoesophagusiscommon.Chronic

atrophicgastritismayoccurduetolymphocyticinfiltrationsimilartothatseen

inthesalivaryglands.

• Subclinicalhyperamylasaemiaisacommonfindinginupto25%ofcasesand

there may be a close link between the ‘autoimmune cholangitis’ of SS and

PBC.Siccasyndromeisfoundin50%ofPBCcases.

• Transaminitis may be due to hepatitis C, which can cause a Sjögren’s-like

diseaseofteninassociationwitha‘mixed’cryoglobulinaemia.

Neuromusculardisease

• Peripheralsensoryneuropathyisthemostcommonneuromuscularfeatureof

SS.Thismaybeasensoryataxicneuropathy(dorsalrootganglionopathy)ora

painfulsmallfibreneuropathy.

• Autonomicneuropathyisrarelyseen.

• Mononeuritismultiplexasaconsequenceofvasculitisiswellrecognizedasis

theisolatedinvolvementofcranialnerves,particularlythetrigeminalandoptic

nerve.

• Involvement of the central nervous system remains a controversy.

Demyelinating,multiplesclerosis-likesyndromesmaybeseen.

• Myalgia is common but myositis is rare. The pattern of myositis is like

polymyositisandistreatedassuchaccordingly(see Chapter14).

Lymphoproliferativedisease

• Patients with SS have an ~16% increased risk of developing a lymphoma,

comparedtoage-,gender-,andrace-matchednormalcontrols.

• The lymphomas are primarily B cell in origin, usually expressing the

monoclonalIgMκ, andof twomajortypes,eitherhighlyundifferentiated,or

well-differentiatedimmunocytomas.

• Theclinicalpictureisdiverse.Theapproachtotherapyshouldbedetermined

bythestageandhistologicalgradeofthedisease.

• Thesalivaryglandsarethemainsiteoflymphomatouschange.Thepresence

of lymphadenopathy, organomegaly, or persistent, painful, and continuously

enlarged salivary glands, in the absence of infection, should raise suspicion

andwarrantsbiopsy.

• Other organsand systems may beaffected includinglungs,kidneys,and GI

tract.

• Risk factors include monoclonal gammopathy, cryoglobulins,

hypocomplementaemia,andganglionopathy.

Cardiovascularsystem

• Anti-Ro andLaantibodies crosstheplacenta andcancause fetal congenital

heartblock.Mothers with theseantibodieshave a 1in 20 riskofhaving an

affectedpregnancy(see Chapter10).

• Fetalheartratemonitoringinspecialistcentresisneeded.

• Oraldexamethasonegiventomothersearlyfollowingdetectionofheartblock

mayreversethecondition.

• Neonatallupuserythematosus(NLE)isalsoseen(see Chapter10).

Fatigue

• FatigueisoftentheworstsymptomformanypatientswithSS.

• Patientsoftenlearntocopewithfatiguewiththemostsuccessfuladoptinga

frame of mind that ‘accepts’ the fatigue; having close relatives and family

realize that fatigue is part of the disease; pacing their activities; and

undertakingsomeregularaerobicexercise.

• Failuretocopewithfatiguemayleadtochronicpain.

OtherpathologyinSS

• Over 50% of patients have antithyroid antibodies and altered thyroid

biochemistrywithoutnecessarilyovertclinicalsymptoms.

• Non-bacterialinterstitialcystitisduetoanintenseinflammationofthemucosa

cancausefrequency,nocturia,andperinealpain.

• Mild normochromic,normocytic anaemiais common.Leucopenia isseen in

15–20%ofpatientswithSS.TheESRisoftenraised(requiringaparaprotein

tobeexcluded),buttheCRPisusuallynormal.

Otherautoimmunediseases

Inarecentretrospectivecasereviewof114patientswithprimarySS,33%had

an additional autoimmune disease, 6% two diseases, and 2% three diseases.

Hypothyroidismwas themost commonconditionseen.Coeliacdiseaseisalso

commonlyassociated.

Investigations

CommonlaboratoryfindingsinprimarySSaredetailedinTable12.4.

Assessmentofsiccasymptoms

• Salivaryflowrates(sialometry)canbemeasuredforwholesalivaorseparate

secretionsfromdifferentsalivaryglands,withorwithoutstimulation.

• Patients with overt SS have decreased unstimulated salivary flow rates.

Measuringsalivaryflowrateissimplebutcanbeconfoundedbyconcomitant

useofdrugswithanticholinergicproperties.

• However, a simple screening test is to have a patient spit all saliva into a

graded measuring sample pot for 10 min. More than 2 mL (>0.2 mL/min)

makesprimarySSunlikely.

• Anatomical changes in the ductal system can be assessed by radiocontrast

sialography.Thiscan,however,bepainfulandthereissomecontroversyasto

itssensitivityandspecificity.

• Scintigraphy,withuptakeof

Tc,mayprovideafunctionalevaluationofall

thesalivaryglandsbyobservingtherateanddensityofuptakeandthetimefor

it to appear in the mouth after IV administration. Scanning has a high

sensitivity albeit low specificity, but has a greater sensitivity and specificity

thanunstimulatedsialometry.

• TheSchirmertestisusedfortheevaluationoftearsecretion.Stripsof filter

paper30mminlengthareslippedovertheinferioreyelidbyafoldatoneend

ofthestrip. After 5minthe lengthofpaper that hasbeenmade wetbythe

tearsismeasured;wettingof<5mmisastrongindicationofdiminishedtear

secretion.

• SalivaryglandUSisemergingasausefulnon-invasivetoolinthediagnosisof

SS.Ithasahighspecificityandhasbeenshowntocorrelatewellwithlabial

glandbiopsyfindings.Itisusedinsomecentrestoestablishwhetheralabial

glandbiopsyisrequired.

Biopsy

AlabialglandbiopsyisoftenessentialtotheestablishmentofadiagnosisofSS,

particularlywhenthepatientlacksanti-Rooranti-Laantibodies.

• Becausethereisariskofsensorynervedamage,thebiopsyshouldbedoneby

asurgeonwithexperienceinthetechnique.

• At least 4–6 glands must be biopsied, since the pathologic process is

invariablyfocal.

• Biopsies shouldnot betaken ifthereismucosalinflammationoverlyingthe

biopsysiteorthereisapasthistoryoftherapeuticheadandneckirradiation.

• Thebiopsymustbescoredforthenumberoflymphocyticfoci(i.e.aggregates

of 50 or more lymphocytes) that surround ducts or blood vessels, and are

adjacenttohistologicallynormalacini.

• Ascoreof1ormorefociper4mm

iscompatiblewithSS.However,focal

lymphocytic sialadenitis can also be seen in hepatitis C, HIV, graft vs host

disease, and patients with autoimmune disease in the absence of sicca

symptoms.

Table12.4CommonlaboratoryfindingsinprimarySS.

Finding Frequency(%)

General Anaemia 20

Thrombocytopenia 13

Leucopenia 16

RaisedESR 22

Monoclonalgammopathy 22

Hypergammaglobulinaemia 22

Cryoglobulinaemia 9

Autoimmuneserology ANA 74

Rheumatoidfactor 38

Ro/SS-A 40

La/SS-B 26

ANCA 6

Antimitochondrial 5

ReproducedfromGarcia-CarrascoM,etal.PrimarySjögrensyndrome:Clinicalandimmunologic

diseasepatternsinacohortof400patients.Medicine2002;81:270–80withpermissionfromWolters

Kluwer.

Treatment

Table12.5summarizesthegeneralandorgan-directedtreatmentoptionsforSS.

Formoreextensivedetailthereaderisdirectedtothe2017BSRGuidelinefor

themanagementofadultswithprimarySjögren’ssyndrome.

• Dentalinputandclosecollaborationisessential.

• Patientsshouldbeencouragednottosmoke,toavoidsugar-ladenfoods,andto

attenddentalhygienistsessionsregularly.

• Periodically, swabbing palate, tongue, and pharynx for oral Candida

overgrowthisprudent,especiallyifdysgeusiadevelops.

• Thereismeritinpatientstriallingtopicalpreparationsforxerophthalmiaand

xerostomiaastheremaybepersonalpreferencetoonepreparationoranother.

• Manypatientsfavourthecombinationuseofarunnyeyedropforfrequentuse

duringthedayandamoreviscouspreparationatnightorinsituationswhere

frequentdropinsertionisimpracticable.

SyntheticDMARDs(sDMARDs)

• Hydroxychloroquine (HCQ) is the most commonly used sDMARD though

evidenceforitseffectivityinSSisweak.

• Significant improvements have been described in a retrospective study in

termsofthesiccafeatures,parotidglandenlargement,oralinfection,myalgia,

arthralgia,fatigue,andjointswellingfollowing12monthsoftreatmentwith

HCQ.

• In a 2014 study reported in JAMA, HCQ was no better than placebo in

improvingpain,fatigue,ordryness.

• There is no evidence that other sDMARDS or anti-TNFα therapies are

effectiveinprimarySS.

BiologicDMARDs(bDMARDs)

• Rituximab(RTX;anti-CD20/anti-B-cellmonoclonalantibody)hasonlyshown

short-lasting benefit in clinical trials, but may be useful for SS-related

cryoglobulinaemia or neuropathy, as well as for other coexisting immune-

drivenconditions,e.g.coeliacdisease.

• Belimumab (anti-BAFF monoclonal antibody (B-cell activating factor, also

known as BLyS, TALL-1, and THANK), is a TNF superfamily member

(TNFSF13B)bestknownforitsroleinthesurvivalandmaturationofBcells)

hasdemonstratedefficacyinopenlabelphaseIItrials,butsalivaryflowand

theSchirmertestdidnotimprove.

• Tocilizumab(anti-IL-6receptormonoclonalantibody)iscurrentlyundergoing

phaseII/IIItrials.

• Epratuzumab,(humanizedanti-CD22monoclonalantibody)hasdemonstrated

responseinanopenlabelphaseI/IIstudy.

For greater detail on all drug therapies including immunosuppressants,

seeChapter23

Prognosis

TherearefewstudiesontheprognosisofprimarySS.

• Some studies suggest the presence of vasculitis, cryoglobulins, or low

complementmaybeadverseprognosticmarkers.

• OutcomesinsecondarySSarelikelytocorrelatewiththeassociatedcondition.

Table12.5ThetreatmentofSjögren’ssyndrome

Condition Treatment

Xerophthalmia Artificialtears(preferablypreservativefree)

Topicalciclosporindrops

Punctalocclusion(plugs)

Treatmentofmeibomianglanddysfunction(withwarm

compresses).Inpersistentinflammationandblepharitis,

doxycycline50mgoncedailyforatleast3monthsmaybe

considered

Xerostomia Frequentsipsofwater,goodoralhygiene(e.g.chlorhexidine

mouthwash),high-concentrationfluoridetoothpastes)

Sugar-freegumandlozenges(e.g.Salivix

orSST

pastilles)

Artificialsalivaormouthlubricatingsprays

Siccafeatures Mayimprovewithpilocarpine5mgupto4timesdaily

(side-effectsincludeflushing/sweating),orcevimeline,

whichiscurrentlynotlicensedintheUK(fewerside-

effects)

Vaginal

dryness

Patientsmayrespondtopropionicacidgels.Rigorous

treatmentofinfection.Adviceonlubricants,useof

pessaries,andforintercourse,thepresenceofdyspareunia

Salivarygland Infection—tetracycline(500mg,4timesaday)and

NSAIDs.Persistentpainandswelling—biopsy

Arthralgia Hydroxychloroquine200–400mg/dayifRAandgeneralized

inflammatoryOAhavebeenruledout(though

hydroxychloroquinemaybeeffectiveforjointsymptoms

associatedwiththesediagnoses)

Systemic

vasculitis

Necrotizingvasculitisandglomerulonephritis—prednisone

and/orcyclophosphamide.Leucocytoclasticvasculitis—no

specifictherapybutMMForazathioprinemayhavearole.

Liverdisease Cholestasismayrespondtoursodeoxycholicacid10–15

mg/kg/day

Chronic

erythematosus

candidiasis

Topicalnystatin,miconazole,orketoconazole

Interstitiallung

disease(LIP)

Prednisolone,cyclophosphamide

Chapter13
Systemicsclerosisandrelateddisorders
Introductionanddefinitions
Epidemiologyandpathophysiologyofsystemicsclerosis(SScl)
ClassificationofSScl
ApproachtodiagnosisofSScl
ClinicalfeaturesofSScl
TreatmentandprognosisofSScL
Morphoea,localizedscleroderma,andscleroderma-likefibrosingdisorders
Introductionanddefinitions
Systemicsclerosis(SScl)isageneralizedautoimmuneconnectivetissuedisease.
Scleroderma—thecutaneouslesionwhichisprominentandkeytoadiagnosisof
SScl—is epidermal-dermal tethering associated with microangiopathy and
excessive collagen production and fibrosis. Morphoea essentially describes
localizedsclerodermaanditcanexistinanumberofformsthoughallformsare
notassociatedwithsystemicdisease/internalorganlesions(unlikeinSScl).
• TheclassificationofSSclisshowninTable13.1.
• Raynaud’s disease (RD) describes (usually cold-induced) peripheral digital
vasospasmandishighlyassociatedwithSScl(See Plate25).
• Thespectrumofmorphoeaconditionsincludes:
• Generalized morphoea which is characterized by widespread indurated
plaquesandpigmentarychanges.
• Linear scleroderma is localized scleroderma, which is characterized by a
lineofthickenedskinwhichcanaffectthebonesandmusclesunderneathit.
Itmostoftenoccursinthearms,legs,orforehead.Itisalsomostlikelytobe
onjustone sideofthebody.Linearsclerodermagenerallyfirstappearsin
youngchildren.
• Other: morphoea profunda, morphoea-lichen sclerosis et atrophicus,

frontolinearscleroderma(morphoeaencoupdesabre).(See ‘Morphoea,

localized scleroderma, and scleroderma-like fibrosing disorders’, pp.

422–423)

Table13.1ACR/EULARclassificationcriteriaforSScl

Feature Details Weight/score

Skinthickeningofthefingersof

bothhandsextendingproximalto

MCPJs(sufficientcriterion)

Skinthickeningofthefingers(only

countthehigherscore)

Puffyfingers 2

Sclerodactylyofthe

fingers(distaltoMCPJs,

proximaltoPIPJs)

Telangiectasia 2

Abnormalnailfoldcapillaries 2

Pulmonaryarterialhypertension

and/orinterstitiallungdisease

Raynaud’sdisease 3

SSc-relatedautoantibodies

(anticentromere,anti-topoisomerase

I,anti-RNApolymeraseIII)

Addtomaximumweightineachcategorytocalculatethetotalscore

Patientshavingatotalscoreof≥9areclassifiedashavingSScl

ReproducedfromvandenHoogenFetal.2013Classificationcriteriaforsystemicsclerosis:an

Americancollegeofrheumatology/Europeanleagueagainstrheumatismcollaborativeinitiative.Annals

oftheRheumaticDiseases2013;72:1747–1755withpermissionfromtheBMJ.

Epidemiologyandpathophysiologyofsystemic

sclerosis(SScl)

Epidemiology

• TheincidenceandprevalenceofSSclvariesindifferentpopulations.

• SSclappearstobelessprevalentinEurope(80–150casespermillionadults)

comparedwiththeUSA(276casespermillionadults).

• There isaracial difference in theprevalence of SScl—greaterin Europeans

thaninAsians.

• Mild disease often remains undiagnosed. Therefore, the true prevalence of

SSclisprobablyunderestimated.

• Annualincidenceisreportedat1–20casespermillion.Malesandfemalesare

bothaffected.

Pathophysiology

SScl is characterized by three main pathogenetic features: microvasculopathy,

immune activation with inflammation, and increase of extracellular matrix

depositionintheskinandinternalorgansresultinginfibrosis.

General

(For a recent review, see reference 1). Currently, the mechanisms involved in

SSclpathogenesisremainunknownandarelikelytobeverycomplex.Evidence

suggests a close connection between environmental factors and SScl

pathogenesis.

Immunecellactivationandcytokines

• The activation of T cells is considered to play an important role in the

developmentofthevasculopathyandfibrosisinSScl.

• ActivatedoligoclonalCD8Tcellsmaybedetectedinthebloodandlungsof

SScl patients and effector memory CD8 T cells may be involved in the

pathogenesisoforganinvolvementinSScl.

Genetics/epigenetics

• ThegeneticheritabilityforSSclis<0.01;however,thereisahigherincidence

inpatientswithafamilyhistorythaninthegeneralpopulationandapositive

familyhistorysignificantlyincreasestherelativerisk(RR)ofSSclby15–19-

foldinsiblings—indicatingageneticinfluenceonpathogenesis.

• EpigeneticeffectssuchasDNAmethylation,histonemodification,non-coding

RNAeffects(microRNA) areallthought toplayakeyrole inpathogenesis.

Forexample,hypomethylationofthegeneencodingintegrin-α9,amembrane

glycoproteinthatmediatescell–cellandcell–matrixadhesion,canproducean

overexpression of integrins causing myofibroblast differentiation and

increasedTGFβproductionpromotingfibrogenesis.

Environmentalfactors

Several chemical agents have been implicated in the development of

scleroderma, although exposures account for only a small fraction of patients

whodevelopsclerodermaorsimilarconditions.

• Possible chemical triggers of scleroderma include silica, organic chemicals,

aliphatic hydrocarbons (e.g. vinylchloride,naphtha),aromatic hydrocarbons

(e.g. benzene, toluene), drugs (e.g. hydroxytryptophan, carbidopa,

fenfluramine,bleomycin).

Vasculopathy

Vascular injury may be the primary pathophysiological event either by

vasomotor instability or microvascular intimal proliferation and vessel

obliteration. Intravascular pathology in the form of increased platelet activity,

redcellrigidity,andthrombosismayalsobeafactor.

Inflammation

Occurs early in SScl, and may no longer be present at the time of diagnosis.

Causesoedematous(notindurated)skin.

Fibrosis

Consequence of inflammation, widespread and non-organ-specific in SScl.

Excessextracellularmatrixproteinintheskinandinternalorgans.

• TGFβ plays a crucial role particularly through the activation of collagen

productionthatleadstofibrosis.

Reference

1. Barsotti S, Stagnaro C, d'Ascanio A, et al. One year in review 2016: systemic sclerosis. Clin Exp

Rheumatol2016;(34Suppl100):S3–S13.

ClassificationofSScl

Classificationanddiseasepatterns

Patients with SScl have a potentially wide range of features of pathology

affecting different organ systems, and can present in varied ways. The

ACR/EULAR2013classificationcriteriaforSScl(Table13.1)haveasensitivity

of91%andspecificityof92%.

• Clinicalfeaturesarewiderangingandtheirclassification,inassociationwith

typicalserologicalfindings,withindiseasepatternsisshowninTable13.2.

• Table13.2highlightsthetwomainclinicalformsofSScl:limitedcutaneous

(lcSScl)anddiffusecutaneous(dcSScl).Over60%ofcasesareinthe‘limited’

subset,wherevisceralinvolvementislate,andsome10–30yearsafteronsetof

Raynaud’sdisease(RD).

• The definition of ‘limited cutaneous’ subsumes the definition of CREST

(Calcinosis, Raynaud’s disease, (o)Esophageal dysmotility, Sclerodactyly,

Telangiectasia) syndrome,althoughthis acronymis ausefulreminder ofthe

commoncharacteristicsoflcSScl.

• SScl can develop insidiously and in early disease non-SScl scleroderma-

associateddisordersneedtobeconsidered(see Table13.3,p.409).

Table13.2Patternsofclinicalandserologicalfeaturesinthedifferentformsofsystemicsclerosis(SScl)

EarlySScl Raynaud’sphenomenon,nailfoldcapillarychanges

Disease-specificantinuclearantibodies(ANAs):

• Antitopoisomerase-1(Scl-70)

• Anticentromere(ACA)

• Anti-RNApolymeraseIII

• Nucleolar

Diffuse

cutaneous

SScl

Skinchangeswithin1yearofRaynaud’s.Truncalandacral

(face,arms,hands,feet)skininvolvement

Tendonfrictionrubs

Early,significantorgandisease:

• Interstitiallungdisease

• Sclerodermarenalcrisis

• Myocardialdisease

• GIdisease

Nailfoldcapillarydilatationand/or‘dropout’

Scl-70antibodiesinupto60%ofpatients

Limited

cutaneous

SScl

Raynaud’sphenomenonformanyyears

Acralskininvolvement

Lateincidenceofpulmonaryhypertensionwithorwithout

interstitiallungdisease

Skincalcificationandtelangiectasia

Nailfoldcapillarydilatationand/or‘dropout’

ACAantibodiesin70–80%ofpatients

SSclsine Raynaud’s

scleroderma

Noskininvolvement

Presentationwithlungfibrosis,renalcrisis,cardiac,orGI

disease

ANA

ApproachtodiagnosisofSScl

Differentialdiagnosis

Theprinciplesthatunderliediagnosisincludeconsideringfirstwhetherthereisa

form of systemic sclerosis (dcSScl or lcSScl; Table 13.2) or a disease that

mimicsSScl(Table13.3)orascleroderma-associatedfibrosingdisease(seelater

in this chapter,  ‘Morphoea, localized scleroderma, and Scleroderma-like

fibrosing disorders’, p. 422. Then, if SScl is likely, establish the extent of

disease.

• The input of a dermatologist may be very helpful if a scleroderma-like

fibrosingdisorderispossible.

• Nephrologyinputshouldbeconsideredearly.

• Askinbiopsyshouldnotbetakenunlessdiscussedwithadermatologistand

pathologistfirstandprobablyshouldonlybedoneoncethepatienthasseen

thedermatologist.

• The extent of involvement of SScl requires a methodological approach to

evaluatingorgansandbodilysystems(seelaterinthistopic).

• Assessmentmaybeaidedbyanappreciationofhowearlyorlatethediseaseis

likelytobe(Table13.4).

Essentialinitialinvestigations

The extent of organ involvement disease should be assessed by baseline

investigationsasfollows:

• Bloodpressuremeasurementandurinalysis.

• Bariumswallow/GIendoscopydependingonsymptoms.

• Chestradiographandlungfunctiontests.

• High-resolutionCTlungscanifauscultationofthelungsrevealscracklesorif

lungfunctionabnormal.

• Laboratorytests:renalandliverfunction,paraprotein,FBC,ESR,CRP,TSH,

randomglucose,ANA/ENAs;RF,complementC3,immunoglobulins.

• ECGandtransthoracicechocardiography (withestimateofpulmonaryartery

pressure).

• Nailfold capillaroscopy and distal upper limb thermography with cold

stimulationchallenge(inspecialistcentres)canhighlightabnormalpatternsof

diseaseandcanpointtosystemicdiseaseincaseswithlimitedearlyfeatures.

Table13.3ThedifferentialdiagnosisofSScl

Metabolicand

inherited

conditions

Carcinoid

syndrome

Scleroderma-likelesionscanbefoundwith

malignantcarcinoid

Acromegaly Associatedwithskinpuffinessand

increaseinsebumandsweat

Phenylketonuria Phenylalanine-restricteddietmayimprove

skinchanges

Amyloidosis Plaquesfromdirectdermalinfiltrationcan

mimicSScl;morecommonarealopecia,

ecchymoses,andnaildystrophy

Immunological

and

inflammatory

conditions

Chronicgraftvs

hostdisease

Skinchangesfavourthetrunk,hips,and

thighs,butcanaffecttheentirebody.

Associatedwithpruritusand

hypopigmentation

Eosinophilic

fasciitis

Associatedwithpainfulindurationofthe

skin,hypereosinophilia,and

hypergammaglobulinaemia.Earlyskin

changesdescribedas‘peaud’orange’

Scleroedema Occurswithdiabetes,monoclonal

gammopathies,andafterinfections(e.g.

post-streptococcalthroatinfection).

UnlikeSScl,canoccurwithoutRaynaud’s

phenomenon

Sclero-

myxoedema

Waxyindurationoftheskinalongthe

forehead,neck,andbehindtheears.Not

associatedwithRaynaud’sphenomenon

Nephrogenic

fibrosing

dermopathy

Rapidindurationoftheskinandother

organsassociatedwithexposureto

gadolinium-basedcontrastusedforMRI

POEMS Polyneuropathy,organomegaly,

endocrinopathy,M-protein,andskin

changes.Hyperpigmentationismost

common,butacrocyanosis/skin

thickeningareseen

Acquired Lipodermato-

sclerosis

Hyperpigmentationandindurationof

lowerlegsassociatedwithchronicvenous

insufficiency/stasis(‘champagnebottle

legs’)

Eosinophilic

myalgia

syndrome

AcutesyndromecausedbyexposuretoL-

tryptophan

Bleomycin

exposure

Usedasamodeltostudyscleroderma

Table13.4Characteristicfindingsinearly-andlate-onsetSScl

Earlyonset(<3yrs

fromdiseaseonset)

Lateonset

(>3yrsfromdiseaseonset)

dcSScl

Constitutional Fatigue,weightloss Minimal

Vascular Raynaud’s(often

mild)

SevereRaynaud’s.

Telangiectasia

Cutaneous Rapidprogression

involvingarms,face,

andtrunk

Stableorsomeregression

Musculoskeletal Arthralgia,myalgia,

stiffness

Flexioncontractures

Gastrointestinal Dysphagiaand‘heart

burn’

Moreseveredysphagia.Midgut

andanorectaldisease

Cardiopulmonary Myocarditis,

pericarditis,lung

fibrosis

Progressionofestablished

disease/pulmonaryhypertension

Renal Maximumriskof Crisisuncommonafter4years

sclerodermarenal

crisis

lcSScl

Constitutional None Worsenedbyvasculopathy,GI

symptoms.

Vascular SevereRaynaud’s.

Telangiectasia

Digitalulcerationorgangrene

Cutaneous Mildsclerosison

face

Stable,calcinosis

Musculoskeletal Occasionaljoint

stiffness

FlexioncontracturesMoresevere

symptomscommon.

Gastrointestinal Dysphagiaand‘heart

burn’

Midgutandanorectaldisease

Cardiopulmonary Rarelyinvolved Slowprogressivelungfibrosis.

PulmonaryhypertensionRight-

sidedheartfailure

Renal Nodirect

involvement

Rarelyinvolved

ClinicalfeaturesofSScl

Raynaud’sdisease(RD)

The overall prevalence of RD is 3–10% worldwide, variation depending on

climate,skincolour,andracialbackground.

• InSScl,RDispresentin95%ofcases.

• History:classictriphasicresponsetocoldstartingwithepisodicpallorofthe

digits (due to ischaemia, see  Plate 25), followed by cyanosis (due to

deoxygenation),andthenrednessandsuffusion.Thelaststageofrednessisa

reactive hyperaemia following the return of blood and is the most painful

phase,alsoassociatedwithtingling/numbness.

• Continuous blueness/cyanosis with pain is not characteristic of RD and the

maindifferentialdiagnosisthenischilblainsorvasculitis.

• SymptomsthatmightsuggestsecondaryRDincludeanonsetinmen,patients

>45years,symptomsallyearround,digitalulceration,andasymmetry.

• ANAshouldbe testedand nail-foldcapillaroscopy obtained(see Plate 9).

Pathological changes seen on capillaroscopy include nailfold capillary

dilatation,haemorrhage,anddrop-out.Bothhaveahighpredictivepowerfor

detectingthosepatientslikelytodevelopSScl.

• Conservativemeasuresshouldbedirectedatkeepingthecorebody(i.e.base

ofneckanduppertrunk)temperaturewarm.

• Smokingcessationisessential.

• SevereRDcancausedigitalulceration(DU).Ulcerscanbecomeinfectedand

mayleadtoosteomyelitis.Treatmentisusuallyconservativewithantibiotics.

• Earlyfingerpulptissuethreat/pathology(hardening,cracks,callusandsmall

erythematouslesions)—canbepainful.Skininfectioncanensue—theprocess

worsened by subcutaneous calcification. Regular application of fusidic acid

andhydrocortisonecreamcanhelpsoftentheskinandlessenpain.

• Digitalgangrenemayoccurfollowingprolongedischaemia,leadingtoauto-

amputationofdigits.Surgeryisusuallyavoidedduetopoorwoundhealing.

• RDcanoccurinfingers,toes,earlobes,andevengenitaliainSScl.

Table13.5ThetreatmentofRaynaud’sdisease

Treatment Examples Comments

Simple Handwarmers.Protective

clothing

Universallyhelpful

Eveningprimroseoil Effectiveinclinicaltrials

Fish-oilcapsules

Parenteral

vasodilator

Nifedipineoramlodipine

(calciumchannel

blockers)

Effective,butmaycauseoedema,

hypotension,headache,resultingin

poortolerabilityetc.

Losartan(angiotensinII

receptorblocker)

25–50mgoncedaily

Fluoxetine 20–40mgoncedaily

Sildenafil

(phosphodiesterase

inhibitor)

25–50mgthreetimesdaily

Topicalglyceryltrinitrate Highrateofdiscontinuationdueto

sideeffects

Epoprostenol Forsevereattackswithprolonged

ischaemia,digitalulceration

gangrene,andpriortohandsurgery.

Sideeffectsincludeheadache,

nauseaandhypotension

Bosentan(endothelin

receptorantagonist)

Endothelinreceptorantagonist.In

England—forusewhendigital

ulcersarepresentdespitetreatment

withsildenafilandepoprostenol

Surgery Chemicaloroperative

lumbarordigital

sympathectomywithor

withoutbotulinumtoxin.

Debridement.Amputation

Cautionpriortoanysurgeryas

woundhealingispoor.

Skin—scleroderma

SclerodermaindcSSclandlcSSclusuallyproceedsthroughthreephases:early,

classic,late.Intheearlystagetheremaybenon-pittingoedemaofthehandsand

feet,markedin the morningsandassociated with RD.Theskin then becomes

taut, the epidermis thins, hair growth ceases, and skin creases disappear—the

‘classic’ changes of scleroderma become pronounced. The classic changes

remainstaticformanyyears.

• Thelatephasemayevolveatanytime.Truncalandlimbskinsoftenssuchthat

itcanbedifficulttoknowthatapersoneverhadsclerosis.However,thehand

changes rarely resolve and continue to show the ravages of fibrosis and

contractures.

• During the late phase, digital pitting scars, loss of finger pad tissue, ulcers,

telangiectasia,andcalcinosiscanoccur.

• AllpatientswithSSclwillhavesomeinvolvementofthefaceandthedigits

(although this involvement may be mild). Skin thickening limited to the

fingers,butsparingtheproximalupperextremitiesiscalledsclerodactyly.

• lcSScl is associated with skin involvement limited to the face and distal

extremities(belowtheelbowsandknees).

• dcSScl is associated with taut hypo- or hyperpigmented skin involvement

proximaltotheelbow,knee,orclavicle.

Gastrointestinal

The GI tract is probably the most commonly involved system in SScl (Table

13.6).

• Over 90% of all patients with lcSScl and dcSScl develop oesophageal

hypomotility,with>50%ofpatientswithlcSSclhavingseriousdisease.

• ThecauseofGIdysfunctioninSSclisnotentirelyclear.Possiblecontributing

factorsincludeneuraldysfunction,tissuefibrosis,andmuscleatrophy.Inthe

earlieststagesofneuraldysfunctionmostpatientsareasymptomatic.

• Prokinetic drugs such as metoclopramide may help some patients with

oesophagealhypomotility.

• Manypatientsdeveloprefluxoesophagitis.Simpleadvicesuchasraisingthe

headofthebed,takingfrequentsmallmeals,andavoidinglatenightsnacks,

mayhelp.Patientsoftenrequirehigh-doseproton-pumpinhibitors.

• Small bowel disease with hypomotility can lead to weight loss and

malabsorption; bacterial overgrowth may exacerbate the situation requiring

rotationalcoursesofantibioticsandtheuseofprokineticdrugs.Ultimately,the

smallbowelmayfail,necessitatingtotalparenteralnutrition.

• Atony and hypomotility of the rectum and sigmoid colon may cause

constipation and incontinence, best managed with bulking agents, although

severe cases may need limited surgery or the use of implantable sacral

stimulators.

• AnaemiaduetovascularlesionsintheGImucosaisnowwidelyrecognized.

The classic appearance in the stomach is now called gastric antrum venous

ectasia(watermelonstomach),andtheselesionsmaybetreatedbyargonlaser

therapyifbloodlossissignificant,althoughthisisnotcurative.

Pulmonaryandcardiacdisease

PulmonarydiseaserankssecondtooesophagealdiseaseinSSclinfrequencyof

internalorganeffects(Table13.7).

• PulmonarydiseaseisnowthemajorcauseofdeathinSScl.

• The major lesions are parenchymal lung disease (interstitial lung disease,

organizing pneumonia, and traction bronchiectasis) and pulmonary vascular

disease(isolatedpulmonaryhypertension,pulmonaryhypertensionassociated

withinterstitiallungdisease,andpulmonaryoedema).

• Far less common lung conditions include pleurisy, aspiration pneumonia,

drug-inducedpneumonitis,andspontaneouspneumothorax.

• Interstitiallungdisease oftendevelopsinsidiouslyand establishedfibrosisis

currently untreatable. Early diagnosis is therefore vital. Most centres would

now treat active disease with oral GCs and either oral or IV

cyclophosphamide.

• TheCXRisnotasensitivetestforearlyfibrosis.Lungfunctiontestscanbe

discriminatory.Thesingle-breathdiffusiontest(diffusioncapacityforcarbon

monoxide(DLCO))isabnormalin>70%ofearlycasesandlungvolumesare

oftendecreased.

• LowDLCOwithnormallungvolumesmaysignifypulmonaryhypertension.

• High-resolution lung CT will confirm and stage lung disease and serial

imagingcanbecomparedwithchangesinDLCOandfunctionalindices(e.g.

6-mintimedwalkingtest).

• Fibrosis tends to occur mainly in dcSScl and is associated with anti-

topoisomerase I antibodies; and pulmonary artery hypertension (PAH)

associateswithlcSSclandanti-centromereantibody.

• Heartblockhasbeenreported,butisrare.

• Severe left ventricle impairment from myocarditis is treated with

cyclophosphamideandanimplantablecardioverterdefibrillator(ICD)maybe

indicatedtotreatventriculararrhythmias.

• RecentstudiessuggestaprevalenceofPAHof12–15%inSScl.

• Right heart catheterization is the gold standard method of diagnosis, but

screening using this method is not practical. Annual transthoracic

echocardiographydonebyexperiencedpractitioners,lungfunctiontests,and

clinicalassessmentareessentialtohelpdetectsubclinicaldisease.

• DETECT( http://detect-pah.com/home)is acompositedata calculatorthat

canbeusedtoscreenforpatientswithSSclwhomayhavePAH,toidentify

patientswhoshouldproceedtorightheartcatheter.DETECThasasensitivity

of96%andspecificityof48%andcomprises:

• FVC%predicted/DLCO%predicted.

• current/pasttelangiectasia.

• anticentromereantibody.

• serumNTpro-BNP.

• serumurate.

• right-axisdeviationonECG.

• echofindingsofrightatrialareaandTRvelocity.

Table13.6GastrointestinalpathologyassociatedwithSScl

Site Disorder Investigation Treatment

Mouth Caries,sicca

syndrome

Dental

radiographs

Oralhygiene.Artificial

saliva

Oesophagus Hypomotility Bariumswallow Metoclopramide(dopamine

receptorantagonist)

Strictures Endoscopy Dilatation

Stomach Gastroparesis Endoscopy Metoclopramide

Gastro-

oesophageal

refluxdisease

Bariumswallow

Endoscopy

Proton-pumpinhibitor.

Dopaminereceptor

antagonist

Small

bowel

Hypomotility Bariumfollow-

through

Metoclopramide

Malabsorption Hydrogenbreath

test

Pancreaticsupplements.

Low-doseoctreotide.

Nutritionalsupport

includingparentalfeedingif

refractory,antibiotics

Jejunal

aspiration/biopsy

Ifserologicevidenceof

coeliacdiseaseispresent

Stoolcultures

Large

bowel

Hypomotility Bariumenema Stoolbulkingagents

Anus Incontinence Rectal

manometry

Surgery.Neurostimulator

Table13.7CardiopulmonarypathologyinSScl

Disease Frequency Investigation Treatment

Pulmonarydisease

Pulmonary

fibrosis

Most

commonin

dcSScl(Scl-

70+)

Chest

radiograph,lung

functiontests,

high-resolution

CTscan

LowdoseGCs,

mycophenolateor

cyclophosphamide

(alkylatingagent)

dependingonextentof

disease.Rituximabisused

inrefractorydiseasewhere

thereisextensivelung

involvement

Pleurisy Uncommon Chest

radiograph

NSAIDs.Low-doseoral

prednisolone

Bronchiectasis Rare ChestCTscan Antibiotics.Physiotherapy

Pneumothorax Rare Chest

radiograph

Chesttube,pleurodesis

Pulmonary

artery

hypertension

(PAH)

10–15%

overall

Doppler

echocardiogram.

Catheterstudies

Endothelial 1 receptor

antagonists (bosentan),

epoprostenol, sildenafil,

ambrisentan/tadalfil

combination, macitentan

orriociguat.

Anticoagulation.Long-term

oxygentherapy

Cardiacdisease

Dysrhythmias

and

conduction

defects

Common,

butrarely

symptomatic

ECG.24h

ambulatory

cardiacmonitor

Dependentonrhythm—

drugs,pacemaker,ICDif

indicated

Pericarditis 10–15%

overall

Echocardiogram Asforpleurisy(seeabove

intable)

Myocarditis Rare Prednisolone,

cyclophosphamide.

Diuretics.ICDifindicated,

betablockersmaybeused

butmaycauseworsening

RDand/ordigitalischaemia

Myocardial

fibrosis

30–50%of

dcSScl

Controversial;consider

diuretics,ACEinhibitors

TreatmentofPAHassociatedwithSScl

• Thetreatmentoptionsandoutcomehavedevelopedrapidlyoverthelast5–10

years.

• Historically continuous parenteral epoprostenol was used for moderate and

severe PAH. However, the treatment improves symptoms and pulmonary

arterypressures,butnotmortality.

• Bosentan,anoralendothelinreceptorantagonist,improvesfunction.

• Sildenafilinhibitsphosphodiesterasetype 5(PDE5),enhancingrelaxationof

vascularsmoothmuscleandalsoinhibitsendothelialcellgrowth.

• Arecentdouble-blindplacebo-controlledstudyofpatientswithidiopathicor

autoimmune connective tissue disease-associated PAH found that sildenafil

significantly improves the 6-min walk times and mean pulmonary artery

pressures.

• Combination treatment with ambrisentan (another endothelin receptor

antagonist) and tadalafil (a PDE5 inhibitor) have improved functional status

andhaemodynamicsinarecentopenlabeltrial.

• Macitentan is a dual endothelin receptor antagonist with a better side effect

profileandlongerdurationofaction,withsimilaroutcomesintherapystudies

ofPAH.

• Riociguat is a soluble guanylate cyclase stimulator that has demonstrated

efficacyinPAH.

Renaldisease

Renaldiseasehasbeensupersededbylungdiseaseasthemaincauseofdeathin

SSclduetotheimpactofACEinhibitorsinthetreatmentofSSclhypertensive

renalcrisis(seealso Chapter25).

• Both epithelial and endothelial damage typically occurs before becoming

clinicallydetectable.

• A renal crisis characteristically occurs in dcSScl within the first 5 years of

diseaseonset.Riskfactorsincludeexposuretoprednisoloneatdoses>20mg,

rapidlyprogressiveskindisease,diffusecutaneousdisease,andthepresenceof

antibodies to Scl-70 or RNA polymerase III. In high-risk patients, the

incidencemaybeashighas20%.

• A renal crisis presents acutely with features of hypertension, acute kidney

injury (mild haemoproteinuria and sometimes casts), micro-angiopathic

haemolytic anaemia often with thrombocytopenia and fragments on blood

film, pulmonary oedema, hypertensive retinopathy, encephalopathy, and

convulsions.Mortalitymayreach10%.

• Essentialbasicinvestigationstoestablishanypresenceofrenalinvolvementin

all patients are blood pressure measurement, urea and electrolytes, NT pro-

BNP, troponin, serum urate, creatinine clearance, and urinalysis for

proteinuria.

• In some patients, a renal crisis can begin indolently, initially with just

hypertension.

• Hypertensionshouldbetreatedrapidly,eveninthepresenceofacutekidney

injury,withACEinhibitorsandtitratedtoaimforatargetbloodpressureof

<150/85mmHg.

• Continuousepoprostenolisoftenalsogivenduringarenalcrisis.Dialysismay

becomenecessary.Itisimportanttoknowthatconsiderablerecoveryofrenal

functioncanbemadeafteranacutecrisisandthatdecisionsinvolvingrenal

transplantationshouldbewithheldforupto2years.

• APL antibodies or lupus anticoagulant can contribute to renal SScl disease

(includingacrisis).

Otherorganinvolvement

Table13.8summarizestheinvolvementofotherorgansinSScl.

Table13.8.OtherorganpathologyassociatedwithSScl

Organ Effect Frequency

Thyroid Hypothyroidismiscommon 20–40%

Liver Primarybiliarycirrhosis 3%oflcSScl

Nervoussystem Trigeminalneuralgia 5%

Carpaltunnelsyndrome 3%

Sensorimotorneuropathy

Autonomicneuropathy

Genital Cavernosalarteryfibrosiscausingimpotence Upto50%

*Antimitochondrialantibodiesfoundinupto25%ofpatientswithSSclandanticentromereantibodies

foundin10–20%ofpatientswithprimarybiliarycirrhosis.

TreatmentandprognosisofSScL

Generaldiseasetreatments

Currently no treatment can induce complete remission of the disease. Some

therapiescanofferpartialreliefandcontrolofend-organdamage,andmanyof

theseareadvised bythe2016 BSR andBHPR guidelinesforthe treatmentof

SScl.

• The evaluation of treatments is extremely difficult given the complexity,

heterogeneity,andepisodicnatureofSScl,aswellasthepaucityofpatients

forrecruitment.

• Active phase skin disease is treated with methotrexate (MTX) or

mycophenolate mofetil (MMF) 1g twice daily, sometimes with low-dose

prednisolone(≤10mgdaily).

• MMFcanbeusedforlungfibrosiswhenthediseasenotextensive.

• TocilizumabimprovesskinscoresinphaseIItrialsandcouldbeanimportant

newtherapyforSScl.

• Cyclophosphamidemayofferbenefitincardiacorlungdisease.

• Rituximabisusedinrefractorycasesofseverepulmonaryfibrosis,withtrial

evidence demonstrating prevention of progression of lung disease and

improvementinskinscore.

• IVIg is useful in SScl overlap syndromes with myositis and may have a

beneficial effect on severe GI manifestations. There are ongoing trials

assessingIVIgeffectivenessintreatingskindisease.

• Autologous stem cell transplantation has been undertaken in severe SScl

disease,buthasahighmortalityrate.

For additional detail on all drug therapies including

immunosuppressants,seeChapter23

Prognosis

SScl has the highest case-specific mortality of any autoimmune rheumatic or

connectivetissuedisease.However,majoradvancesinthemanagementofSScl

havetakenplaceoverthepastdecade,confirmingtheeffectivenessoftreatment.

• Estimatesof 5-yearmortalityinSSclrangefrom34%to73%.Standardized

mortalityratioshavebeenestimatedat3–4×expected.

• Logistic regression modelling suggests three factors (proteinuria, elevated

ESR,andlowDLCO)are>80%accurateatpredictingmortality>5years.

• Patients with renal crisis had a mortality of 50%, although the use of ACE

inhibitors and renal replacement therapies may have reduced this figure in

recentyears.

• Anti-topoisomerase I and anti-RNA polymerase antibodies have also been

associatedwithahigherincidenceofSScl-relatedmortality.

• AdvancesintheunderstandingofmechanismsleadingtoPAHhasledtonew

therapies that, with time, may show significant impact in slowing disease

progression.

Morphoea,localizedscleroderma,and

scleroderma-likefibrosingdisorders

Morphoea

Morphoeamaybe‘circumscribed’withjustoneortwolesionsor‘generalized’.

Thegeneralizedformmaybeverysymptomaticanddistressingasitprogresses.

• The rash is often itchy, violaceous or erythematous, and progresses to firm

‘hide-bound’skinwithhypo-orhyperpigmentationandsubsequentatrophy.

• The‘circumscribed’lesiontendstoresolvewithin3–5yearsandtreatmentis

oftenunnecessary.

• The‘generalized’morphoeaformcanbedisfiguring,leadingtocontractures,

ulceration,andoccasionallymalignancy.

• GeneralizedmorphoeamayrespondtoPUVA,systemic/topicalorintralesional

GC,topicaltacrolimus,MTX,ciclosporin,orMMF.

• Guttatemorphoeaisavariantwithsmall1cmdiameterpapulesandminimal

sclerosis,resemblinglichensclerosusetatrophicus.Thelesionsusuallyoccur

ontheneck,shoulders,andanteriorchestwall.

Linearscleroderma

This describes a band-like pattern of sclerosis, often in a dermatomal

distribution.Thescleroticareasoftencrossoverjoints,andareassociatedwith

softtissueandboneatrophy,andgrowthdefects.

• Treatment is similar to that previously described for generalized morphoea.

Physiotherapyandappropriateexercisesmayhelptominimizegrowthdefects

inthechildhoodform.

• Encoup-de-sabreislinearsclerosisinvolvingthefaceorscalp,andassociated

with hemi-atrophy of the face on the same side. The lesion assumes a

depressedappearancelikeascarfromasabre.

Eosinophilicfasciitis

(Seealso Chapter18.)

• Characterized by the rapid spread of skin changes (‘peau d’orange’) over

extremities.Skinbecomesindurated.

• UnlikeSScl,theepidermis isspared(i.e.superficialwrinkling isintact)and

nail-foldcapillaroscopyisnormal.

• TheconditionmayresolvespontaneouslyorrespondtoGCs.

• The condition may be a paraneoplastic phenomenon in some patients

(haematologicalmalignancy).

• MTXandMMFcanbeusedaswellasGCs(noRCTs).

Nephrogenicsystemicfibrosis

Nephrogenic systemic fibrosis (NSF)—also known as nephrogenic fibrosing

dermopathy—isasystemicdisease,whichcanleadtofibrosisinskeletalmuscle,

myocardium,lungs,kidneys,andtestes.

• NSFischaracterizedbythepresenceofskininduration,nodularplaques,and

flexioncontracturesintheabsenceofRD.

• Lesionsdevelopoverdaystoweeks,andinitiallyfavourthelowerextremities.

• The majority of patients will have end-stage renal disease and a history of

exposuretogadolinium-basedcontrast.

• Histologically,NSFlesionsarecharacterizedbycollagenbundlessurrounded

byfibroblast-likeepithelioidorstellatecells,andmucindeposition,whichcan

extendintothefasciaandmuscles.

• Responsetoimmunosuppressiveagentsisdisappointing.

• Early institution of physical therapy to prevent contractures and muscle

wastingisimportant.Painmanagementmaybeespeciallychallenging.

Scleromyxoedema

Ischaracterizedbywaxyindurationoftheskinalongtheforehead(glabella),the

neck,andbehindtheears.

• Scleromyxoedemamayalsoaffectthemiddleoftheback,whichisgenerally

sparedinSScl.

• Scleromyxoedema can be associated with oesophageal dysmotility and

myopathy.

• Case reports have shown an association with severe neurological sequelae,

includingencephalopathy,seizures,coma,andpsychosis.

• ScleromyxoedemamayrespondtoIVIg.

Scleroedema

Scleroedema is a fibromucinous connective tissue disease, a scleroderma-like

disorder associated with doughy induration of the skin along the back, neck,

face,andchest.

• UnlikeinSScl,theextremitiesaretypicallyspared.

• It is seen in association with poorly controlled diabetes, monoclonal

gammopathyorfollowinginfections(e.g.Streptococcus).

• Prognosisdependsontheunderlyingaetiology.Scleroedemathatoccursafter

infection may resolve spontaneously. Scleroedema associated with diabetes

mayimprovewithbetterglucosecontrol.

• For some patients, ultraviolet light therapy (such as UVA-1, PUVA, and

photopheresis)maybebeneficial.

Chapter14
Idiopathicinflammatorymyopathiesincluding
polymyositisanddermatomyositis
Idiopathicinflammatorymyositis
Polymyositisanddermatomyositis
Investigations
Treatment
Inclusion-bodymyositis
Other(adult)inflammatorymyopathies
Juvenileidiopathicinflammatorymyopathy
Idiopathicinflammatorymyositis
Generalconsiderationsandclassification
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of
conditions characterized by varied patterns of inflammation within striated
muscleandevidenceofautoimmune-mediatedmusclebreakdown.TheIIMsare
believedtobeautoimmuneinnature.Theyhavedistinctpathologicalfeatures,
buttheaetiopathogenesisofeachsubtyperemainslargelyunknown.
• The strongest genetic association of IIMs is with HLA class II alleles. In
Caucasians, HLA-DRB1*0301 and -DQA1*0501 are strongly associated,
compared to HLA-B7 in Asian populations. HLA-DQA1*01 seems to be a
protectivefactor.
• Proximal,symmetrical,andpainlessweaknessof musclesis thehallmark of
IIMs.
• Polymyositis(PM)anddermatomyositis(DM)arethemostcommonformsof
IIM,thelatterdistinguishedbythepresenceofacharacteristicrash.
• Overlapwithotherautoimmunediseasesoccurin15–20%ofcases.
• TheclassificationofIIMconditionsisshowninBox14.1.
• Secondarycausesofmyopathiesarediscussedlaterinthischapter.

• IIMhasanestimatedincidenceof2–8permillion.

• PM and DM are more common in women than in men (2:1), and peak

incidenceisat50–60yearsold.

• The F:M ratio is lower in myositis associated with malignancy, and higher

duringchildbearingyears(5:1).

• There is a latitude gradient of prevalence of PM and DM. DM is more

common closer to the equator correlating directly with UV-light irradiation,

andPMismorecommoninnortherncountries.

• ThecriteriaforPMandDMdiagnosisareshowninBox14.2.

• TheprincipalfeaturesofPMandDMarelistedinTable14.1.

Box14.1ModifiedBohanandPeter’sclassificationofPMandDM

1. Primaryidiopathicpolymyositis.

2. Primaryidiopathicdermatomyositis.

3. 1or2aboveinlist,withmalignancy.

4. Juvenilepoly(dermato)myositis.

5. Overlapsyndromeswithotherautoimmunerheumaticdiseases.

6. Inclusion-bodymyositis.

7. Raremyositis:granulomatous,eosinophilic,focal,orbital.

8. Drug-induced.

InformationfromBohanA,PeterJ.Polymyositisanddematomyositis.NEnglJMed1975;292:344–7.

Polymyositisanddermatomyositis

ApplicationofthecriteriafordiagnosisofPMorDMassumesinfective,toxic,

metabolic,dystrophy,andendocrinemyopathiesareexcluded.

Pathogenesis

• DM has been conceptualized traditionally as a complement-mediated

microangiopathy,butthisparadigmhaslimitations.

• PMarisesfromacytotoxicT-cellimmune-mediatedinflammationonmuscle.

• TypeIinterferonsignatureisupregulatedinDMandPM,butnotinIBM.

• Aberrant expression of major histocompatibility complex (MHC) proteins

contributes to muscle damage bothdirectlyandindirectlyin all subtypes of

IIM.

• A characteristic pattern of autoantibody production often occurs, in PM and

DMandinoverlapmyositisdisorders.

• ThereisevidenceofinflammasomecomplexactivityintheIIMs.

• Toll-like receptors (TLRs) are upregulated in IIMs and may link innate and

adaptiveimmuneprocesses.

• Autophagy is upregulated in IIM tissue, particularly within regenerating

myofibres,andthismayoccurviaactivationofTLR3andTLR4.

• Immatureandregeneratingmusclecellsmayperpetuatetheimmune-mediated

attackinIIMs.

Clinicalfeatures

Myositis

• Muscleweaknessisthemainclinicalfeatureinbothconditionsandisalmost

universal,tending todevelopinsidiouslyovermonths,butoccasionallywith

greatspeed.

• Weaknessisusuallysymmetricalanddiffuse,involvingtheproximalmuscles

oftheneck,shoulders,trunk,hips,andthighs.Thelowerlimbmusclestendto

beclinicallysymptomaticfirst.

• Weaknessofthedistalmusclesisrare,butcanoccurlateinthedisease.The

faceandocularmusclesmayalsobeinvolved.

• Myalgiaoccursinabout50%ofcases:itcanbemildandsometimesdifficult

todistinguishfrompolymyalgiarheumatica.

• Theremaybemuscleatrophyinchronicdisease,moresoinPMthanDM,and

contracturesmayoccurindiseaseoflongduration.

• Oftenthedistinctionbetweenautoimmunerheumaticdiseaseoverlappingwith

PM or DM and an autoimmune rheumatic disease with myositis as a

manifestationcanbeverydifficult.

Box14.2DiagnosticcriteriaforthediagnosisofPMandDM

1. Symmetrical proximal muscle weakness developing over weeks or

months.

2. Elevated serum muscle enzymes: creatine kinase (CK), aldolase, AST,

ALT,andlactatedehydrogenase.

3. Typicalelectromyographicfindings:myopathicpotentials(lowamplitude,

short duration, polyphasic) fibrillation, positive sharp waves, increased

insertionalactivity,complexrepetitivedischarges.

4. Typicalmusclebiopsyfindings.

5. DermatologicalfeaturesofDM:

• Gottron’spapules,involvingfingers,elbows,knees,andmedialmalleoli.

• Heliotropesignaroundtheeyes.

• Erythematousand/orpoikilodermatousrash.

DefinitePM:allofcriteria1–4;probablePM:3ofcriteria1–4;possiblePM:2ofcriteria1–4.

DefiniteDM:3ofcriteria1–4pluscriterion5;probableDM:2ofcriteria1–4pluscriterion5;possible:

1ofcriteria1–4pluscriterion5.

AfterBohanA,PeterJ.Polymyositisanddematomyositis.NEnglJMed1975;292:344–7.

Table14.1KeyfeaturesofPMandDM

PM DM

Typicalpatient Anyage

Unusual in

children

Female and

African

American

predominance

Anyage

Juvenileformcommon

Female and African American

predominance

Musclegroups

affected

Proximal >

distal

Symmetrical

Proximal>distal

Symmetrical

CKelevation 40–50×normal

notunusual

40–50×normalnotunusual

Weaknesssometimesoutofproportionto

CKlevel

Myositis

specific

antibodies

(MSAs)

Anti-aminoacyl

t-RNA

synthetase

antibodies;anti-

SRP

Anti-aminoacylt-RNAsynthetase

antibodies;anti-Mi-2

Histopathology Endomysial

inflammation

CD8+ cells

invading non-

necrotic

musclefibres

Perivascular

Interfascicularinflammation

CD4+ predominance; complement

membrane attack complex present;

capillary obliteration; endothelial

damage;perifascicularatrophy

Malignancy

association

Yes Yes

Otherfeatures Interstitial lung Skin

disease(ILD)

Cardiac

Malignancy

ILD

Cardiac

Intramuscularcalcification

Vasculitis

Malignancy

Skinandcutaneousdisease

• TherashofDMcommonlyprecedestheweaknessbyweekstomonths.The

rash may parallel the weakness or remain independent, persisting after the

myositisresolves.

• Erythematousorviolaceouspapulesorplaques(Gottron’spapules)ormacular

patches (Gottron’s sign) may occur over the metacarpophalangeal and

proximal(occasionallydistal)interphalangealjoints.Therashispresentinup

to80%ofcases.

• Occasionally, these lesions may be found on the extensor surfaces of the

knees,wrists,elbows,ormedialmalleoli.

• PeriungualabnormalitiesaffectingthecapillarynailbedsinDMandPMwith

erythemaandinsomecasestendernesscanbeseen.

• Vascular changes observed at the nailbed resemble those found in other

connective tissue diseases, e.g. systemic sclerosis and SLE. Abnormal

capillaryloopsmayalternatewithareasofvasculardilatationanddropout.

• Amaculareruptionmayinvolvetheupperchest,neck,shoulders,extremities,

face, and scalp. This may develop into poikiloderma, hyper- or

hypopigmentationwithatrophyandtelangiectasia.Typicalfeaturesincludethe

‘V’signatthebaseoftheneckanteriorly,andthe‘shawl’signatthebackof

theneckandacrosstheshoulders.

• The heliotrope rash, found in 30–60% of cases, is a purple/lilac coloured

suffusion around the eyes, often associated with periorbital oedema. It is

characteristic,butnotpathognomonic.

• SomepatientshavetypicalcutaneousDM,butdonotdevelopovertmyositis.

The term ‘amyopathic DM’ is applied. The same risk of malignancy and

systemiccomplicationsremains.

• Calcinosis,cutaneousvasculitis,andulcerationaremorecommoninjuvenile

DM.

Joints

Coexistent polyarthralgia is quite common. It is usually non-erosive and

glucocorticoid(GC)responsive.

Cardiacdisease

• ClinicalfeaturesofheartinvolvementarerareinPMandDM.

• Asymptomaticsubclinicalmanifestationsareoftenreported,andcanoccurin

up to 70% of patients. These are mainly conduction abnormalities and

arrhythmiasdetectedbyECG.

• Cardiovasculardiseaseisamajorriskfactorfordeathinmyositis,andshould

therefore not be overlooked. The most frequently overt manifestations are

congestiveheartfailure,conductionabnormalities,andcoronaryheartdisease.

• The underlying pathophysiological mechanisms responsible include

myocarditis,coronaryarterydisease,andinvolvementofthesmallvesselsof

themyocardium.

Pulmonary

• Shortness of breath may be a consequence of diaphragmatic and intercostal

muscle weakness (as well as other causes that will be discussed later), and

shouldbeassessed.

• ILDiscommon,withavariableresponsetoimmunosuppression.

Gastrointestinal

• Dysphagiaoccursinupto30%.

• Cricopharyngealmyotomyisoccasionallyneeded.

Malignancy

• Studiessuggestamodestincreaseinmalignancieswithin1–2yearsofonsetin

DM.Inthemajorityofcases,cancerandmyositishaveanindependentcourse.

• Thelargestpopulationstudiessuggestmalignancyoccursin15%ofcasesof

DM(relativeriskinmen2.4/inwomen3.4)and9%ofcasesofPM(relative

riskinmen1.8/inwomen1.7).

• CancerdeathsinstudiessuggestanincreaseinDM,butnotPM,supportinga

trueassociationwithDM,ratherthanastudybiasduetointensivesearching.

• The highest cancer riskappearsto be in men >45yearswith DM who lack

myositisautoantibodiesoroverlapautoimmuneconnectivetissuedisease.

• Tumours thatarefrequent in thegeneralpopulation are frequentin PM and

DM. However, there appears to be an increase in ovarian, breast, lung,

stomach,colon,andbladdercancersoutofproportiontothatofothertumours.

• The extent of investigations required is debated. Thorough physical

assessment should always include rectal, pelvic, and breast examination.

Specificinvestigationsshouldincludeachestradiograph,urinalysis,prostate-

specific antigen in men, faecal occult blood testing, mammography, and

cervicalsmear,andprobablypelvicultrasoundandCA125levelsinwomen.

• Furtherbowelinvestigationsareopentodebateanddeterminedbyindividual

patient symptoms. An elevated ALT may be from muscle and need not

indicateliverpathology.

• Malignancycanmanifestasparaneoplasticmyopathy(see Chapter4).

Clinicalassessments

FeaturessuggestinganalternativediagnosistoIIM

It is important to consider whether there are features of non-inflammatory

myopathy,which maypointtowardsstorage diseases,geneticmyopathies, and

neuropathy.

• Drug history: anumberof medications areassociatedwith causing myositis

(Table14.2).

• Weakness/cramp worsened by exercise or dietary changes (e.g. fasting,

carbohydrate intake), which might suggest a metabolic or mitochondrial

myopathy.

• Muscle atrophy without pain or hypertrophy can suggest a muscular

dystrophy.

• Fasciculationormyotoniaandotherneurologicalsignsmaysuggestaprimary

neurologicaldisease(e.g.motorneurondisease).

• Facial and shoulder girdle muscle involvement may suggest

facioscapulohumeraldystrophy.

• Afamilyhistoryofmyopathymaysuggestageneticmyopathy.

Table14.2Drug-inducedmyopathy

Clinicalpicture Examples

Myopathywithweakness,myalgia,

andhighCK

Penicillamine

Anti-TNFα

Cimetidine

L-tryptophan

Zidovudine

Colchicine

Hydroxychloroquine

Lipid-loweringagents

Ciclosporin

Vincristine

Carbimazole,propylthiouracil

Alcohol

NSAIDs—rarewithaspirin

Rhabdomyolysispicture Alcohol

Recreationaldrugs—cocaine,heroin,

ecstasy

Amphetamines

Barbiturates

Statins(particularlyhighdose)

Anaesthetics—malignant

hyperthermia

Psychotropics—neuroleptic-

malignantsyndrome

Assessmentofdiseaseimpact

SeeTable14.3.

Changes in muscle strength and function may change slowly with indolent

disease, or with treatment, and measures of long-term muscle and general

function are important to take regularly. General (Likert scale) patient and

physicianglobaldiseaseactivityscoresareeasytotakeandreproduce:

• HAQorSF36maybeused.

• Musclemetrologyfromanexperiencedphysiotherapist.

• Themanualmuscletest(MMT)isthemostoftenusedtestofmusclestrength,

althoughonlypartlyvalidatedinadultmyositis.

• Quantitativemuscleatrophy(e.g.byMRI).

• Several scalesof compositemeasures areavailable e.g.MYOACT(activity)

andMYODAM(damage)andMDI(diseaseindex).Thelatterhaverecently

beendemonstrated tohavegoodconstructand validityin adultand juvenile

IIM.

1,2

Table14.3SystemicmanifestationsofPMandDM

Organ/system Features

General Fatigue,malaise,weightloss

Fevers—in40%overall

Raynaud’sphenomenon

Pulmonary Duetomuscleweakness:aspirationpneumonia,respiratory

failure(lowTLC,VC,highRV)

Duetolocaldisease:interstitialfibrosis,pulmonary

vasculitis,pulmonaryhypertension(common)

Duetotreatment:hypersensitivitypneumonitis,

opportunisticinfection

Gastrointestinal Oesophagealdysphagia—in30%

Striatedmuscledysfunction

Cricopharyngealdysfunction

Lowoesophagealdysfunction

Stomachandboweldysmotility*

Cardiovascular Cardiomyopathy—<5%

Pericardialeffusion—upto20%

Hypertensionandischaemicheartdisease(common)

Heartblock—rare

Dysrhythmias—uncommon

Skeletal Arthropathy

Deformity,milderosivearthritis

Renal Veryrare.Possiblemyoglobinuria

*Intestinalvasculitis,perforation,andpneumatosiscystoidesintestinalis,featuresofjuvenileDM,are

veryrareintheadult.

RV,residualvolume;TLC,totallungcapacity;VC,vitalcapacity.

References

1.IsenbergDA,AllenE,FarewellV,etal.Internationalconsensusoutcomemeasuresfor patients with

idiopathic inflammatory myopathies. Development and initial validation of myositis activity and

damageindicesinpatientswithadultonsetdisease.Rheumatology2004;43:49–54.

2. Rider LG, Lachenbruch PA, Monroe JB, et al. Damage extent and predictors in adult and juvenile

dermatomyositis and polymyositis as determined with the myositis damage index. Arthritis Rheum

2009;60:3425–35.

3.BohanA,PeterJB.Polymyositisanddermatomyositis.NEnglJMed1975;292:344–7.

Investigations

TheinvestigationofpotentialmalignancyinDM/PMhasbeendiscussedearlier

inthischapter.

Muscleenzymes

• Serum levels of enzymes released from damaged muscle are helpful in the

diagnosisandmonitoringofthedisease.Creatinekinase(CK)ismostwidely

used.Aldolasemaybemoresensitiveinsomecases.

• ThereareanumberofothercausesforraisedCKlevels(Table14.4).Muscle

bulkinfluencestheCKlevels.Butitisalsopossible,despiteactivemyositis,

for the CK levels not be elevated (i.e. relative chronic muscle atrophy). In

these cases, imaging such as MRI may be a useful indicator of

damage/severity.

• The isoenzyme CK-MB can be elevated in myositis and less often in

myocarditis. It is released from regenerating skeletal muscle fibres and also

damagedmyocardiocytes.

• As a guide, patients with myositis without cardiac involvement may have a

CK-MB/totalCKratioof>3%.

• A more specific marker for myocardial damage in myositis is the cardiac

isoformtroponinI.

• Other cardiac troponin isoforms such as troponin C (cTnC) and troponin T

(cTnT)arelessspecificandexpressedinskeletalmuscle,hencelevelscanbe

raisedinvariousmuscledisorders.

Musclebiopsy

• All patients should have a muscle biopsy to confirm the diagnosis and to

excludeconditionsthatmayresembleIIM.

• There is an argument for not obtaining a biopsy in patients with proximal

weakness,elevatedenzymes,typicalEMGchanges,arashofDM,confirmed

myositis-specificautoantibodies,oranoverlapautoimmunerheumaticdisease

andmyositis-associatedautoantibodies.

• Formostpatientshowever,itisimportanttorememberthatthemimicsofIIM

aremorecommonthantheIIMsthemselves.Therefore,patientswithaclinical

diagnosisofPM/DMwhodonotrespondtoimmunosuppressivetreatmentas

expectedshouldhaveabiopsyinordertoconfirmanalternativediagnosis.

• Anegativebiopsydoesnotexcludemyositis,asinflammatorychangescanbe

focal.Therefore thesiteofbiopsyshould bepreferablyfromasymptomatic

musclewhichisnotatrophic.

• Musclebiopsysamplesarestainedwithhaematoxylinandeosin.

• Further immunohistochemical staining for MHC class antigens provide

additionalusefulinformation.ThepresenceofMHCclassIandIIantigensin

musclefibresisafeatureofinflamedmusclestissue.

• There are important histological descriptions that associate with specific

diagnoses:

• Fibrehypertrophysuggestsdystrophy.

• InclusionbodiesareseeninIBM.

• Widespread necrosis with profuse regeneration is the typical finding in

rhabdomyolysis.

• Inflammation affects striated muscle and occasionally heart muscle, but not

smoothmuscle.

• Histologically, the cellular infiltrates of skeletal muscle involve mainly T

lymphocytesandmacrophages.Dendriticcells,Bcells,andplasmacellscan

alsobefound.

• IIMsoftenhavespecificbiopsyfeatures:

• In DM, there are mainly perivascular and perimysial inflammatory

infiltrateswithapredominanceofCD4+Tcells.

• InPM,thereis endomysial(intramuscular)inflammatoryinfiltrateswitha

predominance of CD8+ T cells causing destruction of muscle fibres and

fattyreplacement.

• In IBM, the early disease may be indistinguishable from the histological

appearances of PM. Characteristic findings are intracellular amyloid

deposits or basophilic intracellular vacuoles (‘inclusion bodies’) seen on

electronmicroscopy.

• Optimal processing, evaluation, and minimizing of artefacts require

coordination with the pathologist prior to biopsy, to ensure appropriate

handlingofsamplesandmaximumdiagnosticinformation.

Table14.4Causesofaraisedcreatinekinase

Cause Examples

Strenuous

prolonged

exercise

Delayed-onsetmuscularstrain(DOMS)

Muscletrauma

Diseasesaffecting

muscle

Myositis

Metabolic(e.g.glycogenstorage)

Musculardystrophy

Myocardialinfarction

Rhabdomyolysis

Drugs(alsosee

Table14.7)

Necrotizingmyopathy(statins,ciclosporin,labetalol,

alcohol,anti-TNFα)

Inductionofmyositis(L-tryptophan,L-dopa,phenytoin,

lamotrigine,hydroxycarbamide)

Amphiphillic((hydroxy)chloroquine,amiodarone)

Microtubule(colchicine,vincristine)

InhibitionofCKexcretion(morphine,diazepam)

Metabolic

abnormalities

Hypothyroidism

Hypokalaemiaincludingdruginduced(diuretics,

laxatives,GCs)

Ketoacidosis

Renalfailure

Normalvariants Ethnicgroup(oftenhighernormalvaluesintheblack

population)

Increasedmusclemass

Technicalartefact

Autoantibodies

• Autoantibodies are present in ~60–70% of patients with PM and DM. The

mainantibodyisantinuclearantibody(ANA).

• Myositis-specificautoantibodies(MSAs)areassociatedwithspecificclinical

phenotypes,andfavourPM/DMoverothermyopathies.

• ThemostprevalentMSAisanantibodydirectedagainsthistidyltransferRNA

synthetase(anti-Jo1)presentinaround11–33%ofpatientswithPM/DM.

• Histidyl isoneof anumberof amino-acyl transferRNA synthetaserelevant

targetsforantibodyformation.

• Thevariousclinicalassociationsofthemainmyositis-associated(MAAs)and

MSAsareshowninTable14.5.

• Anti-signal recognition peptide (SRP) antibodies occur in ~5% of myositis

patientsandheraldanacute-onsetaggressivedisease.Itisnotlinkedtoskin

manifestations.Musclebiopsytendstoshowanecrotizingmyopathywithfew

inflammatorycells.Treatmentresponseisoftenpoor.

• Anti-Mi2andanti-CADM-140arefoundin10–20%ofDMcases.

• Statin-induced myopathy is associated with anti-HMG-CoA antibodies. The

presenceoftheseantibodiesisnotlinkedtostatinexposureineverycase.

• Anti-p155/p140(anti-MJ)isfoundinupto25%ofcasesofjuvenileDMand

isassociatedwithcalcinosis.

• DetaileddescriptionofallMAAs/MSAsisbeyondthistext.Newantibodies

aredescribedregularly.Itisworthnotingup-to-datepublicationsinthisarea

given that antibody immunological tests through specialist labs can help in

difficultcaseswheremalignancyanddrugsarebeingconsideredascauses.

Electromyography

• Electromyography (EMG) cannot establish the diagnosis of PM/DM with

certainty, but can demonstrate a myopathic process, and help to exclude

neuropathiesanddistinguishsomemyopathies.

• 90%ofpatientswillhaveabnormalEMGstudies.

• Early findings include low-amplitude, short-duration, polyphasic potentials,

with early recruitment and full interference patterns (i.e. more fibres are

required to achieve a given force). The latter features are in contrast to

neuropathieswherethereisdecreasedrecruitmentandinterference.

• Withtime,re-innervationofdenervatedfibresleadstohigh-amplitude,long-

duration,polyphasicpotentials.

• Otherfeaturesincludespontaneousactivityinupto75%ofcases,fibrillations,

and repetitive discharges akin to myotonia, but of constant amplitude and

startingandstoppingabruptly.

Imaging

• Magnetic resonanceimaging (MRI),ultrasound (US),computed tomography

(CT),

99m

Tc,andthalliumhavebeenusedtoassessthedistributionofdisease.

• MRI with T2-weighted images and fat suppression or short tau inversion

recovery(STIR)isbestatidentifyingareasofmuscleinflammation,atrophy,

orfattyinfiltration.

• OnMRI,activemyositisresultsintheappearanceoffluidsignalchangesin

muscle—interpretedasoedema.

• When evaluating a patient for weakness, MRI may be particularly useful in

distinguishing weakness due to active inflammation from weakness due to

previous damage or GC myopathy (which would not be expected to show

muscleoedema).

• Becausemuscleinvolvementmaybepatchy,MRIcanhelpidentifyanoptimal

siteformusclebiopsy.

Table14.5AntibodiesinPMandDM

Antibodyclass Antibody

subclass

Percentageof

PM/DM

Myositissubgroup

Myositis-

specific:

Intotal30–40

Anticytoplasmic Anti-Jo-1 20 Antisynthetase

syndrome

Anti-PL-7/PL-

12/OJ/EJ

<5each

Anti-SRP 4 PM

Antinuclear Anti-Mi-2 8 DM

Anti-56kDa 90 All

Myositis-

associated

Anti-PM-Scl 8 PM/DM–SScloverlap

Anti-U1-RNP 12 PM/DMoverlap

syndromes

Anti-U2/U5-

RNP

<2 PM

Anti-Roand

Anti-La

5–10 SLE.PrimarySjögren’s

syndrome

Othertests

• The ESR is elevated in 50% of cases, but correlates poorly with disease

activityandresponsetotherapy.

• CRPisnotspecific;highlevelssuggestaconcurrentinfection.

• ComplementlevelsinPM/DMareusuallynormal.

• Proteinuriamaybetheresultofmyoglobinuria.

• Serialspirometryforrespiratorymuscleweaknessmayberequired.

Treatment

Treatment should be started promptly pending completion of investigations,

particularly in acute-onset weakness, dysphagia, respiratory insufficiency, and

systemiccomplications.

• GCs have never been tested adequately in randomized, placebo-controlled

trials,butarethecornerstoneoftherapy.

• 90% of patients will have at least a partial response to GC therapy. Most

requiretreatmentwithaGC-sparingagenttomaintaindiseaseremissionand

tominimizeGCexposure.

• Anexerciseprogrammehelpsimprovefatigueandmusclestrength.Exercise

shouldbeusedwithcautionduringperiodsofdiseaseactivity,butthereisno

evidence that it causes prolonged worsening in muscle enzyme levels or

inflammation.

Glucocorticoids.

Seealso p.660

• Most clinicians use a starting oral prednisolone dose of 1–2 mg/kg until a

declineinCKand/orasubstantialimprovementinmusclestrengthisseen.

• LowerGCdosesof0.5mg/kgmaybesufficient.Severecases(orextraskeletal

involvement) may be treated with IV methylprednisolone 0.5–1 g/day for 3

daysbeforestartingoralprednisolone.

• As high doses are required for several months, early vitamin D/calcium

supplementation and bisphosphonates should be considered to prevent GC-

inducedosteoporosis.

• IIM patients are at increased risk of developing osteoporosis also due to

decreasedskeletalloadingandimmobility.

• Acase–controlstudyhasalsoshownthatmostIIMpatientshavelowserum

levels of vitamin D. This may confer a risk factor for developing adult

myositis,suggestingvitaminDreplacementtherapyisimportant.

• Mostpatientswillrespondtotreatment,butthiscanbeslowandpartial.CK

levelsoftenimprovequickerthananyapparentimprovementinstrength.

• Failure to respond despite 4–6 months of treatment may be due to one of

severalreasons(especiallyiftheANAisnegative):

• Incorrectdiagnosis.

• Hereditarymyopathyor‘inclusion-body’myositis.

• GCmyopathy.

• Permanentlossofstrength.

• NoresponsetoGCtherapy.

Syntheticdisease-modifyingantirheumaticdrugs(sDMARDs).Seealso

pp.662–80

• Methotrexate (MTX) and azathioprine (AZA) have demonstrable efficacy;

AZAmaybeabetteroptionforpatientswithILDorhepatitis,butmaytake

longertoshoweffectiveness.

• StudieshaveshownasynergisticeffectofMTXandAZAwhereasingledrug

hasfailed.

• Cyclophosphamide (CYC) has had variable results and is used in resistant

casesorinthosecaseswherethereissevereextraskeletalinvolvementsuchas

vasculitisorlungdisease.

• Tacrolimus has been used in refractory patients with PM/DM-ILD, with

improvementinmusclestrength,lungfunction,andcutaneousmanifestations.

• Ciclosporin can be a useful therapy in patients where MTX and AZA have

beenineffective/nottolerated.IthasbeenusedincombinationwithMTXor

IVIg.

• Mycophenolate mofetil (MMF) and chlorambucil have been reported to

achievediseaseremissioninsomerefractorycases.

Intravenousimmunoglobulin(IVIg)

• EfficacyofIVIghasbeendemonstratedinsmalldouble-blindcontrolledtrials

andoneopen-labeltrial,showingsignificantclinicalimprovementinmuscle

strength and reduction in CK levels after 3 months of treatment, compared

withplacebo.

• CasereportshavesuggestedefficacyofIVIginthetreatmentofPM/DM-ILD,

andithasbeenusedinonecaseofrefractoryamyopathicDM-ILDwithgood

response.

• High-doseregimensintheformof2g/kg/dayfor2–5dayseverymonthfor3–

6 months have been advocated, and can be used concomitantly with other

sDMARDs.

• Durationofefficacyofeachtreatmentmaybelimitedtoafewmonths,butthe

dose or interval can be changed based on severity of disease and treatment

responsiveness.

• A major advantage of IVIg is that it is safe to use in the context of active

infections,butitshighcostmayrestrictlong-termuse.Thereisalsoariskof

tachyphylaxis.

Biologictherapies

There is growing interest in evaluating biologics that target various pathways

involvedinthepathogenesisofIIM.

• Anti-TNFαtherapyhasbeenstudiedinsmallpatientseries.Therehavebeen

suggestionsthatitmaytriggerIIM,thereforetheyshouldbeusedwithcaution.

• Inopenlabelstudies,rituximab(RTX)hasbeenusedinrefractoryDMwith

reportsofclinicalimprovement.

• The first placebo-phase trial to assess the efficacy of RTX in refractory

myositis did not show a significant difference between the two treatment

groups.

• ArecentsummaryofpublishedevidenceforRTX effectinIIMsuggesteda

majority of patients derived benefit though markers of response varied and

therewasofcoursemarkedheterogeneityofdiseaseattheoutset.

• Further research is required to assess the role of biologic therapies though

manytreatmentshavebeentried(Table14.6).

Treatmentofextramusculardisease

• The rash of DM may respond to the treatment of the myositis. If lesions

persist,hydroxychloroquine(HCQ)at200–400 mg/dayortopicaltacrolimus

maybeofbenefit.Photosensitivitycanrespondtosunscreens.TopicalGCsare

oftennotsuccessful.

• ThetreatmentofamyopathicDMiscontroversial.SunscreensandHCQcan

beusedandinsome severecases, GCsor immunosuppressivesarejustified

for the cutaneous disease. If treatment is withheld due to an absence of

myositis,thepatientshouldbefollowedclosely,especiallyinthefirst2years

afteronsettoavoiddelayintreatmentshouldmyositisdevelop.

• Calcinosis, principallya problemin juveniledisease, isdifficultto treatand

does not respond to immunosuppression. Surgical resection may help for

accessibledeposits.

• Activeexerciseisdiscouragedduringacuteinflammation,butpassiverangeof

motion exercises should be commenced early to avoid joint contractures.

Isometric exercise should be introduced once inflammation subsides. This

mustbesupervisedbyaphysiotherapisttoavoidmuscleoveruse.

• ILDismanagedasinotherautoimmuneconnectivetissuediseaseswithoral

GCsandoralorIVCYC.

• Distal oesophageal dysmotility does not generally respond to

immunosuppression,butmeasuressimilartotreatmentofrefluxmayhelp.

PrognosisinPMandDM

• PM and DM are diseases with a high mortality and morbidity. One

retrospective study estimated a mortality rate of 22%, mostly due to

malignancyandpulmonarydisease.

• Inmostcases,thecourseofdiseaseiseithermonophasic,remitting/relapsing,

orchronicprogressive.

• Asmallnumber(5–10%)makeafullrecoveryfollowingtreatment.

• The use of prolonged immunosuppressive therapy increases the risk of

infection,especiallywithunusualorganisms.

• Casereportshavedescribedatypicalmycobacterialinfectionsinpatientswith

long-standingPM/DM.

• A worse prognosis is associated with increasing age, bulbar muscle, and

cardiopulmonaryinvolvement.

Table14.6BiologictherapiesusedfortreatingIIMs

Biologic Levelofevidence

Adalimumab Onecasereportofa‘hard-to-treat’patientshowingincreased

musclestrengthandreducedCKlevels

Etanercept Pilottrialof16treatmentnaïvepatientsshowednobenefits,

apartfromGCsparing

Infliximab Retrospectivestudies.UtilityinIIMslimitedduetopotential

forinducingPMandDM.Notrecommended

Rituximab Double-blindtrialshowingprimaryoutcomesnotmet,but

mostachievedtheIMACS*definitionofimprovement

Tocilizumab 3casereportsofrefractoryIIM.Someclinicalbenefitsseen

withreducedenzymelevelsineachcase

Anakinra 12-monthopenlabeltrial.Improvementin7/15patientswith

refractorymyositis.Inflammatoryinfiltratesinrepeat

biopsiesdidnotresolveandIL-1expressionwasnot

correlatedtoclinicalresponse

Alemtuzumab 1casereport(PM/ILD)showingrapidimprovement.Post

infusion-relatedreaction/respiratorycompromise.Concerns

aboutimmunosuppressivepropertiesandinfectionrisk

Abatacept Ongoingclinicaltrial(ARTEMIS).Favourableoutcomesin

JDMwithcalcinosisandrefractoryanti-SRPmyositis

Sifalimumab Phase1btrial.Suppressionofgenesinducedbytype1IFNγ

(bloodandmuscle)withimprovedmusclestrength

*InternationalMyositisAssessmentandClinicalStudiesGroup(IMACS)

AdaptedfromMoghadam-KiaSetal.ModernTherapiesforIdiopathicInflammatoryMyopathies

(IIMs):RoleofBiologics.ClinRevAllergyImmunol.2017Feb;52(1):81–87withpermissionfrom

Springer.

References

4. Muscle Study Group. A randomized, pilot trial of etanercept in dermatomyositis. Ann Neurol

2011;70;427–36.

5.ZongM,DorphC,DastmalchiM, et al. Anakinratreatmentinpatientswithrefractoryinflammatory

myopathiesandpossiblepredictiveresponsebiomarkers:amechanisticstudywith12monthsfollow-

up.AnnRheumDis2014;75;913.

Inclusion-bodymyositis

• Inclusion-bodymyositis(IBM)isadistinctdisorderthatcomprises20–30%of

idiopathicmyositiscases.IBMusuallybeginsaftertheageof50yearsandis

3×morecommoninmen.ThedifficultyindistinguishingitfromPMandits

insidiousonsetcanleadtoconsiderabledelayindiagnosisby3–5years.

• Distalweaknessandwastingcanbeascommonasproximal,ofteninvolving

thelowerlimbsbeforetheupper,andsparingtheface.

• Unlike PM or DM, IBM can present with diminished hand-grip strength, in

additiontoproximalmuscleweakness.

• Dysphagiaisafeaturein40%ofcases,andmyalgiasin20%.

• Anopenbiopsy(asopposedtoneedlebiopsy)isessentialtodiagnoseIBM.

• A needlebiopsy maynotbe sufficient toallow therecognitionof important

cluesthatpointawayfromotherformsofmyositis.

• Thereisasignificantinflammatorycomponentearlyinthediseasecourse,that

may partially respond to GCs, though generally patients are usually non-

responsivetoGCs.

• Theremaybeaperiodofstabilizationforafewmonthsbutthismayreflect

thenaturalhistoryofdisease.

• ProlongedadministrationofGCsmayresult inworsening ofdisease despite

improvementsinCKlevels.

• Treatmentusuallybeginswithhigh-doseGCsfor3months,addinginMTXor

AZA if clinical improvement or in patients with another autoimmune

connectivetissuedisease.Ifthereiscontinueddeclineinstrengthorfunction,

immunosuppressionshouldbediscontinued.

• Anti-T-lymphocyte globulin, interferon-β, MMF, and anabolic GCs such as

oxandrolone,mayhavebeneficialeffectsasinsomereports.

• Weakness willprogress inmost patientsbut thisis oftenvery slow. Patients

may need assistance with daily activities within 10 years and some may be

wheelchairboundwithin15yearsfromonsetofsymptoms.

Other(adult)inflammatorymyopathies

Drug-inducedmyopathies

• The range of myositis severity caused by different drugs varies, from

asymptomatic increases in CK to necrotizing severe myopathies resulting in

rhabdomyolysis.

• HMG-CoAreductaseinhibitors(statins)cancausemyalgiaandcrampsalong

withanelevatedCKlevelandmaybeexacerbatedbytheuseofotherdrugs

(ciclosporinandfibrates)orotherdiseases(hypothyroidism).

• Patientsonanydrugssuspectedofcausingmyositis,presentingwithmyalgia,

shouldhavetheirrenalfunctionandCKcheckedandthedrugstopped.

• See Table14.2,p.431foranoverview.

PM/DMwithinterstitiallungdisease

Polymyositisordermatomyositisoccurringtogetherwithinterstitiallungdisease

(PM/DM-ILD)maybeadistinctcondition.

• Characteristicfeaturesincludemyositis,ILD,Raynaud’sdisease,‘mechanic’s

hands’(i.e.dry,crackedskinacrossthedigits),andsmalljointpolyarthritis.

• Associatedwitharangeofautoantibodiesdirectedagainstaminoacyltransfer

RNA synthetases includinghistidyl-tRNA synthetase (HRS; termedtheanti-

Jo1autoantibody).

• Anti-Jo-1ispresentin~20%ofPM/DMpatientsandtitreofantibodycanbe

associatedwithdiseaseactivity.

• Canbeassociatedwithfeversatonsetorduringflares.

• SomepatientspresentingwithILDorarthritismaygoontodevelopmyositis

later,sopresentationofcomponentsofthediseasemaynotbeconcordant.

• Patientsneedtobemanagedwithachestphysicianmonitoringlungfunction

testsandinflammatorydiseaseactivity.

• CYC, MMF, and RTX give alternative choices for therapies in addition to

GCs.

Juvenileidiopathicinflammatorymyopathy

Introduction

• ThejuvenileIIMsareheterogeneousinflammatoryconditionsinyoungpeople

<17yearsofagecharacterizedbyproximalmyopathy,rashes,andotherorgan

involvement.

• Juvenile IIMs are classified into groups that share similar clinical and

laboratoryfeatures,treatmentresponses,andprognosis.

• ThejuvenileIIMsare:

• juveniledermatomyositis(JDM):80%.

• juvenilepolymyositis(JPM):5%.

• overlapmyositis:10%.

• rare forms: macrophagic myofasciitis, focal myositis, granulomatous, and

graft-vs-hostmyositis.

• inclusion body myositis and cancer associated myositis are exceptionally

rareinchildren.

• Aformofinclusionbodymyositisalsooccursincriticalillnessmyopathyseen

inintensivecareunits.

• Benign acute childhood myositis is self-limiting and typically presents with

calfpain,walkingdifficulty,andveryhighCKlevels.

• Benign acute myositis can be misdiagnosed as something more severe or

complexresultinginunnecessarytests,admission,andfollow-up.

• Although the 1975 ‘Bohan and Peter’ criteria

 remain in principle the

diagnosticcriteria(see Box14.2,p.427),theinvasivenatureofEMGand

biopsymeanstheyarerarelyusedandMRIandUSareoftensubstitutedfor

confirmationofmuscleinvolvement.

Differentialdiagnosisofmuscleweaknessinchildhood

Muscleweaknessmaybeasignofmusclediseaseoramanifestationofamuscle

function-relatedpathologyorevengeneralpathology.

• Viralmyositisorbenignacutechildhoodmyositis.

• Drug-inducedmyopathy.

• Criticalillnessmyopathy(e.g.patientsinintensivecareunits).

• Musculardystrophyandcongenitalmyopathy.

• Juvenilefibromyalgia.

• Othermultisysteminflammatorydiseases(MCTD,SLE,vasculitis).

• Skeletaldysplasias.

• Electrolyteimbalances(potassiumandcalcium).

Juveniledermatomyositis(JDM)

• JDM is by far the commonest inflammatory myopathy in children and

adolescents and in typical circumstances does not require a search for

neoplasia.

• Theincidenceis2–4permillion(USAandUK)withamedianageofonsetof

7yearsold(25%are<4yearsoldatdiagnosis).

• Presentation is typically with a classical rash and insidious onset of muscle

weakness.

• A facial rash is common with a photosensitive malar distribution and

nasolabial-sparingcharacteristicofSLE.

• DistinguishingJDMfromSLEisimportant.WithJDMthereareshinyraised

redmarksontheknuckles,elbows,knees,andankles(Gottron’spapules)and

aduskypurple-redhuetotheuppereyelids(heliotroperash).

• Weaknessmanifestsasdifficultygettingupstairsoroutofbed,difficultywith

puttingonajumperorT-shirt,ortiringmorequicklythanusualduringsport.

• Other features include low-grade fever, weight loss, arthralgia, abdominal

pain,melaena,changeincharacterofvoice,anddifficultyswallowing.

• ILDanddilatedcardiomyopathymayoccurinchronicdisease.

• TheclinicalcourseofJDMfallsintodifferentpatterns:

• Monocyclic(lastingupto3years)in25–40%.

• Polycyclic (periods of remission and relapse relapse) or chronic, both of

whichcanbelifelong,in50–60%.

• Ulcerativein10–20%.

Myositis-specificautoantibodies(MSAs)

• MSAshavebeenidentifiedin~70%ofJDMpatients.

• AllautoantibodiesareseeninJDM.MorecommonMSAsinclude:

• anti-TIF1-gamma associated with classical JDM (18%), extensive skin

involvement(andlipodystrophy),andchroniccourse.

• anti-MJ, anti-NPX2(15%): bothassociated witha monocycliccourse, but

moreseverecalcinosis,dysphonia,andjointcontractures.

• MDA5 (6%):patientsare lesslikelyto be weak,but cutaneous ulceration

andarthritisarecommon.AssociatedILDisuncommon.

Treatment

• Managing JDM requires a multidisciplinary approach to optimize muscle

strength,function,andqualityoflifewhilecontrollinginflammationofskin,

muscle,gut,andotherorgans,andaimingtoavoidcalcinosisevolving.

• Calcinosiscutis(occurringinupto35%ofJDMcases)canbeamajorcause

ofmorbidityduetopain,cosmeticproblems,tetheringofskin,muscles,and

nerves,andasanidusforinfection.

• GCs are the mainstay of treatment and universally supplemented with

syntheticDMARDs(MTX,HCQ,ciclosporin,andIVIg).

• Earlyaggressivetreatmenttorapidlyandcompletelycontrolinflammationis

essentialtofullyrestoremusclefunctionandavoiddamageandcalcinosis.

• Consensus guidelines (CARRA 2012, USA) recommend escalating

immunosuppressionforthefirst2monthsdependingondiseaseseverity.

• ThetreatmentregimensutilizeSCMTX,andaGCtaperingschedulebasedon

weightandseverityofdisease(e.g.seeTable3inreference7).

• IV methylprednisolone is added for rapid induction especially for severe

diseaseandtoreplaceoralprednisolonewhenthereisgutinvolvement.

• If there is initialclinical improvement, then prednisolonedoseis reduced at

weekly intervals initially and then monthly at lower doses with the aim of

beingoffGCsby10–12months.

• CYCistypicallyusedforulcerativecases,severemuscledisease,andILD.

• IVIg is used for refractory and skin-predominant disease, or when there is

severeweakness.

• More recently MMF, RTX, and anti-TNFα agents have been used for

refractorydisease.

AmyopathicJDM

• Hasthecharacteristicrashbutnoobviousmuscledisease,althoughtypically

muscleinflammationandweaknessissubclinicalandinsidiousinonset.

• AmyopathicJDMisnotgenerallyassociatedwithcalcinosisorILD.

Overlapmyositis

• Occurswithscleroderma,SLE,JIA,Sjögren’sdisease,andtype1diabetesand

moreofteninnon-Caucasianpopulations.

• ItisoftenassociatedwithRaynaud’sandILDresultinginahighermortality.

Juvenilepolymyositis

• Isveryrareandresultsinmoreclinicallyapparentproximalanddistalmuscle

weaknesswithlittleskininvolvement.

• Itisusuallysevereatonsetwithvery highCK levels,affectsolderchildren

(adolescents),andfrequentlyhascardiacinvolvement.

• A muscle biopsy is required to differentiate from muscular dystrophy and

showsendomysialinfiltrates.

References

6.BohanA,PeterJB.Polymyositisanddermatomyositis.NEnglJMed1975;292:344–7.

7. Huber AM, Robinson AB, Reed AM, et al. Consensus treatments for moderate juvenile

dermatomyositis: beyond the first two months. Results of the second Childhood Arthritis and

RheumatologyResearchAllianceconsensusconference.ArthritisCareRes2012;64:546–53.

Chapter15
Primaryvasculitides
Introduction
Largevesselvasculitis
Takayasuarteritis
Polymyalgiarheumaticaandgiantcellarteritis
Polyarteritisnodosa
ANCA-associatedvasculitides
Smallvesselvasculitis
Childhood-onsetvasculitides
Introduction
• Thevasculitidesareaheterogeneousgroupofrelativelyuncommondiseases
that can arise as primary conditions or secondary to an established disease
such as rheumatoid arthritis (RA) (see  Chapter 5) or systemic lupus
erythematosus(SLE)(see Chapter13).
• The vasculitidesarelinkedbythepresenceofvascularinflammation, which
canleadtooneoftwocommonoutcomes:
• Vesselwalldestruction:leadingtoaneurysmorrupture.
• Stenosis:leadingtotissueischaemiaandnecrosis.
• In 1990, the American College of Rheumatology (ACR) developed a
classification system based on vessel size, with the inclusion of a division
betweenprimaryandsecondaryvasculitis(Table15.1).
• Thisclassificationsystemisnotperfect.Patientswith‘largevesselvasculitis’
and‘smallvesselvasculitis’canhavediseasethataffectssomemedium-sized
vessels.Moreover,notallpatients with‘antineutrophilcytoplasmicantibody
(ANCA)-associated vasculitis (AAV)’ have detectable levels of ANCA.
However, thisis ausefulframeworkfortheclinician,sincecategorizingthe
patient into one of these groups can narrow the differential diagnosis

considerably.

• The Chapel Hill Consensus Conference (CHCC)in1994haddeveloped the

mostwidelyusednomenclaturesystemformostformsofvasculitis.Thiswas

revisedinthe2012CHCCtoincludenewinsightsgainedoverthepasttwo

decades, add new forms of vasculitis, and address issues surrounding

eponyms.(Box15.1).

• Thenotablechangesofthe2012CHCCare:

• theadoptionofnewnamesforseveralconditions,consistentwiththetrend

ofreplacingeponymswithdiseasenamesthatreflectpathology.

• formallyadoptingthetermANCA-associatedvasculitis(AAV)forthemajor

systemicsmallvesselvasculitissubtypes.

• adoption of additional categories to include variable vessel vasculitis and

secondaryformsofvasculitis.

• Thisnomenclaturedoesnotsubstitutetheclassificationcriteria.

• TheAAVshaveapredilectionfortherespiratorytractandkidneys.

The AAVs are granulomatosis and polyangiitis (GPA; formerly Wegener’s

granulomatosis), microscopic polyangiitis (MPA), and eosinophilic

granulomatosiswithpolyangiitis(EGPA;formerlyChurg–Strausssyndrome).

Antineutrophilcytoplasmicantibody

• ANCA exists in two main forms based on neutrophil autoantibody

immunofluorescencepatterns:

• Cytoplasmic(C-ANCA;antibodiesagainstproteinase-3(PR3)).

• Perinuclear(P-ANCA;antibodiesagainstmyeloperoxidase(MPO)).

• Other ANCA-staining patterns (i.e. non-cytoplasmic, non-perinuclear) can

occur.

• P-ANCA pattern may be caused by antibodies against antigens other than

myeloperoxidase.Thesearesometimesreferredtoas‘atypicalANCA’,anddo

not predict the presence of vasculitis, although they can be found in

inflammatory bowel disease, immune-mediated neutropenia, and other

autoimmunediseases.

• C-ANCAisfoundinpatientswithGPA.

• PatientswithMPAandEGPAtendtobeP-ANCApositive.

• Counterintuitively,patientswithAAVcanbeANCAnegativeinupto50%of

cases.

• AAV patients with active or untreated disease are more likely to be ANCA

positive.

• The role that ANCAs play in the pathogenesis of vasculitis remains

controversial.

Table15.1Aclassificationofsystemicvasculitis

Dominantvessel Disorders

Largearteries Giantcellarteritis.Takayasu

arteritis.Isolatedcentral

nervoussystemangiitis

AortitisinAS.Infection,

e.g.syphilis

Mediumarteries Classicalpolyarteritisnodosa,

Kawasakidisease

Infection,e.g.hepatitisB.

Hairycellleukaemia

Medium

arteries/small

vessel

AAVs(e.g.GPA,

EGPA/Churg–Strauss,

microscopicpolyangiitis)

Vasculitis secondary to

autoimmune disease.

Malignancy.Drugs.

Infection,e.g.HIV

Smallvessel

(leucocytoclastic)

Henoch–Schönleinpurpura.

Essential mixed

cryoglobulinaemia.

Cutaneousleucocytoclastic

angiitis

Drugs.Malignancy.

Infection,e.g.hepatitis

B/C

Box15.1The2012CHCCnomenclatureofvasculitis

Largevesselvasculitis

• Takayasuarteritis(TA)

• Giantcellarteritis(GCA).

Mediumvesselvasculitis

• Polyarteritisnodosa(PAN)

• Kawasakidisease(KD).

Smallvesselvasculitis

AAVs

• Microscopicpolyangiitis(MPA)

• Granulomatosiswithpolyangiitis(GPA)

• Eosinophilicgranulomatosiswithpolyangiitis(EGPA).

Immune-complexsmallvesselvasculitis

• Anti-glomerularbasementmembrane(anti-GBM)disease

• Cryoglobulinaemicvasculitis

• IgAvasculitis(Henoch–Schönleinpurpura)(IgAV)

• Hypocomplementaemicurticarialvasculitis(HUV)(anti-C1qvasculitis).

Variable-sizedvesselvasculitis

• Behçet’sdisease(BD)

• Cogan’ssyndrome(CS).

Single-organvasculitis

• Cutaneousleucocytoclasticangiitis

• Cutaneousarteritis

• Primarycentralnervoussystemvasculitis

• Isolatedaortitis

• Others.

Vasculitisassociatedwithsystemicdiseases

• Lupusvasculitis

• Rheumatoidvasculitis

• Sarcoidvasculitis

• Others.

Vasculitisassociatedwithprobableaetiology

• HepatitisCvirus-associatedcryoglobulinaemicvasculitis

• HepatitisBvirus-associatedvasculitis

• Syphilis-associatedaortitis

• Drug-associatedimmunecomplexvasculitis

• Drug-associatedAAV

• Cancer-associatedvasculitis

• Others.

Modified from Jennette et al. ‘2012 Revised International Chapel Hill Consensus Conference

NomenclatureofVasculitides’Arthritis&Rheumatism,65:1–11withpermissionfromWiley.

Generalprinciplesofvasculitismanagement

• Tobecomplete,anyevaluationofachronicdisease(suchasprimarysystemic

vasculitis)mustincludebothanassessmentofdiseaseactivityandofdisease

damage. The concept of damage denotes the aspects of disease that are

unlikely to reverse with immunosuppression (such as pulmonary fibrosis or

renalinsufficiency).

• ClinicaltrialsofvasculitiscommonlyusetheBirminghamVasculitisActivity

Score (BVAS) and Vasculitis Damage Index (VDI) to assess activity and

damage,respectively.

• Other clinicalindicesexist. The French Vasculitis Study Group(FVSG)has

developedaprognosticFive-FactorScore(FFS).Thisindexprovidesanother

useful method of classifying patients with vasculitis. Patients with PAN or

AAVwhohaveaFFS>0havesubstantiallyhighermortalitythanpatientswith

aFFS=0.

• TheFFSwasrevisedin2008,andnowincludesthefollowing:age>65,renal

insufficiency, cardiac involvement, and gastrointestinal (GI) manifestations.

The presence of ear, nose, and throat signs was found to correlate with an

improvedoutcomeamongpatientswithGPA.

Largevesselvasculitis

• The‘largevessels’includetheaortaanditsmainbranches(i.e.thesubclavian,

carotid, andbrachiocephalicarteries). Primary and secondary forms oflarge

vesselvasculitisareshowninTable15.2.

• TheclassicformsofprimarylargevesselvasculitisareTA(see ‘Takayasu

arteritis’,pp.454–455)andgiantcellarteritis(GCA).GCAisassociatedwith

PMR.

• Recent studies demonstrate that many patients with polymyalgia rheumatica

(PMR) have subclinical aortic inflammation, which seems to validate this

classificationscheme.

• Theclinicalmanifestationsof largevesselvasculitiscanbepredictedbythe

patternofvesselinvolvement.Archaortitisleadstoaneurysmaldilatationand

aortic regurgitation. Subclavian involvement causes arm claudication and

diminished pulses on examination. Carotid involvement may lead to visual

loss,jawclaudication,andstroke.Involvementofanymajorbloodvesselmay

causebruitsofphysicalexamination.

Table15.2Causesoflargevesselvasculitis

Primary Takayasuarteritis

Giantcellarteritis

Secondary

†

Infection:bacterial,fungal,mycobacterial,spirochaete

Rheumatoidarthritis

Seronegativespondyloarthritis

Systemiclupuserythematosus

Sarcoidosis

Relapsingpolychondritis

Juvenilearthritis

Giantcellarteritisisdiscussedinthischapterinthesectiononpolymyalgiarheumatica.

†

Thesecondarycausesoflargevesselvasculitisarediscussedintheirrespectivesections.

Takayasuarteritis

Takayasuarteritis(TA)isachronicgranulomatousarteritisthataffectstheaorta

andthegreatvessels.Thepulmonaryarteriescanalsobeinvolved,althoughthis

isrelativelyuncommon.

Epidemiology

• ItismostcommoninJapan,SoutheastAsia,India,andMexico.Itisrareinthe

UKandintheUSA,itsannualincidenceisestimatedat2.6permillion,where

itisnotlimitedtopatientsofAsiandescent—themajorityofpatientsinthe

USAareCaucasian.

• TAtendstoaffectwomen(90%ofcases)withadolescentsandyoungadults

20–40yearsoldatgreatestrisk.

• The hallmark of the disease is arteritic inflammatory infiltrates that cause

luminal narrowing or occlusion presenting with bruits, claudication, and

diminished(orasymmetric)pulses.

Presentation

• Systemicsymptomsarecommonintheearlyphaseofthedisease,including

fever,malaise,weightloss,andfatigue.

• As the disease progresses, consequences of vascular inflammation and

insufficiencycanbecomeapparent.

• Arthralgiasandmyalgiasarecommon.

• Clinicallyevidentsynovitisisrare.

• Lightheadedness, visual disturbance,andstrokes can occur. Subclavian steal

canbeanimportantcauseofneurologicalsymptoms.

• Hypertensionmaydevelopasaconsequenceofrenalarterystenosis.

• Myoarthralgiasarenotuncommon.

• Cardiovascularcomplicationsareanimportantcauseofmorbidity,andinclude

aorticinsufficiency,congestiveheartfailure,systemichypertension,andostial

involvementofthecoronaryarteries.

Investigation

• Traditionally, the diagnosis of TA has depended on angiography to

demonstrate the characteristic changes of arterial dilatation, thrombosis, and

aneurysmformation.

• Conventional angiography has the added benefit of allowing a comparison

betweencentralandperipheralbloodpressures—importantbecausesubclavian

stenosis is a common consequence of this disease and a standard arm cuff

blood pressure reading may underestimate hypertension. Angiography may

also allow for therapeutic intervention, e.g. angioplasty or stenting of the

stenoticvessels.

• Magnetic resonance imaging/angiography (MRI/MRA) have excellent

resolutionatthelevelofthelargevessels.MRIcanalsodemonstrateevidence

ofvesselwallinflammation,whichcouldsupportadiagnosisofTA.

• High-resolutionUSissensitivefordetectingcarotidlesions.

•

F-FDG PET-CT scanning is useful for identifying the presence of large

vesselvasculitis,butitisnotclearwhetheritcanbeusedtomonitorresponse

totherapy.

Treatment

• Initial medicaltreatment is withglucocorticoids (GCs) suchasprednisolone

40–60mgperdayinanaverage-sizedadult.

• Tapering GC dose is attempted when symptoms and laboratory tests of

inflammation subside. About one-half of all patients have steroid-resistant

disease. In this group, methotrexate (MTX), azathioprine (AZA),

mycophenolatemofetil(MMF),orleflunomide(LEF)maybetried.

• In severe forms of the disease, or if there is continuing evidence of disease

activity,cyclophosphamide(CYC)maybegiven.

• Experiencewithbiologicsislimited.Anti-TNFαagentsortocilizumab(anti-

IL6r)maybetriedinsevereorresistantcases.

• Hypertension can be difficult to manage, and may require angioplasty or

surgerytoaddressrenalarterystenosis.

• Surgicalmanagementrangesfromangioplastytobypassprocedures.Theseare

bestperformedduringtheinactivephaseofdisease.

• Angioplastyisoftenatemporizingmeasure,andlesionstendtorestenoseover

time.Restenosisislesslikelyfollowingbypassgrafting.Operativemortalityis

4%—mostlywithaneurysmrupture.

• The prognosis depends mainly on the presence of hypertension and aortic

incompetence.Themajorityofpatients(75%)willhavesomeimpairmentof

dailyliving,and50%arepermanentlydisabled.

• Mortalityislow,with5-yearand10-yearsurvivalratesreportedas80%and

90%,respectively.

• TAisnotacontraindicationtopregnancy.Cytotoxicagentsshouldbestopped

andGCskepttoaslowadoseaspossible.

• Obstetric decisions can be made on their own merits and not because of

coexistenceofTA.Themaincomplicationsareexacerbationofhypertension

andcongestivecardiacfailure.Theanaesthetistshouldbemadeawareofthe

diagnosis, as the patient may require invasive blood pressure monitoring

duringdelivery.

Polymyalgiarheumaticaandgiantcellarteritis

Polymyalgiarheumatica

Polymyalgiarheumatica(PMR)ischaracterizedbypainandstiffnessaffecting

structuresoftheshoulderandpelvicgirdleareas.Neckpainandstiffnessisalso

afeature.

Epidemiology

• PMRisrareinpatients<50yearsold.Themeanageofonsetis70years.

• Prevalence among patients older than 50 years is 1 in 133, and women are

affectedmorethanmen(ratio2:1).

• Thereisahigherfrequencyofdiagnosisinnorthernlatitudes.

Pathology

• Parainfluenza, parvovirus B19, Mycoplasma pneumonia, and Chlamydia

pneumoniae infections have been shown to have a temporal relation to

incidencepeaksofPMR,althoughotherstudieshavefoundnorelationship.

• HLA-DRB1

04and-DRB

01predictdiseasesusceptibility.

• PMR and GCA have a close clinical relationship. One-half of patients with

GCA have symptoms of PMR and up to 20% of patients with PMR have

histologicalorclinicalevidenceofGCA.

• Thepathogenesisofbothconditionsisnotknown.

Presentation

• ThediagnosisofPMRisbasedonclinicalfeatures.ThecriteriaofJonesand

Hazleman1981

aresuccinctandpractical(Box15.2).

• The European League Against Rheumatology (EULAR) and the ACR have

proposedclassificationcriteriatobeusedasaresearchtooltoidentifypatients

withPMR.

• EULAR/ACRcriteriainclude3requiredcriteriaand4pointsfromadditional

criteria:

• Required criteria include age ≥50 years, bilateral shoulder aching, and an

abnormalESRorCRP.

• Ascoringalgorithmwasdevelopedfortheadditionalcriteria,whichinclude

morningstiffness≥45minutes(2points);painorlimitedrangeofmotionat

hip(1point);absenceofRForanti-CCP(2points);absenceofperipheral

jointpain(1point).

• Theremaybeapparentmuscleweaknessontesting,whichisduetopainrather

thanintrinsicmuscledisease.

• Symptomsmaystartasymmetrically,butsoonbecomebilateral.

• Systemicfeaturesofmalaise,weightloss,low-gradefever,anddepressionare

common.

• Arthralgia and synovitis may occur. Up to 5% of patients with RA (see

Chapter5)haveaninitialPMR-likepresentation.

Investigation

• The lack of specific clinical features, a specific laboratory test, and the

presence of several conditions that can present with PMR-like symptoms,

makesPMRadiagnosisofexclusion(seeBox15.3).

Box15.2CriteriaforthediagnosisofPMR

Allthefollowingneedtobevalid/relevant:

1. Shoulder and pelvic girdle pain which is primarily muscular in the

absenceoftruemuscleweakness.

2. Morningstiffness.

3. Durationofatleast2months(unlesstreated).

4. ESR>30mm/hourorCRP>6mg/dL.

5. Absenceofinflammatoryarthritisormalignancy.

6. Absenceofmuscledisease.

7. Promptanddramaticresponsetoglucocorticoids.

CriteriafromJonesJG,HazlemanBL.TheprognosisandmanagementofPMR.AnnRheumDis

1981;40:1–5.

Box15.3ConditionsthatcanpresentwithPMR-typesymptoms

1. Rheumatoidarthritis

2. Inflammatorymyopathy

3. Hypo/hyperthyroidism

4. Myelomaorothermalignancy

5. Chronicsepsis

6. Bilateralshouldercapsulitis

7. Calciumpyrophosphatedepositiondisease

8. Spondyloarthritis/PsA

9. Inflammatoryphaseosteoarthritis

10. Parkinsonism.

Giantcellarteritis(GCA)

GCA is a granulomatous arteritis of the aorta and larger vessels, including

extracranialbranchesofthecarotidartery.Fordiagnosticcriteria,seeTable15.3.

Epidemiology

• GCA is the most common form of primary systemic vasculitis. In North

Americatheannualincidenceisestimatedat18per100,000.

• LikePMR,thefemaletomaleratiois2:1.

Pathology

• InfectiousandgeneticassociationsarealsosimilartoPMRwithevidenceof

disease‘clustering’.

• Increasing ageandethnicity arethemajor riskfactorsfor developingGCA.

GCAisrareamongAfricanAmericans.

Presentation

• Severeheadacheandscalptendernesslocalizedtotheocciputortemporalarea

arecommoninitial symptoms, andarepresent in 70%ofcases. The critical

featureoftheheadacheisthatitisnew.

• Headache is often localizedtothetemples, but may be frontal,occipital,or

generalized.

• Thetemporalarterycanbeswollen,tender,andpulseless.

• Jawclaudicationispresentinabouthalfofthepatients.Somepatientsreport

tongue claudication. Jaw claudication is strongly associated with a positive

biopsy.

• Scalpnecrosishasalsobeenreported.

• Large arteries are affected in 15% of cases, leading to claudication, bruits,

absentneckandarmpulses,andthoracicaortaaneurysmanddissection.

• Visualdisturbanceisusuallyanearlyfinding.Patientsmaydescribesymptoms

ofamaurosisfugaxbytemporary ‘curtaining’ofthevisualfield.Visual loss

dueto retinalischaemiamay beirreversiblewithin hours.Ahistory ofprior

transientvisuallossisthestrongestpredictorforsubsequentpermanentvisual

loss.

• Diplopiaandptosismayalsooccur.

• Fundoscopy may show optic disc pallor, haemorrhages, and exudates. Optic

atrophyisalatefinding.

• Arteriticanteriorischaemicopticneuropathyisthemostcommonfinding,and

mustbedifferentiatedfromnon-arteriticanteriorischaemicopticneuropathy,a

causeofvisuallossthatdoesnotrespondtosteroids.

• Malaise,fatigue,weightloss,fever,andanaemiaarecommon.

Investigation

• TheESRandCRParecharacteristicallyelevated,butcanbenormalinupto

3%ofcases.

• PatientssuspectedofhavingGCAshouldbeevaluatedwithbilateraltemporal

arterybiopsies,takingsegmentsof1.5cmeach.

• Treatment should not be delayed. Biopsies may be helpful to confirm the

diagnosisupto2weeksaftersteroidsarestarted.

• Unlike mostformsof vasculitis,GCA does notcausefibrinoid necrosisand

thepresenceoffibrinoidnecrosisonatemporalarterybiopsyshouldprompta

search for another form of vasculitis, such as GPA or cryoglobulinaemic

vasculitis.

• Temporal artery biopsies may be negative in 12% of patients. A negative

temporalarterybiopsydoesnotexcludeadiagnosisofGCA.

• DataregardingtheusefulnessofDopplerultrasoundforthediagnosisofGCA

aremixed.Variousabnormalitiesdescribedincludestenosis,occlusionandthe

presenceofahypoechoic‘halo’(halosign)aroundthetemporalarteries.

• ThesensitivityandspecificityofthehalosignforthediagnosisofGCAare

69%and82%,respectively.

• MRA is useful to diagnose GCA, identify regions of temporal artery

involvement,helpgaugediseaseactivity,andassessresponsetotreatment.

•

F-FDG-PET-CT may be useful in showing abnormal metabolic activity in

theaortaofmanypatientswithGCA(see Plate26).Directevaluationofthe

temporalarteriesisnotpossibleusing

F-FDG-PET-CT.

Table15.3DiagnosticcriteriaforGCA

Jonesand

Hazleman

Allthefollowing:

• Positivetemporalarterybiopsyorcranialarterytenderness.

(1981)

• One or more of: visual disturbance, headache, jaw pain,

cerebrovascular insufficiency; ESR >30 mm/hour or CRP >6

mg/L;responsetoglucocorticoids

ACR

criteria

Threeormoreof:

• Ageatonset>50years.

• Newheadache.

• Temporalarterytendernessordecreasedpulsation.

• ESR>50mm/hour.

• Abnormal artery biopsies showing necrotizing arteritis with

mononuclearinfiltrateorgranulomatousinflammationusually

withmultinucleatedgiantcells

InformationfromJonesJG,HazlemanBL.TheprognosisandmanagementofPMR.AnnRheumDis

1981;40:1–5andHunderGetal.TheAmericanCollegeofRheumatology1990criteriaforthe

classificationofthegiantcellarteritis.ArthritisRheum1990;33:1122–8.

TreatmentofPMRandGCA

• Both conditionsrequire GCtreatment;however, the amountand durationof

treatmentrequiredarequitedifferent.

3,4

• PMRrespondsdramaticallytolow–moderatedosesofGC(i.e.prednisone15–

20mgdaily)within24hours.

• Somepatientsrespondimmediatelytoprednisolone,andthevastmajorityof

patientshaveasubstantialimprovementwithindaysofstartingtreatment.

• ACR/EULAR suggest use of the minimum effective dose of prednisolone,

rangingfrom12.5–25mgprednisolone(orequivalent)perday.

• Lowerdosesof7.5–10mgprednisolonemaybesufficientinthosewithmild

symptoms.

• Persistent symptoms despitetreatmentmandate consideration ofanalternate

diagnosis.

• Aftertreatmentfor2–4weeks,theprednisonedosemaybedecreasedby2.5

mgevery2weeksuntilthepatientreachesamaintenancedoseof10mg/day.

Prednisonemaysubsequentlybetaperedin1mgpermonthincrements.

• GCArequirestreatmentwithhigh-doseGCs(i.e.prednisone40–60mgdaily)

andthepatientmaytakeaweekorlongertoexperiencesubstantialrelief.

• Treatment with GCs should be instituted once a diagnosis of GCA is

suspected,evenbeforeitisconfirmed.

• Aftertreatmentfor1month,prednisonemaybegraduallytaperedover9–12

months.

• In patients who have GC-resistant or GC-dependent disease, or develop

significant adverse effectswithtreatment,MTX may be added as a steroid-

sparingdrug.

• Ameta-analysis (of161 patients)showedthattheuseofMTXresultedin a

cumulativereductioninthesteroiddoseover48weeks.

• TocilizumabcanbeeffectiveasGC-sparing,asdemonstratedinasmalltrialof

30patientswithnewlydiagnosedorrelapsingGCA.

• SmalluncontrolledstudieshavesuggestedthatCYCmayalsobeconsidered

forthisindication.

• Patients with visual symptoms associated with GCA should be treated with

intravenouspulse methylprednisolonetherapy(1gdaily for3days)priorto

initiatingtherapywithprednisone.

• Daily low-dose (e.g. 75 mg) aspirin may prevent cranial ischaemic events,

such as stroke and blindness, and should be considered if there is no

contraindication.

• OsteoporoticfractureprotectionagainstGC-inducedosteoporosisisessential.

All patients with either GCA or PMR should be commenced at the time of

starting GCs,oneither a weekly oralbisphosphonateor IVzoledronicacid,

alongsidedailycalciumandvitaminDsupplements.

References

1. JonesJG,HazlemanBL.Theprognosisandmanagementofpolymyalgiarheumatica.AnnRheumDis

1981;40:1–5.

2. Dasgupta B. 2012provisional classificationcriteria for polymyalgia rheumatica: a European League

Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum

2012;64:943–54.

3. DasguptaB,BorgFA,HassanN,etal.BSRandBHPRguidelinesforthemanagementofpolymyalgia

rheumatica.Rheumatol(Oxf)2010;49:186–90.

4. DasguptaB,BorgFA,HassanN,etal.BSRandBHPRGuidelinesforthemanagementofgiantcell

arteritis.Rheumatol(Oxf)2010;49(8):1594–s7.

Polyarteritisnodosa

Polyarteritisnodosa(PAN)wasthefirstformofsystemicvasculitisdescribedin

the literature. It is characterized by a necrotizing vasculitis of medium-sized

arteries,whichcanleadtocutaneousulcers,kidneyinfarction,GIhaemorrhage,

andmononeuritismultiplex.

The CHCC created a distinction between ‘classic’ PAN (i.e. an ANCA-

negative, medium vessel vasculitis associated with renal infarcts) and

microscopic PAN (i.e. an ANCA-positive, medium vessel and small vessel

vasculitis characterized by glomerulonephritis). This re-classification (and the

hepatitisBvaccine)hasmadePANincreasinglyuncommon.

Aetiology

• SomecasesofPANhavebeenlinkedtoinfectionwithhepatitisB.

• PatientswithPANshouldbescreenedforviralhepatitis,asantiviraltherapy

maybeneededinadditiontoimmunosuppression.

Presentationandclinicalfeatures

• TheclinicalfeaturesareshowninTable15.4.

• Patientsoftenpresentwithnon-specificfeaturesofsystemicdiseaseincluding

myalgias,arthralgias,weightloss,andfever.

• About 50% of cases develop a vasculitic rash, which includes purpura,

nodules, livedo reticularis, bullous and vesicular lesions, ulcers, often with

‘punchedout’borderinthelowerextremities.

• GIinvolvementoccursin upto 50%ofcases.Non-specificabdominal pain,

gut/gallbladderinfarction,andpancreatitisareallfeatures.

• Renalinvolvementoccursinupto50%ofcasesintheformofrenalinfarct

andhypertension.Renalimpairmentisoftenmildandpresentinaround20%

ofcases.

• Mononeuritismultiplexoccursinupto70%ofpatients.

• Isolated organ involvement is rare, but disease affecting the skin, testes,

epididymis,breasts,uterus,appendix,andgallbladderhasbeenreported.

Treatment

• Treatmentandprognosisinallthesmallvesselandmediumvesselvasculitides

AREdiscussedattheendofthissection.

Table15.4Clinicalfeaturesatpresentation(as%ofcases)

Clinicalfeature PAN MPA EGPA

Renalimpairment 25% 90% 50%

Pulmonarydisease 40% 50% General50%,asthma100%

Fever 60% 40%

Skinvasculitis 40% 50% 50%

Gastrointestinaldisease 45% 20% 60%

Cardiovascular 15% 20% 45%

Peripheralneuropathy 10% 10% 60%

Ear,nose,andthroat 10% 20%

Oculardisease 10% 20%

ANCA-associatedvasculitides

Granulomatosiswithpolyangiitis(formerlyWegener’sgranulomatosis)

• Granulomatosis with polyangiitis (GPA) is the most prevalent of the AAVs.

Renal-limitedvasculitisanddrug-inducedAAVareless-commonmembersof

thisgroup.

• The CHCC has defined GPA as: ‘necrotizing granulomatous inflammation

usually involving the upper and lower respiratory tract, and necrotizing

vasculitis affecting predominantly small to medium vessels (e.g. capillaries,

venules, arterioles, arteries and veins). Necrotizing glomerulonephritis is

common.’

Epidemiology

• GPAisaworldwidediseasewithanincidenceof4–9permillion.

• Itisslightlymorecommoninmenthanwomen.

• Itmostoftenappearsinthefourthandfifthdecades.

Presentationandclinicalfeatures

• GPAisoftenaclinicaltriadwithmanifestationsaffectingtheupperrespiratory

tract,lowerrespiratorytract,andkidneys.

• Patientscanpresentwithawiderangeofclinicalmanifestations.

• Somepatientshaveanindolentpresentationcharacterizedbyrespiratorytract

involvement,suchassinusitisandpulmonarynodules.

• However,rapidlyprogressiveglomerulonephritisandpulmonaryhaemorrhage

canoccur(Box15.4).

Musculoskeletalsymptoms

• Rheumaticsymptomsareseenin60%ofcases.

• Symptomscanrangefrommildmyalgias(in50%ofthecases)andarthralgias

to overt arthritis. 20–30% of rheumatic symptoms may be related to a non-

erosiveandnon-deformingpolyarthropathy.

• MigratoryarthralgiasareaclassicpresentationforGPA.

Box15.4AmericanCollegeofRheumatology1990classificationcriteria

ofGPA*

Diagnosisrequirestwoormoreofthefollowing:

1. Nasal or oral inflammation: development of painful or painless oral

ulcersorpurulentorbloodynasaldischarge.

2. Abnormal chest radiograph: the chest radiograph may show nodules,

cavities,orinfiltrate.

3. Urinarysediment:microscopichaematuriaorredcellcasts.

4. Histologicalchangesofgranulomatousinflammationonbiopsy.

5. PR3-ANCA(C-ANCA)positivity.

*Thenknownas‘Wegener’sgranulomatosis’.

ReproducedfromLeavittetal.(1990),TheAmericanCollegeofRheumatology1990criteriaforthe

classificationofwegener’sgranulomatosis.Arthritis&Rheumatism,33:1101–1107withpermission

fromWiley.

Ear,nose,andthroatsymptoms

• Upto90%ofpatientshaveear,nose,andthroatinvolvement.

• ChronicsinusitisisacommoninitialpresentationforGPAandtypicallymany

patientswill havebeentreatedwithseveralcoursesof antibioticsbefore the

correctdiagnosisisreached.

• Othermanifestationsincludenasalseptalperforation,bloodynasaldischarge

(‘crusts’), and nasal bridge collapse due to erosion of underlying cartilage

(‘saddlenose’).

• Patientsmayalsocomplainofdiminishedhearing,eitherduetosensorineural

hearinglossorEustachiantubedysfunction.

• Subglottic stenosis is a classic feature of GPA and may present with

hoarsenessandstridor.Subglotticstenosismayworsenevenwhenapatientis

otherwiseinremission,andrespondsbettertosteroidinjectionsthansystemic

therapy.

• Intheoralcavityandoropharynx,inflammationcanleadtomucosalulcersor

gingivitis(‘strawberrygums’).

• It is thought that Staphylococcus aureus has a role in disease pathogenesis.

NasalcarriageinGPApatientsis3×thatofthehealthypopulation.Theexact

mechanismsleadingtodiseaseareunclear,buttrimethoprim/sulfamethoxazole

maybenefitpatientswithGPAbyeliminatingS.aureuscolonization.

Pulmonarydisease

• 80%ofcaseshavepulmonarydisease.

• The tracheobronchial tree may be locally involved before any signs of

generalizeddisease.

• Subglottic pseudo-tumours and/orstenosiscause stridor or dyspnoea.Lower

bronchialstenosismaycauseatelectasisandobstructivepneumonia.Multiple

nodules with or without cavitation are found in the lungs of asymptomatic

patients.

• Severepulmonarydiseaseisassociatedwithalveolarcapillaritis,haemorrhage

and haemoptysis, with infiltrates on CXR (typically an alveolar or mixed

alveolar–interstitial pattern; the distribution is often like that of pulmonary

oedemaandfocalinfection).

Renaldisease

• Upto90%ofpatientswith‘severe’GPAhaverenalinvolvement.

• Renal involvement can range from milder focal and segmental

glomerulonephritistofulminantdiffusenecrotizing(rapidlyprogressive) and

crescentic glomerulonephritis, which can rapidly lead to end-stage renal

disease.

• The milder form of the condition is most common, manifesting in the

asymptomaticpatientasanephriticpictureofmicroscopichaematuria,active

sediment,andmildrenalimpairment.

Skindisease

• 40%ofcaseshaveskindisease.

• Featuresincludepalpablepurpuraduetoaleucocytoclasticvasculitis,necrotic

papules (‘Churg–Strauss nodules’), livedo reticularis, and pyoderma

gangrenosum.

Nervoussystem

• About 30% of patients with GPA have involvement with mononeuritis

multiplexanddistalsensorimotor polyneuropathy themainlesions. Seizures

andcerebritisaremuchlessfrequentevents.

• Disseminated granulomatous lesions (‘pachymeningitis’) can involve the

retropharyngealareaandskullbaseaffectingcranialnervesI,II,III,VI,VII,

andVIII.Pachymeningitiscanalsobeassociatedwithdiabetesinsipidusand

meningitis.

Eyedisease

• Granulomatous lesionsmayobstruct thenasolacrimalduct and causeorbital

pseudotumour, with optic nervecompressionfrommasses developing in the

retrobulbarspace.

• Rarely a purulentsinusitismay spread andcausesecondary bacterial orbital

infection.

• ManifestationsinthegeneralizedstageofGPAincludeepiscleritis(redeye),

vasculitisoftheopticnerve,andocclusionofretinalarteries,inadditiontothe

granulomatouslesionsdescribedearlier.

Investigation

(See Table4.3,p.214forlaboratoryteststoconsider.)

• A biopsy should be done in patients with suspected AAV to confirm the

diagnosis. In some patients, biopsy is not feasible and so a presumptive

diagnosisismadeontheclinicalfeaturesandANCA.

• Laboratory investigation should include FBC with differential, routine

chemistry,ESR,CRP,andurinalysistolookforactivesediment.

• ApositiveANCAstronglysuggeststhediagnosisofvasculitis;however,false-

positiveandfalse-negativeresultsareseen.

• About 82% of patients with GPA have a positive ANCA. This is usually

specificforproteinase-3.

• 10%ofGPAcasesareANCAnegative.AnegativeANCAdoesnotexclude

thediagnosis.

• CXR and HRCT chest should be considered in all cases as the chance of

pulmonarylesionsishighdespitesometimesfewsymptoms.

Treatment

• TreatmentandprognosisofGPAisdiscussedlaterinthissectionwiththeother

AAVs.

ANCA-associatedvasculitides:microscopicpolyangiitis

• MPAisclassifiedasapulmonary-renal(haemorrhage)syndrome,agroupthat

also includes Goodpasture’s disease and SLE. GPA may also occasionally

presentasapulmonary-renalsyndrome.

• MPA lacks the granulomatous manifestations characteristic of GPA, such as

sinusdiseaseandpulmonarynodules.

• Unlike GPA, MPA is characterized by MPO-ANCA antibodies, which are

associated with a P-ANCA immunofluorescence pattern. Up to 80% of

patientswithMPAwillbeANCApositive.

• LikePAN,themaletofemaleratiois2:1,withthemajorityofpatientsbeing

Caucasian.Themeanageofpresentationis50years.

• MostpatientswithMPAwillpresentwithrenalinvolvementintheformofa

necrotizingglomerulonephritis,similartowhatcanbeseenwithGPA.Unlike

mostformsofvasculitis,glomerulonephritisfromAAVis‘pauci-immune’(i.e.

there is only minimal immunoglobulin deposition on immunofluorescence

stains).

• Pulmonary haemorrhage presents as haemoptysis, and can be surprisingly

subtle in some patients. Bronchoscopy with bronchoalveolar lavage will

demonstratehaemosiderin-ladenmacrophages.Chronicpulmonarycapillaritis

mayeventuallyleadtopulmonaryfibrosis.

• OtherclinicalfeaturesofthediseaseareshowninTable15.4.

ANCA-associatedvasculitides:eosinophilicgranulomatosiswith

polyangiitis(EGPA/formerlyChurg–Strausssyndrome)

• EGPAisoftendescribedasaclinicaltriadofadult-onsetasthma,eosinophilia,

andvasculitis.

• Typically,theasthmagraduallyworsensinintensityuntilthepatientrequires

dailyoralsteroidsforsymptomcontrol.Manyofthesepatientswillhavebeen

treated with a leukotriene inhibitor (although leukotriene inhibitors do not

causethedisease).

• Peripheral blood hyper-eosinophilia is typically mild and resolves quickly

upontreatmentwithoralsteroids.

• Other manifestations of hyper-eosinophilia include ‘fleeting’ pulmonary

infiltrates, myocarditis, and interstitial nephritis; frank glomerulonephritis is

muchlesscommoninthisdiagnosis.

• Nerve involvement is a common manifestation of vasculitis among patients

with EGPA, and patients should be examined for evidence of a sensory

neuropathyormononeuritismultiplex.

• Cutaneous granulomata that form along the elbows and fingers are called

‘Churg–Strauss nodules’. Ironically, they appear more commonly in

associationwithGPA.

• Cardiac involvement is one of the more serious manifestations of EGPA,

accountingforapproximatelyhalfofalldeathsinpatientswithEGPA.Clinical

manifestationsincludearrhythmias,pericarditis,andheartfailure.

• Treatmentandprognosisinallthesmallvesselandmediumvesselvasculitides

arediscussedattheendofthissection.

ThetreatmentofANCA-associatedvasculitides

• Assessment of disease activity in GPA or MPA is usually done using the

BVAS.

• BVASrangesfrom0to68;withascoreof0indicatingremission.

• AAVaremanagedwithtreatmentaimingtoprovideremissioninductionand

thenremissionmaintenance.

• Currenttreatmentchoicesarebasedonclassifyingpatientsashaving‘severe

generalized disease or poor prognosis’ versus ‘localized, early systemic

diseaseorgoodprognosis’.

• InitialimmunosuppressivetherapyconsistsofGCsincombinationwitheither

CYCorrituximab(RTX).MTXwithGCscanbeusedinpatientswithmild
extrarenaldisease.
• Inaselectgroup,thosewhopresentwithseveredisease,plasmaexchangemay
betried.
SeveregeneralizedGPAandMPA
• TheNationalInstitutesofHealthregimenconsistedof1yearoforalCYC(2
mg/kg daily) with prednisolone (1 mg/kg daily tapered over 6–12 months).
ThishasbeenmodifiedinthelastdecadetominimizeexposuretoCYCand
GCs.
• Theinductionphaseconsistsof3–6monthsofCYC,followedbyeitherAZA
(CYCAZAREMtrial)
5
orMTX(WEGENTtrial)
6
tomaintainremission.
• MMF was found to be inferior compared to AZA in a randomized trial
(IMPROVEtrial).
7
• IVIgleflunomideandcalcineurininhibitorshavebeenusedinasmallnumber
ofpatients,butdatatoaccesstheirefficacyisinsufficient.
• Etanerceptwasfoundtobeineffectiveinmaintainingremissioninaplacebo-
controlledtrial(WGETtrial).
8
• Theoptimallengthofmaintenancetherapyisunclearbutcontinuationfor12–
18monthsafterremissionisreasonableasthemajorityofpatientsflareafter
therapyisdiscontinued.
• The CYCLOPS trial compared daily oral to IV pulse CYC.
9
Bothregimens
resultedinsimilarratesofremission.Extendedfollow-upforadurationof4.3
yearsshowedcomparablesurvivalratesofabout80%,andsimilarsideeffect
profile.However,relapsesweremorecommonwithpulsetherapy.
• RTXhasdemonstratedefficacyandshort-termsafetycomparabletoCYCand
AZA.
• In the RAVE trial, 64% of patients who received RTX for 6 months
discontinuedprednisolonecomparedto53%whohadCYC.
10
RTXwasmore
efficacious compared with CYC in those who had relapsing disease at
baseline.
• At 12 months, 42% of patients in the RTX arm remained in remission
comparedwith38%intheCYCarm.
• IntheRITUXIVAStrial,about90%ofpatientsattainedremissioninboththe
RTXandCYCarms,and90%and85%respectivelyremainedrelapsefreeat
12months.
11
• RTX may be preferable to CYC for induction of remission in patients with
concernsaboutfertilityorthosewithahighriskofmalignancy.

LocalizedandearlygeneralizedGPAandMPA

• Disease may respond to a combination of MTX and prednisolone. In the

NORAMtrial,

whichcomparedMTXwithCYC,remissionat6monthswas

achievedinabout90%ofpatientsinbothtreatmentarms.Butrelapsesafter

drugdiscontinuationweresignificantlyhigherinthosegivenMTX.

• Trimethoprim-sulfamethoxazole may decrease the risk of relapse in patients

withlocalizeddisease.

Othertreatments

• Plasma exchangehasbeen used with someeffectinthose with severerenal

disease,althoughthebenefitistransient.

• IVIg has a short-lived benefit, but may be used in patients at high risk of

systemicinfection.

• Treatmentofavasculitis associatedwith aninfectiousdisease(e.g.hepatitis

B-associatedPAN,hepatitisC-associatedcryoglobulinaemicvasculitis)should

includetreatmentofthepathogen.

• There is evidence that respiratory tract infections may trigger a relapse of

GPA. Trimethoprim-sulfamethoxazole in patients with stable disease on

maintenancetherapymaydecreaserespiratoryinfection,andisalsousefulfor

preventionofpneumocystisamongpatientstreatedwithCYC.

EGPA

• Patientswithoutpoorprognosticfactors(FFS=0)achieveremissionwithGCs

alone in >90% of cases. Although about a third may relapse, the long-term

prognosisisexcellent.

• Inpatientswithpoorprognosticfactors(FFS≥1)IVCYCpulsesareeffective.

Flares are frequent on CYC discontinuation. Extrapolating results from

GPA/MPAtrials,AZAmaybeusedformaintainingremission.

• Successful treatment with RTX has been described in case series and case

reports.

• Mepolizumab, an anti-IL5 monoclonal antibody, has demonstrated

encouragingresultsinpilottrials.

PrognosisofANCA-associatedvasculitides

• Prior to the introduction of CYC and GCs, mortality associated with AAV

approached 100%. Modern immunosuppressive regimens have transformed

thesediseasesintochronicconditions,characterizedbycyclesofrelapseand

remission.

• For many patients, the consequences of treatment (such as GC-associated

complications) may lead to greater morbidity than the underlying disease

itself.

• Mortality due to infection continues to be an important consideration for

patients treated for AAV; indeed, patients with ‘treatment-resistant’ AAV

shouldbe carefullyevaluatedforthepresenceofNocardia,Aspergillus, and

otherinfectionsthatcanmimicsomeofthemanifestationsoftheAAV.

References

5. JayneD,Rasmussen N, AndrassyK, etal. A randomized trialof maintenancetherapy for vasculitis

associatedwithantineutrophilcytoplasmicautoantibodies.NEnglJMed2003;349:36–44.

6. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-

associatedvasculitis.NEnglJMed2008;359:2790–803.

7. Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine for remission

maintenanceinantineutrophilcytoplasmicantibody-associatedvasculitis:arandomizedcontrolledtrial.

JAMA2010;304:2381–8.

8. Wegener'sGranulomatosisEtanerceptTrial(WGET)ResearchGroup.Etanerceptplusstandardtherapy

forWegener'sgranulomatosis.NEnglJMed2005;352:351–61.

9. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of

remissioninantineutrophilcytoplasmicantibody-associatedvasculitis:arandomizedtrial.AnnIntern

Med2009;150:670–80.

10. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated

vasculitis.NEnglJMed2010;363:221–32.

11. JonesRB,TervaertJW,HauserT,etal.RituximabversuscyclophosphamideinANCA-associatedrenal

vasculitis.NEnglJMed2010;363:211–20.

12. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus

methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-

associatedvasculitis.Rheum2005;52:2461–9.

Smallvesselvasculitis

The definition of small vessel vasculitis is open to different interpretations.

Small vessel disease can be one feature of GPA, MPA, and EGPA. However,

therearearangeofclinicalandpathologicalfeaturesthatdefineaspecificgroup

ofsmallvesselvasculitidesoutlinedinTable15.5.Seealso Table4.3,p.214

foradviceonlaboratoryinvestigation.

Leucocytoclasticvasculitis

• Histologically,leucocytoclasticvasculitisappearsasaneutrophilinfiltrationin

and around small vessels, with fragmentation of the neutrophils

(leucocytoclasis), fibrin deposition, and endothelial cell necrosis. Immune

complexdepositionappearstobeimportantinpathogenesis.

• Small vessel vasculitis usually presents in the skin, although the

microvasculatureofanytissuemaybeaffected.

• Some forms ofcutaneousvasculitis are predominantly lymphocytic,without

evidence of neutrophils or leucocytoclasis. However, the division into

leucocytoclastic and non-leucocytoclastic (lymphocytic) vasculitis is not

absolute.Likewise,theclinicalpresentationofcutaneousvasculitiscanvary

considerably.

• The finding of leucocytoclasis should prompt a thorough review of drug

treatment (e.g. sulfonamides, penicillin, thiazides), a search for infection

(hepatitis B, HIV, β-haemolytic streptococcus), a screen for autoimmune

rheumaticdisease, malignancy(in particularmyelo- andlymphoproliferative

diseases), inflammatory bowel disease, chronic active hepatitis, and

cryoglobulinaemia(seelater).

Allergic(hypersensitivity)vasculitis

(Seealso Table4.2,p.212.)

• Allergicvasculitisisthemostcommonpatternofpresentationinadults,both

sexesbeingaffectedequally.

• Non-blanching haemorrhagic papules (palpable purpura), purpuric macules,

plaques, pustules, bullae, and ulcers may occur, classically distributed

maximallyoverthelowerleg.

• A low-grade fever, arthralgias, and microscopic haematuria may accompany

suchpresentation.

• Oftentheconditionisself-limitingandidentifiablecausesshouldbemanaged

as appropriate. Analgesia may be needed and systemic steroids may be

requiredforacuteorgandisease,especiallyprogressiverenalimpairment.

• AZAmaybeappropriateforrefractorydiseasebutremovaloftheoffending

drugorexposureisthemosteffectivetreatmentstrategy.

Table15.5Conditionsassociatedwithsmallvesselvasculitis

Leucocytoclastic

vasculitis

Allergicvasculitis(hypersensitivityangiitis):drugs,

infection,inflammation,autoimmunedisease,malignancy,

Henoch–Schönleinpurpura

Urticarialvasculitis(hypocomplementaemicvasculitis)

Cryoglobulinaemia

Hypergammaglobulinaemia

Erythemaelevatumdiutinumandgranuloma

faciale

Non-

Drugs(penicillins,thiazides)

leucocytoclastic

vasculitis

(lymphocytic

vasculitis)

Nodularvasculitis(see ‘Panniculitis’,p.560)

Livedoidvasculitis

Pityriasislichenoides

Henöch–Schönleinpurpura(HSP;IgAvasculitis)

• HSPoccursmostofteninchildren(see ‘Childhood-onsetvasculitides’,pp.

474–481),butcanaffectadultsofanyage.IgAisusuallydetectedinskin,gut,

orrenalbiopsies.

• The classic presentation is with purpura, and in adults: arthritis (50%),

haemorrhagicGIdisease(40%),andglomerulonephritis(50%).

• GCs given early may relieve joint and GI symptoms, but there is little

evidence that they prevent progression of renal disease or influence overall

outcome.

• If renal function is rapidly deteriorating, pulsed methylprednisolone and/or

plasmapheresismaybeofbenefit.

• Patientswhopresentwithanephriticornephroticsyndromehaveanincreased

lifetimeprevalenceofrenalcomplications,includinghypertension.

• Although most cases are self-limited, HSP can (rarely) become a chronic,

relapsing disease. Such patients should be evaluated for the presence of a

monoclonalIgAantibody,whichmayheraldapre-malignantlesion.

Urticarialvasculitis

• Urticarial lesions with arthralgias are the most common features of this

condition,withmenoutnumberingwomenby2:1.Thetypicalageofonsetis

40–50years.

• Morphologically, theskinlesions resembleordinary urticariaandsometimes

maybemistakenforerythemamultiforme.

• Unlikeordinaryurticaria,urticarialvasculitistendstolastfordays(nothours)

andtendtobeburningandpainful(notpruritic).

• Patientswithhypocomplementaemicurticarialvasculitistendtodevelopmore

systemic features such as renal, GI, and pulmonary disease. Less common

manifestations include lymphadenopathy, uveitis, and benign intracranial

hypertension.

• Systemic antihistamines are widely used, but their effects tend to be

disappointing.

• Thereareanecdotalreportsofsuccesswithindometacin,hydroxychloroquine

(HCQ), colchicine, ciclosporin, and dapsone. AZA may be particularly

effective.

• For the majority of patients, the condition is chronic and benign. For those

withend-organdamage,chronicimmunosuppressionmaybenecessary.

Cryoglobulinaemicvasculitis

• Cryoglobulins are immunoglobulins that precipitate when cold. They are

dividedintothreetypes:typeI(monoclonal),typeII(mixedmonoclonaland

polyclonal),andtypeIII(polyclonal).

• Mixed cryoglobulins are associated with autoimmune rheumatic diseases,

infection,andlymphoproliferativedisorders.HepatitisBandCviralinfection

shouldalwaysbeexcluded;thelatterinparticularisstronglyassociatedwith

mixedessentialcryoglobulinaemia.

• Mixed essential cryoglobulinaemia presents with purpuric skin lesions

showing a leucocytoclastic vasculitis on biopsy; polyarthralgias (70%),

weakness, progressive renal disease (55%), and transaminitis (70%) are

common.

• Womenareaffectedtwiceasfrequentlyasmen.

• Lesscommonproblemsincludeoedema,hypertension,legulcers,Raynaud’s

disease, abdominal pain, neuropathy, and susceptibility to bacterial

pneumonia.

• Theprognosisisworsewithrenaldisease.

• The main causes of death among patients with cryoglobulinaemia include

renalfailureandinfection.

• Treatmentrequiresmanagementoftheunderlyingcause;immunosuppression

byitselfisfrequentlyunsatisfactory.

• Choice of immunosuppression should be dictated by the disease

manifestations;themostsevereformsmayrequiretreatmentwithCYC,pulse

steroids,andplasmapheresis.

Hypergammaglobulinaemicpurpura

• This is a rare, benign IgM condition presenting as long-standing

leucocytoclastic purpura similar to the cutaneous features of Sjögren’s

syndrome(see Chapter12).

• It should not be confused with Waldenström’s macroglobulinaemia, a

monoclonalIgMparaproteinaemiaassociatedwithlymphoma.

Erythemaelevatumdiutinumandgranulomafaciale

• These are rare distinctive forms of chronic localized leucocytoclastic

vasculitis.Therearenosystemiceffectsandtheaetiologyisunknown.

• Erythema elevatum diutinum (EED) is characterized by slowly enlarging

oedematous purplish-brown plaques or blisters over the backs of the hands,

elbows, or knees. They heal very slowly (months to years) with fibrosis. It

mayrespondtodapsone.

• Granuloma faciale (GF) presents as single or multiple pink-brown, well-

defined,smoothpapulesandplaquesontheface.Theypersistforyears.Itis

distinguished histologically from EED by the presence of eosinophils and a

normal collagen beneath the epidermis. It may respond to intralesional

steroids.

Non-leucocytoclastic(lymphocytic)vasculitides

• Thedifferentialdiagnosisofnodularformsofcutaneousvasculitisembracesa

wide range of disorders, including the panniculitides (see Chapter 18 and

Chapter4,p.206).

• Nodular vasculitis is regarded as a distinct group characterized by recurrent

subcutaneous nodules. Patients are otherwise healthy though it may be

associatedwithstreptococcalinfection.

• Bazin’s disease is sometimes used to describe the nodular vasculitis that

occurs in tuberculosis. The condition resolves spontaneously, but may take

manyyears.Intralesionaltriamcinolonemayhelp.

• Livedoid vasculitis is characterized histologically by endothelial cell

proliferationandintraluminalthrombosisleadingtoischaemia.

• Livedoid vasculitis has been attributed to defects in the tissue plasminogen

activator (tPA) gene, although similar lesions can be seen in the

antiphospholipid syndrome. The lesions heal with white atrophic scar

(‘atrophieblanche’).

• Pityriasislichenoidesisanuncommondisorderofpinkpapules,whichenlarge

rapidly and may become haemorrhagic before becoming necrotic and heal

with scarring. It is usually self-limiting and may respond to ultraviolet B

irradiation.

Childhood-onsetvasculitides

• The primary vasculitides in children are rare but life-threatening conditions.

ThecommonestareKawasakidisease(KD)andtheacuteusuallyself-limiting

Henoch–Schönleinpurpura(HSP).

• Suspicion of the chronic vasculitides (Table 15.6) arises in the presence of

fever(oftenlowgrade),weightloss,rash,andmultisystemclinicalfeatures.

• Asinadults,perivascularinflammationoccursandthesiteandsizeofaffected

vesselsinfluencesthespectrumofpresentation.

• Ahistoryshouldbetakenofinfection,immunizations,familyhistoryanddrug

exposure.

• The first paediatric specific classification of vasculitis by EULAR and the

PediatricRheumatologyEuropeanSociety(PRES)wasdevelopedin2005and

validatedin2010.

Table15.6Childhood-onsetvasculitides

Predominantlylargevessel Takayasuarteritis

Predominantlymedium-sizedvessel Kawasakidisease

SystemicPAN

Cutaneouspolyarteritis

Predominantlysmallvessel Non-granulomatous:

HSP,leucocytoclastic,MPA,

urticarialvasculitis

Granulomatous:

GPA/Wegener’s;EGPA/Churg–

Strauss

Variablesizedvesselinvolvement Behçet’sdisease

Childhoodprimaryangiitisof

theCNS

Cogan’ssyndrome

Associatedwithsystemicdiseasesor

clearaetiologicfactors

Relapsingpolychondritis

Cryoglobulinaemia(/hepatitisC)

Malignancies

Autoimmuneconnectivetissue

diseasesDrugs

Epidemiologyofchildhoodvasculitis

Theincidenceandprevalenceofchildhood-onsetvasculitidesarenotaccurately

describedandvarydependingonthepopulationstudied.

• TheprevalenceofHSPis3–20per100,000ofthegeneralpopulation,andof

KDis9–32per100,000ofthepopulationintheUSAand134per100,000of

thepopulationinJapan.

• The other childhood-onset vasculitides occur in 1–10 per million of the

population.

Kawasakidisease

• KD is the leading cause of childhood acquired heart disease in developed

countries and includes coronary artery aneurysms (in 15–25% of untreated

cases)whichoftenappearlate.

• Pericarditis,myocarditis,andmyocardialinfarctionmayoccur.

• WithrapiddetectionandIVIgtreatment,aneurysmsoccurinlessthan5–10%

ofpatientsandmortalityisreducedfrom3–4%to<1%.

• The burden of adult cardiovascular disease and premature atherosclerosis is

thesubjectofongoingresearch.

Epidemiologyandpathogenesis

• TheannualUKincidenceofKDis5–8per100,000ofthepopulation,witha

peakincidenceinchildrenaged1–2years (0–5years typically),differingto

Japanwithapeakat6–12monthsofage.

• 5–10%ofKDcasesoccurinchildrenaged5–10years.

• Theaetiologyisunknown.Pronouncedseasonalityandclusteringsuggestsan

infectiousorenvironmentaltriggeringeneticallysusceptibleindividuals.

• Recentepidemicshavebeenlinkedtolarge-scaletroposphericwindcurrents

originatingincentralAsia.

Presentation

• Diagnosticcriteriarequireahighspikingfever(usually≥40°C)for≥5days;

plus≥4ofthefollowing(allcriteriaarenotrequiredatonetime):

• Widespreadpolymorphicerythematousrash.

• Bilateralconjunctivalinjectionorcongestion.

• Reddening of the palms and soles, indurative oedema, and subsequent

desquamation(Beaulinesareseeninretrospect).

• Reddening/cracking of lips, strawberry tongue, oral and pharyngeal

injection.

• Acute,usuallysingle(>1.5cm),non-purulentcervicallymphadenopathy.

• Fevermayoccurabruptlybutthereisaprodromeincludingcoryza,abdominal

pain,diarrhoea,vomiting,andarthralgia.

• Irritabilityisconsidereduniversal.

• KDisalsodiagnosedwhenthereare<5featureswithcoronaryaneurysmor

dilatationorinaninfantwithpronouncedirritability.

• Incomplete KD is diagnosed in patients with a fever and fewer than 4

additionalfeaturessothattheyreceiveIVIgbefore10daysfromfeveronset.

Thisismostcommonininfants.

• Atypical KD is diagnosed in children older than 9 years, younger than 6

months,andwhenthereareadditionalinflammatoryfeatures.

• Other features include induration or redness at the BCG inoculation site;

arthritis, uveitis, aseptic meningitis, pneumonitis, intestinal obstruction,

hydrops of the gallbladder and jaundice, encephalopathy, macrophage

activationsyndrome,andSIADH.

• Persisting additional features should raise the possibility of alternative

diagnoses.Coronaryectasiacanoccurinotherconditionsincludingsystemic

onsetJIA,TA,andPAN.

Investigations

• Echocardiographyshouldbedoneatdiagnosis,2weeks,and6–8weeksafter

disease onset to detect myocardial inflammation and coronary aneurysmal

formation.

• ECGwillshowconductiondefects.

• There are no diagnostic blood tests but marked thrombocytosis may alert

clinicianstoKD.

• Viral serology (IgG and IgM) for mycoplasma pneumonia, enterovirus,

adenovirus,measles,parvovirus,Epstein–Barrvirus,andcytomegaloviruscan

bepositive.

Treatment

Thereductioninriskoflong-termcardiacdiseaseisbestachievedwithIVIgand

aspirinstartedwithin10daysofonsetoffever.

• IVIgreducestheriskofcoronaryarteryaneurysmformationfromabout20%

to6%.

• IVIg(2g/kg)isadministeredover10–12hours,exceptininfantswithcardiac

failurewhenthedoseissplitover2–4days.

• If the fever recurs or persists 36 hours after initial IVIg, a second dose is

given.

• Although the evidence supports early use of IVIg, it may be given after 10

daysofillness.

• Aspirinisinitiallygivenatadoseof80–100mg/kg/day,andreducedto2–5

mg/kg/daywhenthefeverhassettled(lowdose).

• Low-dose aspirin can be continued for a minimum of 6 weeks. It is then

stopped if echocardiography is normal or when aneurysms have returned to

normal.

• However,thereisdebateovertheuseofaspirinasRCTdataarenotavailable,

andthepositiveconsiderationsofitsusemustbebalancedagainsttheriskof

Reyesyndrome.

• Clopidogrel or dipyridamole may be temporarily substituted for aspirin in

patients who develop influenza or varicella. Warfarin is substituted in the

presenceofgiantaneurysms(>8mm).

• FeverthatrecursaftertwodosesofIVIgistermedIVIgresistanceandoccurs

in10–20%ofcases.Itisassociatedwithanincreasedriskofaneurysm.

• IVIg resistance is often treated with IV methylprednisolone 30 mg/kg

(maximum1g)for1–3daysfollowedbyoralprednisolone(1–2mg/kgdaily)

thenwithgradualdosereduction.

• Alternatively,infliximab(5mg/kg)isassociatedwithfewerdaysoffeverand

hospitalization compared to a second dose of IVIg, but a reduced rate

aneurysmformationhasnotyetbeendefined.

Henoch–Schönleinpurpura

• HSPisthemostcommonsystemicvasculitisinchildhood.

• HSP is a small vessel, non-granulomatous IgA leucocytoclastic vasculitis of

unknownaetiology.

• HSP is generally a benign, self-limiting disease with most patients

experiencingafullresolutionwithin8weeks(<5%ofpatientsdevelopchronic

symptoms).

• One-thirdofchildrenhavesymptomsforuptoafortnight,andanotherthird

foruptoa1month.

• Recurrentdiseaseoccursin50%within6weeks.

• HSPnephritisaccountsforupto3%ofallchildhoodcasesofend-stagerenal

failure(ESRF)intheUK.

Epidemiology

• UK incidence is 20 per 100,000 of the general population per year

(0.8/100,000inadults).

• 75%occursattheageof2–11years,andisrareininfancy.

• HSP is most prevalent during the winter and spring, and associations have

been considered with infectious disease such as group A streptococci,

hepatitis,CMV,HSV,humanparvovirusB19,coxsackievirus,adenovirus,and

somevaccinations.

Presentationandclinicalfeatures

• HSPhasacharacteristicpurpuricrash(in95%atpresentation)affectingbacks

ofthelegs,buttocks,andarms,andinchildrenneedstobedistinguishedfrom

meningococcalsepticaemia, acutehaemorrhagic oedemaof infancy, immune

thrombocytopenic purpura, acute post-streptococcal glomerulonephritis,

haemolytic-uraemicsyndrome.

• Purpurararelyinvolvestrunkorface.Urticaria,angio-oedema,deepbruising,

ornecroticappearancesmayalsooccur.

• Abdominalpainmayprecedetherashby2weeksandmaybeassociatedwith

vomiting,haematemesis,andmelena.

• GI complications are rare but include intussusception, appendicitis,

cholecystitis,pancreatitis,ulceration,infarction,andperforation.

• Arthralgiaorarthritis(47%ofcases),typicallyofthekneesandankles,tends

tobeself-limiting.

• Nephritisaffects25–60%ofpatients.

• However,<5%ofcasesprogresstoCKD,andonly1–2%toESRF(20%of

childrenwithrenaldiseaseandover10–25years).

• Renalprognosisisbestinchildren<7years.

• Renaldiseaseoccursin97%ofchildrenwithin3monthsofdiseaseonsetbut

generally <10% of patients require renal biopsy (usually for persisting

haematuriaandnephropathy).

• Rare manifestations include orchitis, pulmonary haemorrhage, and cerebral

vasculitis.

Treatmentandmonitoring

• NotreatmenthasbeenshowntoshortenthedurationofHSPorsignificantly

improvelong-termrenaloutcome.

• Treatmentisprimarilysymptomatic(rest,analgesia,andhydration).

• Admission can be helpful where there is severe abdominal pain, GI

haemorrhageandrenalfailureandoccasionallyforarthritis.

• Glucocorticoids (GCs) are used for symptomatic improvement and severe

facialorscrotaloedema.Prednisolonedoseisadjustedaccordingtoresponse

and typically started at 1 mg/kg/day orally for 5 days. If higher doses or

methylprednisoloneareused,tertiarycentreinputisrecommended.

• GCs are also used for persisting renal disease and where there are >50%

crescenticglomerularinvolvementonrenalbiopsy.

• Severe renal involvement may require GC-sparing immunosuppression,

antiproteinuric,andantihypertensiveagents.

• Monitoring of the condition should be weekly for the first month, alternate

weeks for 1 month and then monthly—the frequency increasing with renal

involvement.

• Monthlyurinalysisscreeningisrecommendedupto6months.

Leucocytoclasticvasculitis

Leucocytoclasticvasculitisisacommonsmallvesselvasculitisinchildrenand

presents as palpable purpura often with urticaria, vesicles, bullae, or pustules,

butnotitch,pain,orburning.

Presentationandclinicalfeatures

• Internalinvolvementmayincludejoints,GIsystem,andrenalsystem.

• About 50% of cases may be idiopathic, 10–15% secondary to autoimmune

disease (e.g. RA, SLE, IBD),about5%areassociatedwithmalignancy and

other cases attributed to medications or herbal remedies, food additives, or

primarilyunderlyinginfection.

• ~10%ofpatientshavechronicorrecurrentdisease.

• Erythemaelevatumdiutinumandgranulomafacialeareraredistinctiveforms

ofdisease(withpink/purple-brownwell-definedlesions).

Investigations

(Seealso Table4.2,p.212andTable4.3,p.214.)

• Investigations are for underlying infections (group A streptococci, viral

hepatitis,andHIV),autoimmunityormalignancy.

• Measure total haemolytic complement (CH50 or CH100), C3, C4, anti-C1q

antibodiesifurticarialvasculitisisbeingconsideredandcryoglobulinsifthere

isasuggestionofprevioushepatitisC.

• Consider askinbiopsy ifthere ismultisysteminvolvementandappearances

arenottypicalofHSP.

Treatment

• Treatunderlyingconditionsandwithdrawsuspiciousmedications

• TreatmentofprimarydiseaseincludesGCs,colchicine,HCQ,dapsone,AZA,

orMTX.

• RTXhasbeenshowntobemoreeffectivethanCYCforthosewithsystemic

involvement.

Cutaneouspolyarteritisnodosa

CutaneousPANisapaediatricconditionthatrunsabenigncourse,overmonths

toyears,distinctfromsystemicpolyarteritisnodosa.

Presentationandclinicalfeatures

• Arthralgias, myalgias, and neuralgia may occur, but there is invariably no

internalorgandamage.

• Distinct from a leucocytoclastic vasculitis, cutaneous PAN results in larger

inflammatoryplaques,tenderlumpsanderythemanodosum(orotherformsof

panniculitis),ulceration.

• Infarcts attributable to medium vessel and pan-arteritis involvement. Post-

inflammatorypigmentationmayoccur.

• TriggersincludeStreptococcusA,hepatitisBandC,HIV,andparvovirusB19.

Investigations

• Skinbiopsyshouldconfirmthediagnosis.Seealso Table4.3,pp.213–214.

Treatment

• Prednisolone is considered the mainstay of treatment, although there are no

RCTsforglucocorticoids,colchicine,IVIg,orMTX.

• PenicillinisgivenforStrepAinfection.

• Symptomatictreatmentisoftenrequiredforpainandulcers.

(Systemic)Polyarteritisnodosa

• PANisthethirdmostcommonvasculitisinchildrenandadolescents.

• Childhood PAN is now more common than PAN in adults since the

introductionofhepatitisBvaccine.

• PANhasanincidenceof3–7per100,000peryear.

• PAN characterized by a necrotizing vasculitis of medium-sized arteries,

aneurysmal formation, thrombi, ischaemia, and infarction. It spares the

smallestvesselsandvenules.

Presentationandclinicalfeatures

• PANshouldbeconsideredinpatientswithmalaise,fever,weightloss(>5%),

myalgia,arthropathy,and:

• vasculiticrash(especiallyonthelegs,palms,orsoles).

• mono/polyneuropathy(puresensoryormotorormixed).

• testiculartendernessorpain.

• muscletendernessorfocalweakness.

• PANisusuallyidiopathic,butmaybesecondarytoviralhepatitis.

• Permanent morbidity is relatively rare but relapses occur in 35–50% over a

meanof6years.

• Mortalityis4%over5yearsimprovedfrom87%withouttreatment.

• Complicationscaninclude:

• ulcerationsandgangrene.

• stroke,encephalopathy,myelopathy,andneuropathy.

• pericarditis,coronaryaneurysms,MI,andheartfailure.

• GIbleedingandinfarction.

• renalfailure.

• However,lungsarerarelyaffected.

Investigations

• Routine haematology, ESR, CRP, liver and renal biochemistry, CK, and

hepatitisserologyshouldbechecked.Seealso Table4.3,p.214.

• Conventional renal and mesenteric angiography shows aneurysms and

stenoses(notgenerallyshownbyCTorMRIangiography).

• ConsiderEMG,suralnerve,andmuscle(e.g.vastuslateralis)biopsy.

• Biopsy ofnodules anddeepdermalulcermarginsmaybehelpful; however,

renalbiopsyisunhelpfulandoftenassociatedwithpostoperativebleedingand

fistulae.

• Other features include hypertension, retinal vasculitis, unexplained

tachycardia, psychiatric symptoms, polymyositis, livedo reticularis, and

Raynaud’sdisease.

Treatmentandprognosis

• Active or latent hepatitis B may require concurrent antiviral therapy (e.g.

lamivudine)inadditiontoimmunosuppression.

• GCtherapyshouldbecombinedwitheitherMMF,MTX,orAZA.

• CYCisusedforseriousorganinvolvementorsteroid-refractorydisease.

• Theroleofplasmapheresisremainstobedetermined.

• Prognosticscoring,usingtheFFSmaybeuseful(FFS=1hasamortalityof

25%;FFS =2 hasamortalityof45%;etc.).The fivefactors—each scoring

one—are.

• Renalfailure.

• Proteinuria(>1g/dL).

• GIbleedorperforationorinfarctionorpancreatitis.

• Cardiomyopathy.

• CNSinvolvement(<10%).

Primaryangiitisofcentralnervoussysteminchildren(cPACNS)

• CNSvasculitisisincreasinglyrecognizedinchildrenbutpresentsadiagnostic

challenge.Alackofconsensusondiseaseclassificationhasmadeitdifficultto

establishthetrueincidenceofthedisease.

• Brainworks (  http//www.sickkids.ca/research/brainworks/) is helping to

better clarify this condition and provides support when there is diagnostic

uncertainty.

• Secondary CNS vasculitis occurs in a broad set of systemic conditions,

includingneurosarcoidosis,whichisadifferentialdiagnosis.

Presentationandclinicalfeatures

• Clinical presentation is typically with non-focal symptoms including

headachesandalteredmentalstate(in50%ofcases).

• Alternatively, children present with localizing symptoms include lateralized

weakness(30%),aphasia,ataxia,visualsymptoms,andseizures(each~15%).

• Thespinalcordisinvolvedin5–15%ofcases.

• Systemicfeaturesarerare.

• MimicsofCNSvasculitisshouldbeconsidered,andinclude:

• Moyamoyadisease.

• Thrombophilicconditions(e.g.antiphospholipidsyndrome).

• Neurologicalconditions(e.g.multiplesclerosis,Devic’sdisease).

• Metabolicconditions.

• Sarcoidosis.

• Malignancy.

Investigations

• Diagnosticcriteria

require:

• Anacquiredneurologicaldeficit.

• Angiographicand/orhistopathologicalfeaturesofCNSangiitis.

• Absenceofasystemiccondition.

• Catheterarteriographyisthegoldstandarddiagnostictestduetoanabilityto

detect distal lesions affecting smaller vessels and identify lesions in the

posteriorpartofthebrain.

• MRI of brain and/or spine and MRA may demonstrate acute ischaemia of

varying patterns dependent on size of vessel involve and use of diffusion-

weightedimaging(forlargevesseldisease).

• Meningeal enhancement may be seen with MRA which can reveal beading,

tortuosity,stenosis,andocclusionofthevessels.

• Brain biopsy should be considered for difficult cases when arteriography is

negativeorincaseswithapoorresponsetotherapy.

Treatmentandprognosis

• Current therapeutic recommendations are similar to those for systemic

vasculitis:

• InductionwithIVCYC,GCsandlow-doseaspirin.

• 1–2-yearmaintenancetherapywithMMForAZA,simultaneouslyreducing

thedoseofprednisolonebutcontinuingaspirin.

• Fullanticoagulationmayneedtobeconsidered.

• A poor prognosis is suggested by presentation with neurocognitive

dysfunction, seizures, multifocal parenchymal lesions on MRI, or distal

stenosisonarteriography.

ANCA-associatedvasculitides(AAVs)

• Using internationally recognized diagnostic criteria and algorithms, 80% of

paediatricAAVpatientsareGPA,15%areMPA,and5%areEGPA.Casesof

renal-limitedvasculitis(crescenticglomerulonephritis)arealsoincluded.

• The Paediatric Vasculitis Activity Score, PVAS (modified from BVAS), has

beenvalidatedforobjectiveassessmentofchildhoodvasculitis.

• Of all AAV childhood cases, 55% are cANCA positive (almost consistently

PR3 positive), 30% are pANCA positive (90% MPO positive), and 3% are

mixedcytoplasmicandperinuclear.

• Medianageatdiagnosisis14yearswitharelativelyhighburdenofdisease

(medianPVASof19).

• Timefromsymptomonsettodiagnosis isnowquick,averaging2.5 months,

butratesoforgandamageatthistimearestillhigh.

• 80%ofpatientshavepulmonaryorrenaldisease;60%haveboth.

• Pulmonary presentations include alveolar haemorrhage and massive

haemoptysis.

• 10–20%ofcasespresentinrenalfailurewhichrequiresdialysisand5%have

end-stagerenaldisease.

• ENTinvolvementoccursin60%andMSKin50%.

• CYCandGCshavebeenusedmostcommonlytoinducediseaseremissionbut

inkeepingwithpracticewithadultcases,RTXisincreasinglyused.

• The choice of maintenance therapy after induction of remission includes

MTX,AZA,andMMF.

• Plasmapheresis is usually for pulmonary-renal syndrome and alveolar

haemorrhage.

• Low-doseaspirinisusedtodecreasethrombosisrisk.

• Co-trimoxazoleusefornasalStaphylococcuscarriageiscontroversial.

• Highlevelsoforgandamagestilloccur.InonelargestudyofGPAinchildren,

40%hadchronicrenalimpairmentat3yearsofdiseaseduration.

Reference

13. CalabreseLH,FurlanAJ,GraggLA,etal.Primaryangiitisofthecentralnervoussystem:diagnostic

criteriaandclinicalapproach.CleveClinJMed1992;59:293–306.

Chapter16
Metabolicbonediseases
Osteoporosis
VitaminDdeficiency,osteomalacia,andrickets
Hypercalcaemia,parathyroiddisease,andrelateddisorders
Paget’sdiseaseofbone
Childhoodautoinflammatorybonediseases
SAPHOsyndrome
Theosteochondroses
Osteonecrosis
Fibrousdysplasia
Sclerosingbonedisorders
Bonetumours
Osteogenesisimperfectaisincludedin Chapter19
Osteoporosis
Osteoporosiscanbedefinedasadecreaseinbonemassandstrengthresultingin
anincreasedriskoffracturewithminimalornotrauma(‘fragilityfracture’).
• OsteoporosiscanbedefinedusingdualX-rayabsorptiometry(DXA)toderive
anestimateofbonemineraldensity(BMD).
• The clinical consequence of osteoporosis is fragility fracture and its
consequences, which include pain, skeletal deformity, functional loss
(includinglossofmobilityandindependenceintheelderly),andreducedlife
expectancy(e.g.hipfractureintheelderly).
• Theriskofosteoporoticfractureisgreaterinwomenthaninmenandvaries
withsite(Table16.1).
Table16.1Riskofosteoporoticfracturewithsite

Fracturesite Overalllifetimeriskoffracture(%)

Men Women

Hip 6 18

Vertebral 5 16

Distalforearm 2–3 16

Anyofabove 13 40

Pathogenesisandclassification

• Duringchildhoodandadolescence,growthandskeletalmodellingleadtoan

increaseinthesize,shape,strength,andcompositionofbone.Growthceases

with the closure of the growth plates (epiphyseal cartilage). However,

remodelling and mineral homeostasis continue throughout life with bone

resorptionanddepositioncoupledbytheinteractionbetweenosteoclastsand

osteoblasts,respectively.

• Peakbonemass/BMDormaximalbonedensityisusuallyachievedinthethird

decade. Peak bone mass is determined by both genetic and environmental

factors.

• Afterabouttheageof35years,theamountofboneproducedislessthanthat

resorbed during each remodelling cycle. The net effect is an age-related

decreaseinbonemass.TrabecularandcorticalBMDdeclineby~6%and3%

respectivelyperdecade.

• Acceleratedbonelossoccursatthetimeofmenopausewithdecliningovarian

functionandcirculatingoestrogen.Upto15%ofbonemasscanbelostover

the 5-year period immediately after menopause. The andropause (decreased

circulatingbioavailabletestosterone,sodecreasedaromatizationtooestrogen)

occursformanymenovermanyyearsthroughlate-middleandadvancedage.

ThereisamoderatecorrelationbetweenserumtestosteroneandBMD.

• Themechanismofage-relatedbonelossismultifactorialandisaconsequence

ofgenetic,environmental,andcomorbidinfluences:

• decreasedintestinalcalciumabsorption.

• decreasedsynthesisofvitaminD.

• hyperparathyroidism(causedbytheabove).

• factorsincreasingosteoclastfunction(e.g.oestrogenlack).

• reduced osteoblast development (e.g. ageing-related stem cell fate—away

fromosteoblastinfavourofadipocyte).

• increasing immobility reducing the physical stress on bone leading to

activationofboneresorption.

• Riskfactorsforosteoporosis(seealsoTable16.2)include:

• race(CaucasianorAsian>AfroCaribbean).

• increasingageandfemalegender.

• positivefamilyhistory(especiallyparentalhipfracture).

• previous‘fragility’fracture.

• drugs(e.g.glucocorticoid(GC)therapy).

• chronicinflammatorydiseases(e.g.RA,Crohn’sdisease,AS)

• malabsorption(e.g.coeliacdisease)

• endocrinopathies(e.g.hyperparathyroidism,Cushing’ssyndrome)

• lowbodymassindex(BMI<18).

• shortfertileperiod(latemenarche,earlymenopause).

• diseasesofbonemarrow(e.g.mastocytosis,Gaucherdisease)

• immobility,sedentarylifestyle.

• lowintakeofcalcium(<240mgdaily).

• excessivealcoholintake.

• smoking.

• The World Health Organization has developed a Fracture Assessment Tool

(FRAX;  htpp://www.shef.ac.uk/FRAX) to identify patients at risk of

fragility fracture. BMD measurement is incorporated into FRAX. Assessing

BMD alone to predict fragility fracture may lead to an incomplete fragility

fracture risk profile. FRAX takes account of many of the major BMD-

independentfragilityfractureriskfactors(withtheexceptionoffallsrisk)and

allowsacalculationofa10-yearriskoffragilityfracture:

• age,lowBMI,andgender.

• priorfragilityfracture.

• GCuse.

• parentalhistoryofhipfracture.

• rheumatoidarthritis.

• secondaryosteoporosis(selectedcauses).

• currentsmokeranddailyalcohol>3units.

Table16.2Diseasesthatcause,orareassociatedwith,osteoporosis(incomplete)

Malignancies Multiplemyeloma

Leukaemia

Lymphoma

Endocrine Hyperparathyroidism

Hypopituitarism

Thyrotoxicosis

Hypogonadism

Cushing’ssyndrome

Diabetes(T1DM/T2DM)

Turner’ssyndrome

Chronicinflammatorydiseases Rheumatoidarthritis

Ankylosingspondylitis

Crohn’sdisease

Cysticfibrosis

Metabolicdiseases Gaucherdisease

Chronickidneydiseases

3b–5

Alcoholism

Skeletaldiseases Osteogenesisimperfecta

Mastocytosis

Diseasesandconditionsassociatedwith

immobilization

Multiplesclerosis

Paraplegia

Spaceflight

Drugs Glucocorticoids(GCs)

Anticonvulsants

Calcineurininhibitors

Levothyroxine(inexcess)

Heparin

Idiopathicjuvenileosteoporosis

• Idiopathic juvenile osteoporosis (IJO) is uncommon. It occurs before or at

onsetofpuberty.Itaffectsthesexesequally.Thecauseisunknownandthere

arenoconsistentbiochemicalabnormalities.

• IJOshouldbediscriminatedfromosteogenesisimperfecta(OI;see Chapter

19)andosteoporosisfromsecondarycauses(e.g.seeTable16.2).

• The child presents with pain, non-traumatic fractures around the weight-

bearingjoints,andcollapsedvertebrae.Nospecifictreatmentisavailableand

for most, bone mass increases to normal values as puberty progresses;

however,insomecasesfracturesmayleadtodeformity.Supportivephysical

therapyshouldbemadeavailable.

• ChildrenwithIJOandallformsofosteoporosishavelowBMDfortheirage

andskeletaldevelopment.ItisessentialthatDXAscan-derivedBMDdataare

adjusted for skeletal growth if growth deviates from average velocity

significantly (see ISCD position statements online:

https://www.iscd.org/official-positions/) using skeletal growth adjustment

algorithms(forUKdata,usingbonemineralapparentdensity(BMAD)).

Glucocorticoid-inducedosteoporosis(GIO)

• GIO is a common and (as published audits continually suggest) a poorly

managedcondition.

• Numerous guidelines for managing GIO risk exist (e.g. ACR, EULAR,

American Society of Bone Mineral Research (USA), National Osteoporosis

Foundation(USA),NationalOsteoporosisSociety(UK))

• The effects of GIO are greatest in the older patient given the additional

osteoporosisriskfactorsandcomorbiditieslikely.

• TheeffectofGCsontheskeletonismostprofoundwithearlyGCtreatment,

sopreventiveosteoporosisstrategiesneedconsideringatthebeginningofGC

use,particularlyintheelderly.

• Any vitamin D deficiency and secondary hyperparathyroidism requires

correctingattheoutsetofanyGCtreatment.

• GP patient databases suggest patients on long-term inhaled GCs may be at

increased of osteoporosis defined by DXA, but there is no overall evidence

that there is an increased risk of fracture compared to control patients with

underlyinglungdiseases.

• ThepathogenesisofGIOiscomplex.TherearedirecteffectsofGCsonbone

cells and indirect effects through an influence of metabolic and endocrine

factorsthoughconvincingdatainhumansforalltheseeffectsbeingsystematic

arelacking(Table16.3).

• A bisphosphonateshould berecommended,to patients≥65 yearsand50–65

years old with multiple risk factors for osteoporosis, who will take GCs ≥3

monthsandshouldbestartedsimultaneouslywiththeGCs.

• For younger patients FRAX (  http://www.shef.ac.uk/FRAX) is useful to

predictmajorfragilityfractureriskorverylowriskinpatientsbeforestarting

GCs. FRAX can be used without DXA scan data and can be adjusted

dependingonGCdose.

Table16.3Pathogenesisofglucocorticoid-inducedosteoporosis(GIO)

Mechanism Effect

Directeffectsonbone

cells

Reducedrecruitmentofosteoblastsfrombone

marrowprecursors

Induceapoptosisofosteocytes

Possiblecontributing

indirecteffects

Reduceproductionofsexhormones

IncreasedPTHproductionandPTHsensitivity

ReducedGIcalciumabsorption

Decreasedcalciumreabsorptionfromkidney

DecreasedefficiencyofvitaminDactivation

Sarcopeniceffectofsteroids(fallsrisketc.)

Clinicalfeatures

• Osteoporosisfrequentlypresentswithlow-traumafracture.

• Otherpresentationsincludebackpain(vertebralfractureduetoosteoporosis),

lossofheightevidentinthespineby‘xmas-tree’foldsofskinofthebackor

the lower rib cage margin approximating to the iliac crests, thoracic spine

kyphosis (multiple vertebral fractures can cause this though this is not the

commonestcauseforkyphosis).

• Features of the cause of osteoporosis may be obvious or not. For example,

immobilityduetospinalcordinjuryandparaplegia(potentcauseofboneloss)

buthypogonadisminmen,thoughdetectabletoanexperiencedclinician,may

besubtleandrelatively‘invisible’.

• Obviousand/orimportant clinicalfeaturesthatmightbe detectedtoindicate

conditions highly associated with osteoporosis include stigmata for chronic

alcoholexcess,hypogonadismfeaturesinmen,Cushing’sdiseaseappearance,

etc.

• Highfallsriskisanimportantclinicalfeature.Thoughhighfallsriskdoesnot

define osteoporosis, it is arguably the main risk factor for fracture in the

elderly,anditcanbedetectedsystematicallyusingguidelines(seeUKadvice

inNICEClinicalGuideline161).

Investigations

• Peopleaged>50yearsoldwhohaveafragilityfractureshouldbeinvestigated

to exclude secondary causes of osteoporosis (e.g. hyperparathyroidism,

CKD3b–5,myeloma,etc.).

• Anyfractureinaperson>75yearssuggestssomedegreeofskeletalfragility,

regardless of DXA scan-derived BMD; tests for underlying disease is

advisable.

• Plainradiographsareaninsensitivemethodofassessingbonemassbutlateral

spinalimagesare useful for stagingpreviousvertebral fractures, whichmay

haveoccurredwithminimalsymptomology.

• ThestandardtechniqueformeasuringBMDisDXA.Itisquick,accurate,low

inradiationdose,andisfairlyprecise.Sitesmeasurableincludelumbarspine,

femoralneck,forearm,andwholebody.

• DXAistypicallyinterpretedintermsofthe T-scoreorZ-score.TheT-score

(usedonlybyconventionforpostmenopausalwomenandmen>50yearsof

age) is the SD multiple difference between the individual’s BMD compared

withthemeanpeakBMDachievedinthethirddecadematchedforgenderand

ethnicity. The Z score (used by convention in premenopausal women and

childrenandallmen<50yearsofage)isthestandarddeviation(SD)multiple

difference between the individual’s BMD and the age/gender/ethnicity-

matched average. T- and Z-scores can be minus values. In postmenopausal

women,foreverySDdecreaseinBMDthereisatwofoldincreaseintherisk

offracture.

• Quantitative CT allows volume measurements and can distinguish between

corticaland trabecularbone invertebrae. Itis, however,costlyandentailsa

highradiationexposure.

• Boneultrasound(US)oftheoscalcishasbeenusedtopredictfracture.Both

theattenuationandspeedofUSinbonemayrelatetomaterialpropertiesof

bonerelevanttofragilityandfracture.

• Bone biopsy (undecalcified transiliac) may be useful in cases of multiple

comorbiditytodiscriminatehighandlowturnoverdiseaseandwhetherthere

isdemineralizationbutisnotroutinelyintheassessmentofosteoporosis.

• Routine biochemical and haematological tests are usually normal in

osteoporosis. High bone turnover disease may be indicated by high bone

turnovermarkers(e.g.collagencrosslinks(CTX)).

• ReductionofCTXhasbeenlinkedwithbisphosphonateresponseandmaybe

anindicatorofdrugadherence.

Preventionofosteoporosisandfragilityfractures

• The prevention of a first fragility (osteoporotic) fracture is termed ‘primary

prevention’ and prevention of second and subsequent fragility fractures

—‘secondaryprevention’(/treatmentofosteoporosis).

• All people who have a fragility fracture after the age of 50 years (or for

women, if post-menopausal) should be assessed for their risk of further

fragilityfractureand osteoporosis.Typically, thiswillbedoneby aFracture

LiaisonService (FLS)linked totheOrthopaedicUnit(secondaryprevention

assessment).

• Underlyingdiseases(knownorunknown)andmodifiableclinicalorlifestyle

issuesrelevanttoskeletalhealthwillbeidentifiedinmanypatientsbysuchan

assessment. FLSs will triage patients for specialist assessment or secondary

fracture prevention management including DXA scanning and considering

osteoporosismedications.

• Primarypreventionisbestundertakenbycase-findingbasedonthepresence

of osteoporosis risk factors, utilizing the FRAX risk factor tool (

http://www.shef.ac.uk/FRAX) then obtaining DXA in people with multiple

riskfactorsorhighscoresonFRAX.Osteoporosistreatmentcanbeconsidered

basedonBMDandfracturerisk.

Calcium

• Calcium intake, either increased by dietary intake or supplements, has not

beenshowntopreventosteoporoticfractures.

• However,chroniccalciumlackleadstosecondaryhyperparathyroidismwhich

cancauseaccelerated bonelossand this maycontribute to osteoporosisand

bonefragility.

• Providingcalciumsupplementsiswiseifthereisalow-calciumdiet(e.g.poor

indairyproducts)and/orsecondaryhyperparathyroidism.

• Calcium supplementation in pre-pubertal children enhances the rate of

increaseinBMDwithagebutwhetherthistranslatesintohigherpeakBMDis

unknown.

• Atpresenttheuseofcalciumsupplementsisrecommendedfor:

• calcium deficiency indicated by secondary hyperparathyroidismifvitamin

Dlevelsarereplete(butreasonablethentoruleoutcoeliacdisease/poorGI

absorption).

• poorcalciumdietparticularlyinchildren(<400mg/day).

• tooptimizetheeffectofbisphosphonatetherapy.

• Therehasbeenconsiderabledebateastowhethercalciumsupplementationis

associatedwithanincreasedriskofcardio/cerebrovasculardisease.

Exercise

• Thereissomeevidencetosuggestthatweight-bearingactivitydecreasesthe

rateofbonelossaroundthemenopause,althoughthelevelandtypeofactivity

remainsunclear.

• Thereislittleimpactof exerciseinimprovingbonemassonceosteoporotic,

althoughitmayaidinpreventingfurtherloss.

• ProfoundlossesofhipBMDintheelderlymaybehighlyandpredominantly

influencedbyreductionofmobility/weight-bearing.

Hormonereplacement

• Oestrogen replacement therapy is an effective way of preventing post-

menopausal bone loss. The addition of a progestogen allows endometrial

sheddingandminimizesriskofneoplasia.

• The minimum oral dose of estradiol required is 1 mg/day, and conjugated

oestrogen 0.3 mg/day. Estradiol gels and transdermal treatments should be

startedat1mg/dayor25micrograms/day,respectively.

• EvidencesuggeststhattheuseofHRTincreasesriskofDVT,coronaryartery

disease,breastcancer,andstroke.HRTshouldthereforebeusedwithcaution,

shouldbetimelimited,andusedwhentherisksofthesediseasesotherwiseis

lowest.

Bisphosphonates

• Weeklyoralbisphosphonates(risedronateoralendronicacid)reducefragility

fracturesby35–50%atthespineandbylessatthehipinwomenwhohave

hadafragilityfractureorosteoporosis-rangeBMD.

• Monthly ibandronic acid 150 mg is also licensed for postmenopausal

osteoporosis.Cyclicaletidronateisnowadaysseldomused.

• Fracturepreventiondatawithoralbisphosphonatesisnotasextensiveformen

as for women but treatment is considered effective for men with fragility

fractureandwithDXA-definedosteoporosis.

• IV zoledronic acid 5 mg given yearly (×3 years original RCT data), is

available if oral therapies fail, are not tolerated or contraindicated. Fracture

preventionisasmuchas70%forvertebralfracturesin3years.

• Ibandronic acid 3 mg IV (‘push’ injection taking just a few seconds) once

every 3 months is licensed also for postmenopausal women and some bone

physicians considered it relatively safe in mild renal impairment, where

zoledronicacidisnotused(i.e.estimatedGFR25–35mL/min/1.73m

)and

denosumabiscontraindicated.

• Currently most physicians will review the balance of risks and benefits of

long-term bisphosphonate therapy after 5-year oral, and 3-year parenteral,

bisphosphonate use. For those patients still at high fracture risk though,

treatmentcanbecontinuedforafurther3–5yearsaccordingly.

• The emerging concern about the incidence of atypical femoral fractures

(AFFs)inlong-termbisphosphonateusershaspromptedchangesinstrategic

long-term planning of medications for osteoporosis. AFFs can present with

proximalfemoralbonepainformanymonthsbefore(somewhatcatastrophic)

subtrochantericfracture,andcanbebilateral.Causeisunknownbutthoughtto

beacombinationoflowboneturnover/bonereplacementatasiteofcritical

weight-bearingstressonthefemoralbone.

• Ingeneral,bisphosphatesarewelltolerated,butshouldbeusedwithcautionin

renal impairment (estimated GFR <30 mL/min/1.73 m

), history of

oesophagealreflux/hiatushernia,orpoordentitionrequiringdentalwork(risk

ofmandibularosteonecrosis).

• Oralmedicationsshouldbetakenfasting.Absorptionmaybeoptimumiffood

intake is avoided for 60 minutes following taking the tablet. Symptoms of

nauseaandrefluxcanbe lessenedby takingwithplentyofwater andavoid

lyingdownaftertakingthetablet.

• AdherencewithoraltherapyisvariablewithreportsfromtheUSAof<30%,

butreportsintheUKof>80%at2–4years’therapy.Adherenceisbestwhen

treatment is started by a FLS following fragility fracture in comparison to

startingaspartofprimaryfragilityfracturepreventiontreatmentplan.

• TheeffectsofbisphosphonatesareoptimizedifvitaminDremainsrepleteand

there is sufficient calcium intake to prevent deficiency (e.g. no secondary

hyperparathyroidism).

• The therapeutic effect of bisphosphonates can be predicted to a degree by

demonstration of a reduction in bone resorption biomarkers (e.g. CTX)

measuredonserumorplasmabeforeand2monthsaftertreatmentisstarted.

Strontiumranelate

• Strontiumranelate2gdailywasshowntodecreasefractureriskover3years

in men and postmenopausal women (by about 40%), but its use has been

considerably restricted in recent years because it increases vascular disease

risk (e.g. CVD, IHD, and thrombosis). Strontium has now been withdrawn

fromuse.

• Strontium is similar to calcium chemically but much ‘heavier’. It is

incorporatedintothehydroxyapatitebonematrixandnaturallyleadstolarge

increases in BMD, though the relationship of change in BMD to change in

fractureriskisneitherlinearnorproportionaltoBMDchangesassociatedwith

fractureriskreductionseeninothertherapies,forexample.

• The association with markedly increased BMD is important to note when

reviewingserialDXAscandataonpatientspreviouslytreatedwithstrontium.

Teriparatide

• TeriparatideisaparathyroidhormoneanaloguegivenasaSCinjectiondaily

for2years.

• Licensed for use in postmenopausal osteoporosis, though not in men, it

reducedvertebralfractureriskbyabout70%.

• Teriparatideinitiallytriggersosteoblast-mediatedbonematrixproductionthen

an increase in bone turnover. It may achieve therefore a gain in bone

(‘anabolic’)unlikeanti-resorptiontherapies.

• IntheUK,teriparatideisheavilyrestrictedforuseforNHSpostmenopausal

osteoporosis by NICE and cannot be used without specialist application for

individualfundingformenwithosteoporosis.

Denosumab

• Denosumab is a fully human monoclonal antibody that inhibits the RANK

ligand,andisapotentinhibitorofboneresorption.

• DenosumabislicensedinEuropeforarangeofbonelossconditionsincluding

post-menopausal osteoporosis and bone loss in patients being treated with

hormoneablationforprostateandbreastcancer.

• Denosumab 60 mg SC injection once every 6 months reduces vertebral

fractureratebyabout70%inpostmenopausalwomenwithosteoporosisover3

years(FREEDOMtrial).

• TheFREEDOMtrialextensionnowshowsfractureprevention,BMDaccrual,

andnomajorsafetyissuesforupto8years’continuoususe.

Odanacatib

• OdanacatibwasdevelopedacathepsinKinhibitortoinhibitosteoclasticbone

resorption,thenslowingboneloss.

• Phase II data indicate that 50 mg once weekly inhibits bone resorption and

increasesBMD,withonlyatransientdecreaseinboneformation.

• InaphaseIIIRCT,fracturereductionwas shownbutsubsequentlythedrug

waswithdrawnduetoanunacceptablyhighnumberofcerebrovascularevents

inpatientsinthetreatmentarm.

Romosozumab

• Themonoclonalantibodyromosozumabbindstosclerostinthusinhibitingthe

effect of sclerostin, which is an osteocyte-derived inhibitor of osteoblast

activity,thusincreasingboneformation.

• In the phase III FRAME (FRActure study in postmenopausal woMen with

ostEoporosis) study, which enrolled 7180 women, SC 210 mg dose of

romosozumab resulted in a statistically significant 73% reduction in the

relative risk of a new vertebral fracture at 12 months compared to those

receivingplacebo(fractureincidence0.5%vs1.8%,respectively(p<0.001).

• Attimeofgoingtopressthelicensingforromosozumabisonholdpending

furtherinvestigationintocardiovascularadverseeventsinclinicaltrials.

Abaloparatide

• AbaloparatideisanovelsyntheticanalogueofhumanPTHrP(1–34).

• Itcanstimulateboneformationwithlessaccompanyingboneresorptionand

hypercalcaemiceffectsthatcanoccurwithPTH(1–34).

• In postmenopausal osteoporosis, weekly SC abaloparatide, compared with

placebo,reducedtheriskofnewvertebralandnon-vertebralfracturesover18

months(ACTIVEstudy).

• Treatment with a bisphosphonate after an 18-month course of abaloparatide

mayconsolidateBMDandfractureriskreductiongains.

Othertherapies

• Vertebroplasty is the percutaneous injection of bone cement into painful

fractured vertebrae. It can be used to treat osseous haemangiomas and

fracturescausedbymalignancy.

• Initiallyvertebroplastywasreportedtoreducethepainofvertebralfractures

thoughRCTsthenshowedconflictingresults.CurrentlyalargeRCT(vssham

procedure)isinprocess(VERTOSIV).

• Kyphoplasty(ballooninflationinthevertebralbodythenballooninjectedwith

bonecementasforvertebroplasty)isunprovenbyrobuststudyastowhether

there is cost-effectivity of the procedure vs conservative fracture pain

managementorvsvertebroplasty.

Guidelinesformanagingosteoporosis

• In the UK, Europe and North America, numerous societies have generated

guidelinesformanagingosteoporosis.

• IntheUK,NICEguidelinesoperatetocontrolfundingtreatmentsintheNHS.

Guidelinesarebasedoneconomicmodelsofdiseaseandtreatmenteffects,not

on clinical factors alone. The reader is advised to consult the NICE

Technology Appraisal Guidance (TA204 and TA464) and ClinicalGuideline

146.

• In the UK the National Osteoporosis Guideline Group regularly posts

consensusguidelines(e.g.see: https://www.shef.ac.uk/NOGG/).

References

1. NICE. Falls in Older People: Assessing Risk and Prevention (CG161). London: NICE, 2017.

https://www.nice.org.uk/guidance/cg161

2. NICECG146. https://www.nice.org.uk/guidance/cg146

VitaminDdeficiency,osteomalacia,andrickets

• Osteomalacia (adults) and rickets (children) are characterized by defective

mineralization of bone and cartilage and the accumulation of unmineralized

bonematrix(osteoid).

• Ricketsisthetermusedforthisdefectingrowingchildrenbeforetheclosure

oftheepiphyses.

• There is considerable debate over the level of 25-hydroxyvitamin D

(25(OH)D)thatconstitutes‘repletion’and‘deficiency’.Forthemajorityofthe

UK population a reasonable ‘repletion’ level is >50 nmol/L and deficiency

level<30nmol/L.Intheelderly,levelsof‘insufficiency’(30–50nmol/L)may

bepathologicallyrelevantandabetter‘repletion’leveltakenas>75nmol/L.

• Therearemanycausesofosteomalacia,butessentiallytheyalloccurdueto

either a deficiency (low sunlight exposure, dietary lack, or suboptimal

metabolism)orresistancetovitaminD,oranon-PTHrelateddefectinrenal

handlingofphosphate(Table16.4).

• Inbothosteomalaciaandrickets,PTHisinvariablyraisedduetovitaminD-

associatedcalciumlack.HighPTHcanincreaseboneturnover/bonelossand

amplifybonelossinosteoporosis.

• BothvitaminD

(ergocalciferol)fromvegetablesinthediet,andvitaminD

(cholecalciferol) from animal tissues and de novo synthesis in skin, are

metabolizedinthe liverto 25(OH)D(25(OH)D

/25(OH)D

) and then in the

kidney to 1,25-dihydroxyvitamin D

 respectively: the active forms of

vitaminD.

• 1,25-dihydroxyvitaminD

 is considered more biologically potent than 1,25-

dihydroxyvitamin D

 and negatively affects both 1α-hydroxylase (its own

activating enzyme), and transcription of the PTH gene, but increases the

capacityofGIcalciumabsorptionbyenhancingthetranscriptionandtherefore

effectofcalciumsensingreceptors(CaSRs).

• 1,25-dihydroxyvitamin D

 stimulates bone formation through stimulating

osteoblast differentiation and activity thereby increasing coupled bone

turnover.

• 25(OH)D

canbealsobeconvertedinto24,25-dihydroxyvitaminD

whichis

biologicallyinactiveanddestinedforexcretion.

Clinicalandlaboratoryfindings

• Classical symptoms of osteomalacia are bone pain and tenderness, bone

deformity (depending on age of onset), and proximal muscle weakness

(waddlinggait);muscleenzymesandbiopsyarenormal.

• Thehypocalcaemiaofosteomalaciausuallydoesnotcausesymptomsbutcan

cause paraesthesia and tetany. Rarely, it is severe enough to cause cardiac

dysrhythmia,convulsions,orpsychosis.

• Childrenwithricketsmaybehypotonicandapatheticwithgrowthretardation

anddelayedwalking.Onweight-bearing,bonesbecomebowed,andthereis

irregularity of the metaphyseal–epiphyseal junction, usually at the wrist and

costochondraljunctions.The lattergives risetothe feature‘rachitic rosary’.

An indentationmay also arisealongthe attachment ofthediaphragm to the

softenedribs(Harrison’sgroove).Rapidgrowthofthesoftenedskullleadsto

craniotabes,parietalboneflattening,andfrontalbossing.Dentitionisdelayed

andpoor.

• In rickets, many bony deformities persist despite treatment (unless due to

simpledietarydeficiencyandtreatedearly)andmayrequiresurgery,e.g.tibial

osteotomytocorrectlowerlimbalignment.

• The classical radiographic change of osteomalacia is the pseudo-fracture

(Looser’szone).Theseareincompleteradiolucentfracturelinesperpendicular

to the cortex, with poor callus formation and found most often at ribs,

clavicles,pubicrami,femoralneck,metatarsals,andouterborderofscapulae.

• Laboratory investigationsshow low25(OH)D,a loworlow referencerange

serumcalciumand phosphate, elevatedALP, lowurinarycalcium excretion,

andsecondaryhyperparathyroidism.

• Osteomalaciamayexistwithreferencerangelevelsofcalcium,phosphate,and

ALP;thusonlyraisedPTH,reduced25(OH)D,andlowurinarycalcium(24

hour),testedsimultaneously,disclosethediagnosis.

• Levels of 1,25-dihydroxyvitamin D may be in the reference range and are

thereforenotroutinelytested.

• Vitamin D deficiency throughpoordietintake is rare unlesscombinedwith

exposuretosunlight.Itisaphenomenonseenmostofteninthehousebound

elderly,andinimmigrantAsianpopulations.

• Intestinal disorders that lead to fat malabsorption can cause vitamin D

deficiency,asvitaminDisfatsoluble.

Table16.4Asimpleclassificationofosteomalacia

Low Reducedavailability Poordiet,UVskinexposureor

25(OH)D malabsorption

Metabolic Chronicrenalfailure

Anticonvulsantdrugs

Hepatobiliarydisease

Normal

25(OH)D

1α-hydroxylase

mutations

VitaminD-dependentricketstypeI

VitaminDreceptor

mutations

VitaminD-dependentricketstypeII

Phosphate

loss

FGF23excess X-linkedhypophosphataemia

Oncogenic—hypophosphataemia

Tubulardysfunction Fanconisyndrome

Skeletal

toxicity

Defective

mineralization

Aluminium,fluoride

ManagementofhypovitaminosisD,rickets,andosteomalacia

• Thestrategyshouldbetoreplace25(OH)Dtotargetrepletionlevel,provide

enough calcium to mineralize bone normalizing any secondary

hyperparathyroidism, control skeletal pain, pursue a physio-led muscle

rehabilitation regimen if there is any myopathy, and finally prevent the

conditionfromrecurring.

• Quite commonly there may be two lesions in the elderly: osteomalacia and

osteoporosis. It is unknown to what degree bisphosphonate therapy for

osteoporosiswillimpairmineralization/osteomalaciarecoveryiftreatmentfor

bothconditions isgivensimultaneously.Delayingosteoporosistreatment for

4–6weeks isunlikelyto harmandmaygivevaluabletimeforosteomalacia

healingbasedonnecessaryhigherboneturnover(canbeindicatedbyan‘ALP

flare’).

• Bone pain and muscle weakness respond quickly to successful replacement

therapythoughlaboratoryandradiologicalfeaturesmaytakelongertoreturn

tonormal.

• In adults, various regimens for cholecalciferol replacement might be

recommended (e.g. 20,000 IU cholecalciferol weekly for 5 weeks), though

cautionisadvisedinregardof‘over-replacementregimens’,whichhavebeen

associatedwithanincreasedfallsandfracturerisk.

• An alternative (and potentially well-adhered-to regimen) is 3200 IU

colecalciferoldailyintwice-dailydosesforacalendarmonth.Repletionstatus

should then be tested with repeat 25(OH)D check and repeat course of

treatmentgivenifrequired.

• Vitamin-D (and calcium) lack may be habitual as it depends on UV-skin

exposure and dietary preferences. Identification of repeat deficiency then in

futureisfacilitatedbyperiodic25(OH)Dtesting.

• Co-treatment with calcium supplements isn’t necessary in all cases but is

usually safe at daily supplement doses of 500–1000 mg without causing

hypercalcaemia.

VitaminD-dependentrickets

• Type I vitamin D-dependent rickets is a rare autosomal recessive disease

caused by inactivatingmutations in the 1α-hydroxylase gene. Low levels of

1,25-dihydroxyvitamin D result. Children are often affected with rickets

beforetheageof2 years,andfailtorespond tonormallevels ofvitaminD

replacement. Treatment is most effective with physiological doses of 1,25-

dihydroxyvitaminD(e.g.calcitriol).

• TypeIIvitaminD-dependentricketsisanautosomalrecessivedisordercaused

bylossoffunctionmutationsinthevitaminDreceptor(VDR).About70%of

patientswillhavealopecia—animportantprognosticfeaturewhendiscussing

likely outcome of treatment. In patients with normal hair, remission can be

achieved with high levels of 1,25-dihydroxyvitamin D. Only about 50% of

patientswithalopeciawillrespondtoasimilartherapeuticapproach.

Osteomalaciafromalteredphosphatehomeostasis

• Osteomalacia from phosphate depletion is histologically the same in the

skeleton as 25(OH)D deficiency, although serum calcium and 25(OH)D

are/canbenormal.

• X-linked(AD)hypophosphataemicrickets(XLHR)isadisorderofvitaminD

resistance. It is important to diagnose early in young children as treatment

preventsbonedeformity.

• XLHR manifests as delayed growth, short stature, lower limb skeletal

deformity,andrickets.

• InXLHR,dentaldevelopmentcanbedelayedbutdentitionisusuallynormal.

Proximal myopathy is not a feature. Laboratory tests show a low serum

phosphate, normal serum calcium and PTH, and low/normal 1,25-

dihydroxyvitamin D with high FGF23. The renal tubular maximum

reabsorption of phosphate for GFR is low for the degree of

hypophosphataemia(TMP-GFR).

• The treatment of XLHR is a combination of calcitriol (0.125–1.5

micrograms/day)andphosphate(25mg/kg/dayininfants,and1–3gelemental

phosphorusinadults).

• Complications of long-term treatment include hypercalcaemia,

hypercalciuria/renallesions,andhyperparathyroidism.

• TherequirementsforcalcitriolandphosphorustherapyinadultswithXLHRis

generallyreducedandmanagementoftheconditionrefocusesontheneedto

address tertiary hyperparathyroidism, address osteoarthritis, and MSK

symptomscausedbyorassociatedwiththeenthesopathywhichevolvesover

time.

• Renaltubularacidosis(RTA)andFanconisyndromemaybeassociatedwith

osteomalaciaandrickets.

• In RTA, there is a disorder of bicarbonate handling leading to low plasma

bicarbonate,metabolicacidosis,andaninappropriateurinepH.TypeIdistal

tubularRTAoccursasaresultoffailuretosecretehydrogenions.

• Type II proximal RTA is a consequence of bicarbonatewastingandis often

associatedwithFanconisyndrome.Thedevelopmentofricketsinbothforms

of RTA is due to hypophosphataemia. The acidosis should be treated and

vitaminDsupplementsgiven.

• Fanconi syndrome is associated with a number of acquired or inherited

disordersincludingmultiplemyeloma,amyloidosis,heavymetaltoxicity,and

disordersofcarbohydratemetabolism.

• Theneteffectofproximalrenaltubulardefectsisglycosuria,aminoaciduria,

phosphaturia, and hypophosphataemia. Treatment is with phosphate and

calcitriolsupplements.

Oncogenichypophosphataemicosteomalacia

Alsoknownastumour-inducedosteomalacia,thisiscausedby(usuallysmall)

benignmesenchymaltumours,whichsecreteFGF23.See Plate16.

• The condition is cured after removal of the tumour though detection of the

tumourcanbedifficult.

• Tumours can be anywhere including in bone. Many anecdotal reports of

tumoursexistinginoddpositionsexist(e.g.sinuses,in skin,deepfattissue,

labia,etc.).

• Functional imaging with somatostatin receptor or PET scintigraphy (e.g.

gallium-67gadopentetate)isoftenusedasfirst-lineimagingwithCTorMRI

thenusedtopreciselylocatethelesions.

• A milder form of the condition occurs in fibrous dysplasia and

neurofibromatosis.

• Intheabsenceofcurativesurgery,treatmentinvolveslong-termphosphateand

calcitriol supplements and careful monitoring for phosphate-induced

hyperparathyroiddiseaseandeffectsofhypercalciuria.

Hypercalcaemia,parathyroiddisease,andrelated

disorders

Hypercalcaemia

• Theclinicalpictureofhypercalcaemiacanrangefromtheasymptomatictoan

acutemedicalemergency.

• Serumcalciumisnormallybalancedbetweenhomeostaticmechanismsinthe

gut,skeleton,kidneys,andextracellularfluids.

• Hypercalcaemia arises most often from excessive mobilization of calcium

frombonebyosteoclasticresorption,butmayalsooccurduetoexcessivegut

absorption(Table16.5).

• The excessive bone loss, a failure of the kidneys to handle high loads of

calcium,andafailureofbonetoreclaimmineralsquicklyenough,leadstothe

imbalance.

• Accelerated osteoclast activity may be driven by several causes including

excess parathyroid hormone (PTH) or PTH-related protein (PTHrp) and

cytokines(e.g.IL-6,IL-1,TNFα,andTGF-β).

• Clinicalpresentationofmoderatetoseverehypercalcaemiaincludes:

• joint,bone,musclepain.

• muscleweakness.

• dehydrationandpolyuria.

• lethargy.

• fatigue.

• acuteconfusionalstate—unconsciousness.

• abdominalpainsandvomiting.

• renalcolicpains.

• ECGfindings—shortQTinterval,etc.

• Primary hyperparathyroidism(PHPT) andmalignancyare themost common

causes of hypercalcaemia (90% of cases). Other causes include sarcoid,

lymphoma,andgranulomatousinflammatoryconditions.

• ActivevitaminD

(calcitriol/1,25-dihydroxyvitaminD

)canbe producedby

tissue macrophages which generate 1α-hydroxylase.

Macrophage/inflammatory cell calcitriol production (e.g. in sarcoid) is not

regulated as occurs in renal vitamin D

 activation as there is no feedback

inhibitionof1α-hydroxylasenordiversionofitssubstrate(25-hydroxyvitamin

)toaninactiveform(24,25-dihydroxyvitaminD

)byincreasingamountsof

calcitriol,whichhappensinnormalrenalcalcitriolproduction.

• Treatment of hypercalcaemia (Table 16.7) depends on the level of serum

calcium, the presence of symptoms, renal impairment, and the underlying

cause. For example, borderline high serum calcium in an asymptomatic

individualwithamildlyelevatedPTHmaysimplywarrantobservationinthe

absenceof renalimpairment orvitamin Ddeficiency. Onthe otherhand, an

individualwithseverehypercalcaemia,dehydration,andrenalimpairmentdue

toatreatablemalignancywouldrequireurgentaggressivemanagement.

• Withacutehypercalcaemia,dehydrationisverycommon.Earlyrehydrationis

very important and often given for 24–48 hours prior to review of serum

calciumlevelsandtheinstigationoffurthertherapiessuchasbisphosphonates

andloopdiuretics(Table16.6).

Table16.5Somecausesofhypercalcaemia

Common Primaryhyperparathyroidism

Malignancy Lyticmetastasesto

bone

EctopicPTH

(PTHrp)

Tumour-derived

1,25

dihydroxyvitaminD

Uncommon/rare

Drugs Thiazidediuretics

Lithium

Aminophylline

Granulomatousdisease(tissue

macrophageproductionof1α-

hydroxylase)

Sarcoidosis

Tuberculosis

Histoplasmosis

Endocrine/metabolic Thyrotoxicosis

Phaeochromocytoma

ExcessvitaminAor

Renalfailure

Paget’sdiseaseof

bone

Other Immobility±

calcium

supplementation

Table16.6Treatmentofhypercalcaemia

General

principles

Rehydratewithnormalsaline4Lin24hrsifneeded

Correcthypokalaemiaandhypomagnesaemia

Mildmetabolicacidosisneednotbetreated

Specific

treatment

Loopdiureticswhenhydrated

Bisphosphonates

Calcitonin

Glucocorticoids(haematologicalmalignanciesand

granulomatousdiseases)

Hypercalcaemiaininfancyandchildhood

• Chronic hypercalcaemia of infancy may not be associated with the more

commonclinicalfeaturesmentionedpreviously.Moreoftenthereisafailure

tothrive,abdominalpain,andirritability.Acutehypercalcaemiaisveryrarein

children.

• ConditionstoconsiderarelistedinTable16.7.

Table16.7Conditionsthatmayberesponsibleforhypercalcaemiaininfancyandchildhood

Williams’syndrome Aspectrumofaorticvalvestenosisandfacial

dysmorphism(‘elfin’facies)

Idiopathicinfantile

hypercalcaemia

SimilarmilderappearancetoWilliams’syndromecan

beseen.Therearealsofeaturesofinguinalhernias,

hypertension,strabismus,andkyphosis

Familial

hypocalciuric

hypercalcaemia

Seelaterinthissection

Neonatalprimary

hyperparathyroidism

Other Fatnecrosis,sarcoidosis,Jansensyndrome

(metaphysealdysplasia),overdosingofmilk/vitaminD

Parathyroiddisorders

Primaryhyperparathyroidism

• Primary hyperparathyroidism (PHPT) is a relatively common condition;

incidence1in1000.Itoccursatallages,althoughismuchmorecommonafter

theageof60withafemaletomaleratioof3:1.Itisunusualinchildhood—

when it should raise the possibility of familial multiple endocrine neoplasia

(MEN)typeIortypeII.

• Asinglebenignadenomaaccountsfor80%ofcasesofPHPT.

• Generalizedfour-glandhyperplasiaaccountsfor15–20%ofcases.

• Parathyroidcarcinomaisveryrare.

• PHPT is associated with bone, renal, GI, and neuromuscular complications.

BonyproblemscanbeseenonplainradiographsandrangefromlowBMDon

DXA scanning and mild sub-periosteal bone resorption to osteitis fibrosa

cystica, bone resorption of the distal phalanges and clavicles, patchy

osteosclerosis(classic‘ruggerjersey’spine),andmultiplelyticlesionsofthe

skull.

• Generalsymptomsincludefatigueandmyalgias(myopathyisrare).

• CPPD disease is a relatively under-recognized association (look for joint

chondrocalcinosis,crowneddenssyndromeSee Plate22,typicalfeaturesin

OA joints (‘OA-plus’)). Kidney stones are uncommon. GI manifestations

includepepticulcerationandpancreatitis.

• PHPT is easily diagnosed with raised PTH in the context of replete level

25(OH)D,andhigh(orhighreferencerange)serumcalciumandlow(orlow-

reference range) phosphate. Often 24-hour urinary calcium levels are

uninformative.

• Medical management includes adequate rehydration and avoidance of high

calcium intake and calcium supplements, gentle correction of 25(OH)D

deficiencyandabisphosphonatetolimitboneloss.

• Successful parathyroidectomy from minimally invasive targeted surgery is

feasible in the majority of cases for single adenomas identified by imaging

(e.g.

99m

Tc-MIBI scintigraphy and US though (contrast-enhanced, delayed

phase)CTisalsousedinequivocalcases).

• Neckexplorationsurgeryisrequiredifimagingfailstoidentifyanadenoma.

Surgeryshouldonlybedonebyexperiencedsurgeons.

• Conservativemanagementisacceptableifpatientsareasymptomatic,anddo

nothaveosteoporosisthoughalsomaybenecessaryifsurgeryisnotfeasible.

BisphosphonatesdostabilizeBMDlossasindicatedbyDXAandcanbeused

long-term.

• Clinical trials with calcimimetic agents (stimulates the PTH gland Calcium

sensing receptors with consequent inhibition of PTH secretion) such as

cinacalcet,canbeusedincaseswhereparathyroidectomyisnotfeasible/failed

andtherearehypercalcaemicsymptoms.

Secondaryandtertiaryhyperparathyroidism

• SecondaryHPT(SHPT) occursasaconsequenceoflowserum calciumand

PTHglandCaSR‘sensing’ofcalciumlevels.

• CalciumlackandthusSHPTareoftenduetovitaminDdeficiency.

• SHPTfrom calciumlackalone (where thereis replete 25(OH)D)is unusual

thoughmaypointtoasevereGIabsorptionproblem.

• With time, persistent SHPT can lead to autonomous PTH release (tertiary

HPT). This is most often seen in severe or prolonged renal bone disease or

fromlong-termcalcitrioluse(e.g.XLHR).

• CalcimimeticsmayhaveanimportantroletoplayincontrollingtertiaryHPT

butatpresentparathyroidectomyisthebestoption.

Familialhypocalciurichypercalcaemia(FHH)

• FHH is extremely rare. It is inherited as autosomal dominant with high

penetrance. Radiographs, PTH, and renal function are normal in

uncomplicated cases. Although parathyroid gland hyperplasia occurs,

parathyroidectomy is invariably unsuccessful at lowering serum calcium

levels.

• Thetwoindications forparathyroidectomyinFHHareneonatalsevereHPT

andadultrelapsingpancreatitis.

• Useofdiuretics,oestrogens,orphosphatetoregulateserumcalciumhasbeen

unsuccessful. Patients should therefore be followed without intervention

unlesscomplicationsarise.

• FHHneedstobeconsideredwhendiagnosingPHPT(wherehypercalcaemia

andelevatedPTHlevelsaremodest).Firstdiscriminationismadebyrepleting

25(OH)D to 100 nmol/L then retesting all biochemistry. PTH usually

normalizesinFHH,unlessthereistertiaryHPT,butwon’tinPHPT.Alsoif

thecalcium:creatinineclearanceratiois<0.02thenFHHis98%likely(CCCR

=uCa/(uCr×sCr)).

• Inpregnancythethreesituationstobeawareofare:

• asymptomatichypercalcaemiainanaffectedbabyofacarrier.

• neonatal hypercalcaemia in an affected baby of an unaffected mother

(intrauterineSHPT,whichresolvesspontaneously).

• hypocalcaemia in an unaffected baby of an affected mother (fetal

parathyroidsuppression).

Familialprimaryhyperparathyroidsyndromes

• Up to 10% of cases of PHPT may have a hereditary syndrome. The most

commonoftheseisMEN.

• MEN1isautosomaldominant(M=F),isassociatedwithpancreatic,thymic,

gastric,andpituitaryadenomas,andadrenalhyperplasia.

• Pancreatic, thymic, and bronchial neuroendocrine tumours are the leading

causeofdeathinpatientswithMEN-1andshouldberegularlymonitoredfor

(e.g.biannualcomputedtomographyimaging).

• The MEN1gene consistsoftenexons,spanning 10kb, andencodesa 610-

aminoacidprotein(‘menin’—itsfunctionasyetnotfullyknownbutmayplay

aroleintumoursuppression).

• MEN2A (Sipple syndrome) is autosomal dominant and is characterized by

phaeochromocytomas and medullary thyroid carcinoma and is highly

associatedwiththeRETproto-oncogene.

Parathyroidhormoneresistantsyndromes

• Pseudohypoparathyroidism(PHP)isatermappliedtoaheterogeneousgroup

ofdisorderswhosecommonfeatureisend-organresistancetoPTH.PHPtype

1A(PHP1A)ischaracterizedbyresistancetootherhormones,includingTSH

andgonadotropins.

• PHP1A isassociated withclinical featuresreferredto asAlbright hereditary

osteodystrophy (AHO; includes short stature, obesity, round facies,

subcutaneousossifications,brachydactyly,otherskeletalanomalies,andsome

patientshavementalretardation).

• In PHP1A, there is decreased cellular cAMP response to PTH infusion,

decreased erythrocyte Gs activity, and a GNAS1 mutation in the maternally

derivedallele.

• In PHP1B,thereis renalPTHresistance, decreasedcAMP responseto PTH

infusion,normalerythrocyteGsactivity,andimprinting/methylationdefectsat

theGNASlocusresultinginlackofexpressionofthematernalalleleinrenal

tissue.Classically,patientsdonothavefeaturesofAHO.

• PHP1B is not associated with generalized hormone resistance, although

resistancetothyroid-stimulatinghormonehasbeenreported.

• Individuals with AHO without endocrine abnormalities, a normal cellular

cAMP response to PTH infusion, decreased erythrocyte Gs activity and a

GNAS1 mutation in the paternally-inherited allele have

pseudopseudohypoparathyroidism(PPHP).

CKD-mineralandbonedisorders(CKD-MBD)incorporatingrenal

osteodystrophy(ROD)

• Thekidneysarekey inregulatingcalcium andphosphate,areatargetorgan

for PTH and FGF23, and are the primary source for 1α-hydroxylation

mediatedactivationof25(OH)D.

• CKD-MBD (the term was first proposed by Kidney Disease: Improving

Global Outcomes (KDIGO) in 2005) describes a broad clinical syndrome

whichincludesskeletal,softtissue,andvascularabnormalitiesthatdevelopas

aresultofCKD.Renalskeletaldiseasealoneistermed‘renalosteodystrophy

(ROD;Table16.8).

• RODcanbeaspectrumofbonediseasefrom‘highturnover’(duetoprimary

or tertiary hyperparathyroidism) to ‘low turnover’ (termed adynamic) bone

disease where PTH levels are generally low (reference range or modest

elevation).

• Phosphate retention (secondary), FGF23 elevation, hypovitaminosis D,

hypocalcaemia,impairedcalcitriolproduction,andskeletalresistancetoPTH

all contribute to secondary HPT in CKD with relevant effects beginning in

CKD3(estimatedGFR30–60mL/min/1.73m

• Historically low turnover, adynamic ROD has been related to excess

aluminium deposition in bone in dialysis patients—thus more prevalent in

peritonealdialysispatientscomparedwithhaemodialysis.

• Bone fragility and increased fracture risk is a consequence of all types of

ROD.ClinicalmanifestationsofRODareinTable16.8.

Table16.8Theclinicalmanifestationsofrenalosteodystrophy

Clinical

feature

Comment

Bonepain Common

Skeletal

deformity

Common.Affectsappendicularandaxialskeleton

Children:onset<3yrs,rachitic;onset<10yrs,bowingoflong

bones,widenedmetaphyses,pseudoclubbing,slipped

epiphyses

Adults:lumbarscoliosis,kyphosis,distortedthorax

Growth

retardation

Proximal

muscle

weakness

Ectopic

calcification

Soft-tissues.Visceral.Vascular—ifsevere,individualsmay

developischaemicnecrosis

GeneralmanagementofROD

• Earlydietaryrestrictionofphosphatecanmaintainnormalcalciumlevels,but

low-phosphate diets are often unacceptable and normal phosphate levels are

bestachievedwithbindingagents(somecontaincalcium).

• Small doses of calcitriol (vitamin D) may help to lower serum PTH levels.

Someindividualsmaybesensitivetocalcitriolandserumcalciumlevelsmay

increase.Mostpatientsrequiredosesof0.25–0.5microgramsdaily;children

mayrequirehigherdoses.

• Parathyroidectomy is indicated in persistent symptomatic hypercalcaemia,

ectopiccalcification,andseverebonepain.

Ectopiccalcificationandossification

• Ectopic calcification can arise from any one of a number of causes of

hypercalcaemia or hyperphosphataemia. These include renal failure,

hyperparathyroidism, familial hyperphosphataemia tumoural calcinosis

(OMIM211900)andsarcoidosis.Dystrophiccalcificationisalsoafeatureof

systemic sclerosis (see  Chapter 13), dermatomyositis (see  Chapter 14),

andprimarycalcinosis.

• Ectopicossificationcanbeseenposttraumaandfollowingmyositis.Itisalso

a feature of several rare conditions including PHP and myositis ossificans

progressiva. Early signs of muscle ossification are best detected with MRI

scanning.Laterossificationiseasilyvisibleonplainradiographs.Treatmentis

difficult, but includes physiotherapy to maintain suppleness and possibly

heparinsorbisphosphonatestohaltboneformation.

Paget’sdiseaseofbone

• Paget’s disease of bone (PDB) is a localized disorder of bone remodelling

resultinginexpansionanddeformityofbone.

• PDB is common (about 5% of the population >55 years) in the UK, North

America,Australia,andNewZealand,withamaletofemaleratioof3:2.It’s

uncommoninAsia,Africa,Scandinavia,andSouthAmerica.

• The ‘lesion’ in PDB is substantially increased (coupled) bone remodelling,

driven by an excess number of multinucleated, highly active osteoclasts,

producing excessive woven bone (immature bone characterized by erratic

collagenorientation).

• TheoriesofPDBbeingcausedbyviruseshavelargelybeendisproved.

• PDBhasageneticbasis;15–30%PDBpatientshaveapositivefamilyhistory;

there isa7× risk of developing PDBifyour first-degree relative has itand

30%offamilialcaseshavegenemutationsat5q35(thegeneencodesforan

ubiquitin-bindingproteinsequestasome-1(SQSTM1/p62)).

• SQSTM1mutationsindicateseverityofPDB,theproteinplayinganimportant

roleinNFKβsignalling.

• PDBpatientswithSQSTM1mutationscanhaveavariableclinicalphenotype

however,indicatingmodifyinggeneorenvironmentaleffectsalsoarerelevant.

• TheclinicalfeaturesofPDBareshowninTable16.9.

Table16.9ClinicalfeaturesofPaget’sdiseaseofbone

Clinicalfeature Details

Pain Deepunremittingpain,possiblycorrelatedtoblood

flow(e.g.headachefromskullinvolvement)

Boneinvolvement Pelvis75%,skull35%,femur35%,sacrum35%,tibia

30%,radius15%,handsorfeet10%ofcases

Fractures Vertebralfractures,‘fissure’fracturesatsiteof

convexityoflongbone

Neurological

sequelae

Spinalcordcompression,radiculopathy,deafness,

High-output

cardiacfailure

Rarebutcanoccurif>40%oftheskeletonisinvolved

Osteosarcoma 0.1%ofcases

Hypercalcaemia

andhypercalciuria

Unusual.Linkedtopolyostoticdiseaseandimmobility.

Can,ifsevere,leadtokidneystonedisease

Osteoarthritis PDBinboneadjacenttojoint,canacceleratejoint

degeneration

Retinalangioid

streaks

Causeunknown

Investigationandtreatment

• Serum alkaline phosphatase (ALP), a measure of osteoblast-derived bone

formation, is the most useful marker of high bone remodelling and may be

elevatedasmuchas30×abovenormal.

• ReferencerangeALPcanmeanboneturnoverislow(‘inactivePDB’)butis

not specific. The degree of abnormality of ALP often associates with the

number of bones affected, polyostotic disease being associated with higher

ALPvalues.

• The differentialdiagnosis of increased (bone) ALP includes metastatic bone

disease, osteomalacia, hyperparathyroidism, and osteomyelitis or

inflammation.

• Because of the increased bone turnover, other biomarkers will beabnormal:

e.g.increasedurinehydroxyproline,serum/plasmaCTX,P1NP.

• Thereisawidevariationinradiographicappearanceoftheconditionbutthe

main features are localized sclerosis, coarse and irregular trabecular

patterning,andboneexpansion.

• 

99m

TC methylene diphosphonate (MDP) bone scintigraphy is a sensitive

investigationfordefiningtheextentoflesions.See Plate22.

• ThereareseveralindicationsfortreatmentofPaget’sdisease:

• Painarisingfromaffectedsites.

• Deformingdisease.

• Fissurefractures.

• Skulldisease.

• Reductionofvascularityinbonenexttoajointplannedforsurgery.

• Complications—progressiveneurology,hypercalcaemia,high-outputcardiac

failure.

• PDBandrelatedosteoarthriticpainmaybereducedbysimpleanalgesics,but

purepageticbonepainrespondspoorlytothis.

• Full biomechanical assessment, particularly looking for correctable

deformitieswithjudiciousorthosisuse,isinvariablyhelpful.

• First-linetreatmentofPDBisasingledoseofzoledronicacid5mgIV.

• Analternativeisrisedronate30mgdailyfor2months.Therelapseratewith

risedronateissignificantlyhigherthanwithzoledronicacid.

• Historically,etidronate(e.g.6monthsatadoseof5mg/kg/day),pamidronate

(e.g. 90 mg IV ×2 doses fortnight apart) and calcitonin (50–100 IU SC

injectiondaily,reducingto50IU2or3timesperweekonceasymptomatic

responseisachieved(usuallyafter4–8weeks)haveshownbenefitinreducing

PDBpainandALP.However,relapseriskismoderatelyhighcomparedwith

zoledronicacid.Calcitoninoftencausesnausea,flushing,anddiarrhoea.

• Many PDB patients achieve long-term biochemical remission with just a

singletreatmentofzoledronicacid5mg.

• Typicalsideeffectsofzoledronicacid,aswithpamidronate,includestransient

‘flu-like’symptomsoffever,myalgia,andarthralgia.

• Zoledronicacid5mgIVusedforALPrisealonedoesnotappeartobenefit

PDBpatientscomparedwithpatientstreatedonthebasisofPDBsymptoms

alone (PRISM-EZ); indeed, it may be associated with a greater risk of

fractures(innon-pagetoidbone).

• ZoledronicacidiscurrentlybeingstudiedforitsroleinPDBdevelopmentin

high-risk(SQSTM-1mutation-positive)patients.

• Typicalsurgicalinterventionsincludearthroplasty—whereacceleratedOAhas

evolved in joints adjacent to pagetoid bone, fixation of fractures, and

realignment osteotomies where there is significant deformity amenable to

surgicalcorrection.

• VitaminDdeficiencyisincreasedinfrequencyinPDBpatientscomparedto

expected,thusitshouldbesoughtandcorrected.

• Denosumab ispredicted tobe effective atreducing boneturnover, pain,and

ALP in PDB but treatment will be relatively expensive, relapse of PDB is

likely to occur on treatment cessation, and the rebound increase in bone

turnoveratthattime,islikelytoprecludeitsadoptionasaroutinetreatment

forPDB.

Childhoodautoinflammatorybonediseases

Introduction

Autoinflammatorybonediseasesaredisordersprimarilydrivenbyabnormalities

oftheinnateimmunesystem.

• The most common disorders include chronic non-bacterial osteomyelitis

(CNO); synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO)

syndrome;Majeedsyndrome; deficiency ofinterleukin-1 receptor antagonist

(DIRA);cherubism;andjuvenilemandibularchronicosteomyelitis(JMCO).

• Bone inflammation is typically characterized by a subacute or chronic

inflammation that is bacterial culture negative and with no demonstrable

organismonhistopathology.

• NSAIDs are typically used as first-line therapies in CNO. Bisphosphonates

and anti-TNFα drugs have been used for second-line therapies to prevent

pathologicfractures,pain,anddiseaserelapse.

• CNOandSAPHOarediscussedingreaterdetaillaterinthissectionandfor

therarerautoinflammatorybonediseasesseeTable16.10.

Table16.10Featuresoftherarestautoinflammatoryboneconditions

Features DIRA Cherubism Majeedsyndrome

Fever Uncommon No Highfevers

Common

CNOsites

Longbones

especiallyproximal

femur,vertebral

bodies,ribs,

clavicles

Maxillaand

mandible

Femur,tibia,pelvis,

calcaneus,ankle,

vertebrae,and

clavicle

Areaoflong

bones

affected

Metaphyses

predominantly

Longbones

rarelyaffected

Metaphyses

predominantly

Extraosseous

features

Skinpustulosis,

systemicorgan

involvement

Cervical

lymphadenopathy

Congenital

dyserythropoietic

anaemia,

dermatitis,growth

failure,

hepatomegaly,joint

contractures

Inflammatory

markers

Elevated Normaltomildly

elevated

Elevated

Inheritance AR AD AR

Genedefect IL-1RN SH3BP2 LPIN2

Ethnic

distribution

PuertoRican,

European,Lebanese

Worldwide Arabic,Turkish

CNO

The terminology for CNO has changed over the last 40 years. The most

commonly used term is chronic recurrent multifocal osteomyelitis (CRMO);

however,notallpatientshavemultifocalbonelesionsornumerousrecurrences,

hence the term chronic non-bacterial osteomyelitis (CNO) encompasses all

possiblediseasepresentations.

• CNO is a systemic disease that predominantly occurs in childhood. It has

manysimilaritiestoSAPHOsyndrome,adisorderprimarilyseeninadults.

• TheincidenceandprevalenceofCNOisunknown,butthemajorityofreports

are from Scandinavia, Europe, Australia and North America. Female

predominance/meanageofonsetabout10yearsofage.

• CNOisadiagnosisofexclusionestablishedbyclinicalpresentation,imaging

studies,andaculture-negativebonebiopsy.

• Painoccurswithorwithoutswellingatthesiteofabonylesion.Inflammatory

markersarenormalormoderatelyraised.

• Bonelesionstendtoclusteraroundmetaphysis,butcanoccuratsitessuchas

theclavicle(commonlythemedialthird).

• The most common CNO sites include the femur, pelvis, calcaneus, ankle,

vertebrae, and clavicle. Multifocal lesions tend to have a symmetrical

distribution.Unifocaldiseaseoccursin10–20%.

• CNOpatientsfrequentlyhaveothercoexistingchronicinflammatorydiseases

such as psoriasis, arthritis, inflammatory bowel disease, vasculitis,

myositis/fasciitis,andparotitis.

• Imaging to clarify diagnosis: radiographs and MRI. CT can be used, but

exposeschildrentohighradiation,soisnotrecommended.

• Whole-body MRI can assess for asymptomatic (polyostotic) lesions, and

shouldbeconsideredforindeterminateCNOcases.

• Typical radiographic findings include a lytic lesion at or around the

metaphysis,whichmayprogresstosclerosisorhyperostosis.

• Bonebiopsyisoftenrequiredtoconfirmthediagnosis—importantinisolated

bonelesions,asmalignancycanmimicCNO.

Treatment

• NSAIDsarethegoldstandardinitialtherapy.

• CasereportssuggestGCs,methotrexate(MTX),andsulfasalazine(SZP)may

bebeneficial,butresultsareinconclusive.

• Reports on use of anti-TNFα are inconclusive: some responses are

unsustained.

• IV bisphosphonate (e.g. pamidronate) has been used due to its effect on

reducingosteoclast-drivenosteitispathophysiology.

• Several studies have demonstrated high efficacy rates and good clinical

response occurring in the first 3 days, and inducing remission for 12–18

months.

• However,thereareconcernsregardingtheuseofbisphosphonatesinchildren

giventhelackoflong-termsafetydata.

• Themostcommonadverseeventofpamidronateisminorflu-likesymptoms.

Osteonecrosis of the jaw is a rare but serious complication and to date

unreportedinpaediatricuse.

• CNOcanbeadifficultconditiontotreat,withhighratesofnon-responders.If

untreated,thereisincreasedriskofpathologicalfractures,inadditiontoother

possible morbidities such as generalized growth failure, scoliosis, and

hyperostosis.

Reference

3. SternSM,FergusonPJ.Autoinflammatorybonediseases.RheumDisClinNorthAm2013;39:735–49.

SAPHOsyndrome

SAPHO syndrome was originally an acronym from the French term: le

Syndrome Acne, Pustulose, Hyperostose et Osteite but later changed and

terminology anglicized in terminology to Syndrome of Synovitis, Acne,

Pustulosis, Hyperostosis and Osteitis. However, the original description is

notable for the absence of synovitis, which probably is quite an uncommon

lesionofthecondition.

• SAPHO syndrome has similarity to CNO but can also be classified as an

osteoscleroticbonedisease.Furthermore,theremaybeoverlapwiththeSpA

diseases—some features exist in both SAPHO and some forms of psoriatic

arthritisthoughSAPHOisnotB27related.

Patternsandspectrumofdisease

• Typicalpresentationage30–50yearsoldthoughchildhoodformsexist.

• Pathogenesismayderivefromanamplifiedabnormalinnateimmuneresponse

to pathogens, with the most likely triggering pathogen being

Propionibacteriumacnes.

• Apatient’sdiseasephenotypecanbeindistinguishablealsofromaxialskeletal

sarcoid.

• Therearesimilaritiestoandoverlapwithformsofpsoriaticarthritis.

• CRMOhasbeendescribedasthepaediatricpresentationofSAPHO.However,

thelocalizationofinflammationisdifferentbetweenthetwoconditionswith

the extremities more often affected in CRMO than SAPHO whereas for the

latter,axialskeletonwithcosto-sternoclavicularregionisthefocus.

• Both enthesitis and spondylodiscitis are likely to be associated SAPHO

lesions.

Clinicalfeatures

• Painfulosteitislesions,enthesitis,andspondylodiscitisarelikelytoalloccur

inSAPHOlesions.

• Palmoplantar pustulosis (PPP) and severe acne (acne conglobata, acne

fulminans, hidradenitis suppurativa) are among the typical lesions seen in

SAPHO.

• PPPismoreoftenseeninwomenandsevereacneinmen.

• Other skin lesions described in SAPHO include various types of psoriasis;

pyodermagangrenosum;Sweet’ssyndrome;Sneddon–Wilkinsondisease.

• Systemicsymptomsoffeverandfatiguefrequentlyoccur.

Differentialdiagnosis

• Psoriatic arthritis. This can pose diagnostic dilemma since psoriatic arthritis

manifest by spondylodiscitis, osteitis, entheseal/juxta-articular hyperostosis

andpustularpsoriasiscanmimicSAPHO.

• Infection (osteomyelitis) and neoplasia should be considered though MRI is

usuallydiscriminatory.

• Inchildren,thefollowingshouldalsobeconsidered:Ewingsarcoma,Majeed

syndrome,histiocytosis,andDIRA.

Investigations

• 

99m

TC MDP (bone) scintigraphy is characteristic in most cases showing

markedtracer accumulationat sternoclaviculararea lesions(e.g.Bull’s head

sign).

• Onradiographslesionsareoftenprimarilyexpandedandsclerotic.

• MRIdiscriminatesosteitisfrominfectionandmalignancy.

• Laboratory tests are not specific and features of inflammationmaybeseen:

raised CRP, ESR, platelets, C3, ACE. Immunoglobulins are usually normal

andautoantibodiesnotdetected.

• BoneshouldbeculturedforTB,Propionibacterium,andgeneralpathogens.

• Histology ofboneoften showsdense disorganized sclerosiswithfeatures of

increasedboneturnover.

• Histology of skin lesions can show neutrophilic infiltration and pseudo-

abscesses(differentialdiagnosis—Sweet’ssyndrome).

Treatment

• NSAIDsareusedforpain.

• Appropriateantibioticsforculture-positivebonebiopsy.

• Colchicine, GCs, oral and IV bisphosphonates, and sDMARDs (e.g. MTX)

haveallbeenusedwithvariableeffects.

• Anti-TNFα and anti-IL-1 receptor antagonist (anakinra) have shown good

effectpersistentdisease.

• Forskinmanifestations,topicalsteroids,PUVA,andretinoidshavebeenused.

Reference

4. RukavinaI.SAPHOsyndrome:areview.JChildOrthop2015;9:19–27.

Theosteochondroses

Osteochondrosis is a trauma-induced focal disturbance of cartilage in a joint

(articular), at a periarticular epiphyseal plate or tendon or ligament insertion

(apophysis/enthesis).

• Lesionstypicallyoccurinactivechildrenandadolescents.

• Osteochondritis may be associated with a delay in growth-associated

endochondral ossification, with a potential consequence of joint or other

biomechanicaldeformity(see Table16.11).

• Wherethelesionisassociatedwithcleftformationthrougharticularcartilage,

thenthelesionistermed‘dissecans’.

Scheuermann’sdisease

Although not consistently defined, Scheuermann’s disease is a vertebral

epiphysealosteochondritisthatoccursinadolescence.Seealso p.620

• Althoughanincidentalradiographicfinding,Scheuermann’sisalsoassociated

with diffuse spinal pain which is more likely to be present if the

osteochondritisisthoracolumbar(25%),ratherthanthoracic(75%)andifthe

childisanathleteorveryactive.

• It can present with painless dorsal kyphosis with compensatory lumbar

lordosisandlateralspineradiographsshowirregularityofvertebralend-plates,

anterior vertebral wedging, and kyphosis—the latter can develop in late

adolescenceorgraduallyoveryears.

• Inadultswhopresentlate,thevertebraldeformitiesmaybemistakenforgrade

1vertebralfractures.

• Management is with physiotherapy—working on extensor spinal muscular

strength,andjudicioususeofanalgesics.

Legg–Calvé–Perthesdisease

Perthesdiseaseisanosteonecrosisofthefemoralepiphysisandoccursintheage

range3–8years,mostfrequentlyinboys(ratio4:1).

• Perthesdiseaseisbilateralin10–20%ofcases.

• Symptomsincludeaninsidiousonsetoflimpandpaininthegroinorreferred

totheknee/thighthatisrelievedbyrest.

• Theremaybelimitationofhipinternalrotationandabduction(duetoadductor

spasm).

• Leg length inequality suggests femoral head collapse. There may be

spontaneousresolution,especiallyinyoungerpatients,inwhomconservative

managementisindicated.

Osgood–Schlatterdisease

Thisosteochondrosisisprobablyduetorepetitivetraumaatthesiteofpatellar

tendoninsertionintothetibialtubercle.

• Ittypicallyoccursinathleticadolescents,especiallyyoungmalesaged14–16

years.

• Painisusuallyonexerciseandeaseswithrest.

• Thediagnosisismadeclinicallyandondemonstratinganenlargedfragmented

tibialtubercleonalateralviewradiograph.

• Bilateralkneeviewshelptodistinguishnormalfromabnormal.

• DifferentialdiagnosisincludesSpA-relatedenthesitis.

Sinding–Larsen–Johanssondisease

Thisosteochondrosisoccursasaconsequenceofoverloadingofthepatellaatits

secondary centre of ossificationproducingatraction apophysitis at the patella

lowerpole.

• Although not exclusive to the group, it is a typical sports-related injury in

adolescentathleteswhojump,e.g.high-jump,basketball.

• TreatmentiswithsimpleanalgesiaorNSAIDs,andrest.

Köhlerdisease

Thisosteochondrosisisessentiallyanosteonecrosislesionofthetarsalnavicular.

Changesmayrepresentadevelopmentalvariationinossificationanditpresents

witha painfullimp. Weight-bearingis morecomfortable onthe outsideof the

footandthenavicularistender.

Freibergdisease

Anosteonecrosisofthemetatarsal(usuallythesecond)headfollowingtrauma,

ismostcommoninadolescentfemales.Painislocalizedandworseonweight-

bearingwithswellingsometimesdetectable.

Anosteochondritis‘dissecans’lesion

An articular osteochondritis lesion can become a ‘dissecans’ lesion when a

fragment ofarticularcartilage and subchondral bone becomes demarcatedand

mayformanintra-articularloosebody.

• Symptomsofadissecanslesionaremainlyacute-onsetpain,aneffusion,and

limitedmovementofthejoint.

• Plainradiographswillshowawell-circumscribed,scleroticlesion.

• Inyoungpatientsbeforeskeletalmaturitythereisagoodchanceofdissecans

healing.

• Aftertheepiphysishasclosed,however,thereismoreriskofaloosebodyand

secondaryosteoarthritisifadissecanslesionpersists.

• Arthroscopycanassistinassessingthedegreeofdamageandremovingloose

bodies.

• Surgeryrangesfromdrillingthelesioninsituto encouragehealing, tobone

osteochondralallografts.

Table16.11Osteochondritisconditions

Type Site Details

Articular Metatarsalhead

(Freiberg’s)

Typically,2ndmetatarsalhead;bilateralin

10%

Hip(Legg–

Calvé–Perthes)

Slippedcapitalfemoralepiphysis;4–10years

ofage;morecomplicationsif>8yearsofage;

isbilateralin10%

Navicular

(Kohler’s)

3–7yearsofage;maletofemaleratio5:1;

occasionallybilateral

Talus Laterallesionsmostlikelytobeassociated

withsingletraumatrigger

Lunate

(Kienbock’s)

Rare<15yrsold;commonlymales;maybe

associatedwithshortulnarelativetoradius

Non-

articular-

atan

enthesis

Vertebralend-

plate

(Scheuermann’s)

13–17yrs;male:femaleratioequal;usually

lowerthoracic>thanupperlumbar;often

severalvertebraeaffected(3–5)

Tibialtubercle

(Osgood–

Schlatter)

Enthesitisofinsertionofpatellarligament;

typically10–15yrsofage;moreoftenmales

thanfemales;bilateralin25%

Inferiorpatella

pole

‘Jumper’sknee’;typicallymaleadolescents

involvedinsportsandexercise;

5thmetatarsal

base(Iselin’s)

9–15yrsold;typicallysports-relatedtrauma

Calcaneus

(Sever’s)

‘TractionenthesitisatAchilles’tendon

insertion;incidence4/1000children6–17yrs

Epiphyseal

plate

Ulnamedial

epiphysealat

elbow

(Panner’s)

AvulsionenthesitisfrompitchinginLittle

Leaguebaseballtermed‘LittleLeague

elbow’;males<16yrsold;associatedwith

increasedheightvelocity;extensively

reportedinthesportsmedicineliterature

Medial/proximal

tibia(Blount’s)

‘Tibiavara’;infantile<3yrsoldorlateonset

Slippedupper

(capital)femoral

epiphysis

(SUFE)

Commonestadolescenthipdisorder;20%

bilateral;risks:obesity,coxaprofunda,

femoraloracetabularretroversion,

hypothyroidism,ROD,hypopituitarism;25%

riskofprogressiontoosteonecrosis;almostall

casesneedsurgery

Osteonecrosis

Osteonecrosis is regional ischaemic skeletal injury, which can be caused by

trauma,drugs(e.g.GCs),orsystemicconditions—metabolic,haematological,or

endocrine(e.g.sicklecelldisease,antiphospholipidsyndrome).

• Ifsevereand/orprolonged,ischaemiacancauseskeletalcelldeathleadingto

necroticbone,whichcancompromiseregionalskeletalintegrityandstrength

andleadtofracture,damagetoadjacentcartilage,anddeformity.

• Osteonecrosiscanbesymptomaticallysilentandpersist,withnoorminimal

symptoms,foryearsinsomecases.

• Ischaemia occurs after mechanical interruption of blood delivery, non-

traumaticintravascularocclusion,thrombosis,cholesterol,expandingnitrogen

bubblesorothermechanismsthatleadtocriticalischaemia;thendepositionof

vascularizedconnectivetissuecanaccumulateattheinterfaceofnecroticand

normal bone. Calcification can follow and necrotic tissue remains as an

‘island’ofinviablebone.

• Localskeletalfeaturesincludepainordiscomfort.Painevolutionmaydenote

the onset of subchondral bone collapse. If secondary adjacent joint damage

evolvesandprogressesthenfeaturesofmechanicaljointdiseasewillevolve—

painanddiscomfortonmovement,stiffness,swelling,andafunctionalimpact

accordingly.

• There may be tenderness on palpating over osteonecrotic bone and signs of

jointeffusionifthelesionhasaffectedtheadjacentjointcausingcartilageloss

ormicrofracture.

• MRIsignsarecharacteristicandcancontributetograding(e.g.femoralhead

afterFicat).Seealso bonescintigraphyPlate17.

• Practical radiographic-based osteonecrosis grading can be done using

Steinberg(2001)orevenARCO(1992)gradingsystems.

• Laboratorytestingshouldfocusonsystemiccauses(Table16.12).

• Initialmanagement:paincontrol,addressingremediableunderlyingsystemic

causes/associated disease,agreeingand planning what amount of weight-or

load-bearingoftheaffectedboneispermissible.

• In the absence of data from controlled studies of treatment, management is

basedonstageofthelesionanddegreeofeffectontheadjacentjoint,thusfor

early disease with reversible cause, or repair or revascularization possible

before any collapse of the subchondral bone, conservative measures are

appropriate.Butinlatediseasewithsubchondralbonecollapse,arthroplastyis

considered.

• Forosteonecrosisofthefemoralhead(ONFH)consideran8-weekperiodof

non-weight-bearing.

• Evidenceforbisphosphonateuseanditseffectisanecdotalonly.

• Core decompressionforONFH involves removingbone from themedullary

cavityormultiplesmallerholesthroughthebonesurface.Thecavitymaybe

then filled with a vascularized fibular graft or by non-vascularized cortical

bone.

• Osteotomy attempts to shift the weight from the necrotic segment but

subsequent joint replacement is technically more difficult. Hemi-resurfacing

preserves the bone for later arthroplasty and is an option for femoral head

collapseinyoungerpatients.

• Skeletalstemcellscombinedwithimpactionbonegraftingisanoveltreatment

translatedtothetreatmentofONFH.

Table16.12Conditionscausing,orassociatedwith,osteonecrosis

Condition Notes

Trauma Fracturesandfracture-dislocations,Legg–Calvé–Perthes

disease,orthopaedicprocedures

Glucocorticoids

(GCs)or

Cushing’s

disease

Associatedwithacuterepeatedhigh-doseGCsorhigh

cumulativeGCdoses.GCscausehypertrophyand

hyperplasiaofmarrowfatcells.GCsdivertmesenchymal

cellstowardanadipocytelineageasopposedtoosteoblast-

osteocyteone

Alcohol Riskincreases>3-foldinthoseconsuming40 unitsper

weekormore.

Drugs Cocaine;bisphosphonatesanddenosumab(monoclonal

antibodytoRANKL)bothcausingONJ;oral

contraceptives(rare);proteaseinhibitors;thalidomide

Gaucher

disease

Inthetotalpopulationof5894ICGGGaucherDisease

Registrypatients,544experiencedatleastoneepisodeof

osteonecrosis;associatedwithanaemia

SLE Osteonecrosisreportedinupto27%ofpatientstaking

GCs,oftenmultifocal;riskhigherifthereis

hypertriglyceridemia

Transplantation Likelymultifactorialrisks.MainlyassociatedwithGCs

Sicklecell

disease

Prevalenceveryhigh.Mostcommonlyhumeralhead(28–

48%prevalence);ONFHmostprevalentinpatientswith

SCD-SSα-thalassemia

Prothrombotic

risks

Upto50%ofcasesofmultifocalosteonecrosisassociate

withpro-thromboticconditions(e.g.antiphospholipid

syndrome)

Dysbaria Predominantlyaffectsfemoralheadandproximalhumerus

indivers,caissonandtunnelworkers.

HIV Proteaseinhibitor-inducedhyperlipidaemiaandHIV-

associatedantiphospholipidsyndrome

Malignancy All;notablychildhoodleukaemia

Otherprobable

associations

Pancreatitis,hyperlipidaemia,diabetes,pregnancy,

hyperuricaemia/gout

Fibrousdysplasia

Fibrous dysplasia (FD) manifests as either an isolated (monostotic) or

polyostoticconditionasfibrousbonecysts.

• FD presents most often in the second to third decade of life as monostotic

disease,orusually<10yearsofageinpolyostoticdisease.

• FDismanifestbycysticexpansionofbones.Lesionscancausepainandlocal

mechanical effects due to their site and proximity to critical structures (e.g.

nerveforamenintheskeleton).

• FDisduetoactivatingorgain-of-functionGNAS1mutations.

• McCune–Albrightsyndrome isatriadof polyostoticfibrousdysplasia,hyper

pigmented ‘café-au-lait’ patches, and endocrine abnormalities (Cushing’s,

thyroid,precociouspuberty).

• Thereisgenetic mosaicismgiventhemutationinFDandMcCune–Albright

syndromeissomaticinorigin.Thedegreeofextentofpathologyandseverity

therefore depends on the stage of development at which the postzygotic

somaticmutationoccurred.

• When the mutation occurs at an early post-zygotic development stage, the

conditionismoresevere(agermlineGNAS1mutationwouldbelethal).

• FD bone lesions grow under the influence of growth hormone (/IGF-1) and

maystopgrowingatskeletalmaturity,butneedmonitoring.

• AnyFDbonelesioncanproduceFGF23andmildhypophosphataemiaisnot

uncommonandadditionalosteomalaciacanresult.

• Bonepainiscommonanddifficulttotreat.

• Bonepainissometimessevereanditscauseunexplained.

• PaincanbetreatedwithserialIVpamidronateinfusions.Doseregimensvary

andoptionshavenotbeensystematicallystudied.

• SomeFDlesionsdonotcausesymptomsthoughcancausecomplicationssuch

asfracture,neuralcompromise(expansionofboneadjacenttoanervecanal),

orbonecollapsedependingontheirsite.Fracturehealingdoesnotappearto

becompromisedhowever.

• Patient information is available at:  http://www.gosh.nhs.uk/fibrous-

dysplasia and support at:  http://www.fibrousdysplasia.org and also at:

http://www.fdssuk.org.uk

Sclerosingbonedisorders

Sclerosingbonedisorderscomprisethoseaffectingcorticalbone(hyperostotic)

andthoseaffectingtrabecularbone(osteosclerotic).

• Therearemanysclerosingbonedisorders.

Themostcommonaredealtwith

herebutseealsoTable16.13.

Osteopetrosis

Isatermthatdefinesarangeofosteoscleroses(‘theosteopetroses’).

• The osteopetroses are caused by one of a number of genetic abnormalities

which result in functional deficit (mostly regulation of acidification) in

osteoclastic bone resorption (e.g. CLCN7, GL, CA II (causes carbonic

anhydraseIIdeficiency)).

• AD andARforms exist—theformer lethalinchildhood unlesstreated—the

latteroftenbenignandpresentslaterinlife.(See http://www.omim.orgfora

comprehensivereviewofgenetics.)

• Diagnosisismadeonradiographswheretheeffectsofosteoclastfailureduring

endochondralboneformationresultin‘islands’or‘bars’ofcalcifiedcartilage

withintrabecularbone.

• HLA identical bone marrow transplant has been very effective for some

infantileformsofosteopetrosis.

Camurati–Engelmanndisease(CED)andRibbingdisease(RD)

• CED and RD are manifest by slowly evolving long bone hyperostosis in

childrenandadolescents(CED)andinadolescentsandyoungadults(RD).

• Bone sclerosis may be drivenbyrelease of active TGF-β from bone matrix

whichdrivesthedevelopmentandactivityofosteoblasts.

• CEDislikelyaconsequenceofoneoranumberofgermlinemutationinthe

TGF-βgeneorpeptideswhichregulateTGF-βactivation.

• It is unclear whether RD is similar but with variable penetrance or whether

thereareacquiredsystemicfactorsthatcan,similartothefunctionaleffectin

CED,‘switchon’TGF-βactivity.

Primaryhypertrophicosteoarthropathy(HOA)

• HOA is a familial disorder characterized by digital clubbing, hyperhidrosis,

facialskinthickening,andlongbonehyperostosis.

• Therearevariablefeaturesofpachydermia,delayedclosureofthefontanelles,

andcongenitalheartdisease.

• The AD form (pachydermoperiostosis) is very rare and the genetic cause

unknown. AR primary hypertrophic osteoathropathy-1 (PHOAR1) is caused

byahomozygousmutationintheHPGDgeneonchromosome4q34.1.

Pulmonary(secondary)hypertrophicosteoarthropathy(HPOA)

• HPOAdiffersfromHOAandischaracterizedbydigitalclubbingsecondaryto

acquireddiseases,mostcommonlyintrathoracicneoplasm.

Endostealhyperostosis

Theprocessofsclerosischaracterizestwoconditions:VanBuchemdiseaseand

sclerosteosis.

• Both diseases are autosomal recessive and are caused by mutations in the

SOSTgene,whichencodesforsclerostin.

• A loss of function in sclerostin results in de-suppression of osteoblast

differentiation and function thus causing generalized bone sclerosis and

hyperostosis.

• The diseases have informed the development of a therapeutic inhibitor of

sclerostintotreatosteoporosis.

Osteopoikilosis

Is a benign condition often disclosed incidentally on radiographs (‘spotted

bones’).

• Occasionally the condition is associated with the occurrence of connective

tissue nevi and dermatofibrosis (Buschke–Ollendorf syndrome) and

melorheostosis.

HepatitisCosteosclerosis

HepatitisC canbeassociatedwithseveregeneralizedosteosclerosis(cranium-

sparing).

• Remodellingofgoodqualityexcessiveboneseemsacceleratedduringactive

disease, though it will respond to anti-resorption treatment and gradual

spontaneousremissioncanoccur.

• TheconditionmaybecausedbyeffectsofIGFasthereareincreasesinIGF

bindingprotein(‘bigIGF2’).

Table16.13Thespectrumofsclerosingbonedisorders

Type Conditions

Dysplasias

and

dysostoses

Autosomaldominantosteosclerosis;centralosteosclerosiswith

ectodermaldysplasia;craniodiaphysealdysplasia,

craniometaphysealdysplasia;dysosteosclerosis;endosteal

hyperostosis(VanBuchemdiseaseandsclerosteosis);

frontometaphysealdysplasia;infantilecorticalhyperostosis

(Caffeydisease);juvenilePDB;melorheostosis;metaphyseal

dysplasia(Pyle’sdisease);mixedsclerosingbonedystrophy;

oculodentoosseousdysplasia;osteopathiastriata;osteopetrosis;

osteopoikilosis;progressivediaphysealdysplasia;Ribbing

disease;pycnodysostosis;tubularstenosis(Kenny–Caffey

syndrome)

Metabolic CarbonicanhydraseIIdeficiency;fluorosis;heavymetal

poisoning;hepatitisCassociated;hypervitaminosisD/A;

primaryhyperparathyroidism;hypoparathyroidism,

pseudohypoparathyroidism;LRP5gain-of-function(highbone

mass);milk-alkalisyndrome;renalosteodystrophy;X-linked

hypophosphataemicrickets

Other Axialosteomalacia;DISH;Erdheim–Chesterdisease;

fibrogenesisimperfectaossium;pachydermoperiostosis;

hypertrophicosteoarthropathy;ionizingradiation;leukaemias,

lymphoma;mastocytosis;multiplemyeloma;myelofibrosis;

osteomyelitis;osteonecrosis;Paget’s;sarcoidosis;sicklecell

disease;sclerotictumourmetastases(e.g.prostate);tuberous

sclerosis

Reference

5. WhyteMP.Sclerosingbonedisorders.In:RosenCJ(ed)PrimerontheMetabolicBoneDiseasesand

DisordersofMineralMetabolism(8thedn),pp.767–85.NewYork:Wiley-Blackwell,2013.

Bonetumours

Primarytumoursofbonesandjointsarerare,haveapeakincidenceinchildhood

andadolescence,andcanbebenignormalignant.Paget’sdiseaseaccountsfor

mostcasesofosteosarcomaoccurring>40yearsofage.

Osteoidosteoma

An osteoid osteoma (OO) is a benign osteoid-forming tumour that can be an

elusivecauseofintensefocalbonepaininchildrenoradults.

• OOsareuncommonandaccountsfor10%ofbenignboneneoplasia.

• OOsare2–3×morecommoninmenthanwomenandtheincidenceishighest

in the second and third decades of life; >66% occur in long bones and

especiallythefemurandtibia.

• OOlesionsareidentifiedonradiographs(ormorecommonlyCT)asawell-

definedareaof sclerosiswith radiolucentnidusoften containingspeckles of

calcium.

• 

99m

TcMDPscintigraphyisasensitivemethodofisolatingalesionandCTis

valuableforlocalizingthenidusbeforesurgicalresection.

• Pain will respond, in part, to aspirin or NSAIDs. Provided the nidus is

completelyresected,surgeryiscurative.

Osteosarcoma

Thisisararetumourwithanincidenceof0.6–0.9per100,000population.Itis

thecommonestprimarybonetumour.

• Mostpatientspresentat<30yearsofage.

• Thepresentationiswithlocalpainandswelling.

• Radiographsshowexpansionofthebonewithasurroundingsofttissuemass,

oftencontainingislandsofcalcification.

• MRIorCTshouldbearrangedtodeterminetheextentoftumour.

• Patientssuspectedtohaveosteosarcomashouldbereferredtoaspecialistteam

forbiopsy.

• Treatmentdependsonhistologybutgenerallyinvolvessurgicalremovalofthe

tumour (and often radical field surgery including amputation), followed by

chemotherapyandradiotherapy.

• The prognosis is generally good in cases that present in childhood and

adolescence,butpoorinelderlypatientswithosteosarcomarelatedtoPaget’s

diseaseofbone.

Chondrosarcoma

• Thisisthesecondmostcommonprimarybonetumour.Presentationissimilar

to osteosarcoma. Treatment choice is between surgical resection and

radiotherapy. Chondrosarcomasare relatively resistantto chemotherapy. The

prognosisisgoodforlow-gradetumoursbutpoorforanaplastictumours.

Chapter17
Infectionandrheumaticdisease
Introduction
Septicarthritis
Mycobacteriumtuberculosis
Osteomyelitis
Lymedisease
Rheumaticfever
Introduction
Microorganisms have been linked directly and indirectly (through organism-
specific and autoimmune responses) to a number of acute and chronic
inflammatoryrheumaticdiseases.Thischapterwillintroducesomeexamplesof
theinflammatorymechanisms(summarizedinTable17.1)andmicroorganisms
(summarizedinTable17.2)linkedtorheumaticdisease,andthendiscussseptic
arthritis, Mycobacterium tuberculosis, osteomyelitis, Lyme disease, and
rheumaticfever.
Table17.1Pathogenesisofrheumaticdiseaseassociatedwithinfection
Inflammatory
process
Basicprocess Example Susceptibility
Local
infectionat
MSKsites
Infection.Tissue
inflammationanddirect
tissuedamage
Pyogenic
septic
arthritis
Diabetes,
complementand
immunoglobulin
deficiencies
Pathogenand
pathogen-
specific
Infectionandorganism-
specificresponse.Immune
responsetointactorganism
Syndromes
associated
withviral
Notgenerally
established

immune

response

orfragments,probable

immunecomplex-mediated

tissueinjury

hepatitis,e.g.

Sjögren’s

syndrome

Pathogens,

immune

responseand

autoimmunity

i.Cross-reactiveimmune

response.ii.Infection

inferred,butnotestablished,

autoreactivity

Rheumatic

fever,RA,JIA

SLE

HLAclassIand

IIgenes,T-cell

receptorgenes

Table17.2.Examplesofmicroorganismsassociatedwitharthritis

Class Examples Disorder

Bacteria Staphylococcusand

Streptococcus

Septicarthritis,osteomyelitis

Neisseriaspp. Gonococcalarthritis

Brucella Septicmonoarthritis

Klebsiella Spondyloarthritis

Chlamydia Reactivearthritis

Mycobacteria Mycobacterium

tuberculosis

Osteomyelitis,oligoarthritis

Atypical

mycobacteria

M.aviumcomplexM.

malmoense

Septicarthritisin

immunosuppressedpatients

Spirochaete Borreliaburgdorferi Lymedisease

Viruses ParvovirusB19 Fifthdisease

Rubella Polyarthropathy

HepatitisB Polyarteritisnodosa

HepatitisC Cryoglobulinaemia,Sjögren’s

syndrome

HIV Polyarthralgia,myopathy,

vasculitis,Siccasyndrome

Protozoa Toxoplasma Polyarthritis

Giardia Oligoarthritis

Trypanosoma Myopathy

Helminths Toxocara Allcausemyositisandarthritis

Schistosoma

Fungi Histoplasma Monoarthropathy

Cryptococcus

Septicarthritis

Septic arthritis caused by a bacterium is a medical emergency. See also

Chapter25,p.708formanagementinadultsandchildren.

Epidemiology

Incidenceinthegeneralpopulationis2–10per100,000andrisingto30–70per

100,000 in those with autoimmune rheumatic disease or prosthetic joint

replacements.

Pathology

• Most cases are due to haematogenous seeding during transient bacteraemia,

butsepticarthritiscanalsobecausedbydirectpenetrationthroughtheskin,or

bylocalspreadfromacontiguousinfectedsite.

• Jointsdamagedbychronicarthritis(e.g.RAandOA)andprostheticjointsare

atincreasedriskofinfection.

• Riskfactorsincludeadvancingage(>80years),recentjointsurgery,IVdrug

use, alcoholism, previous intra-articular steroid injection, immunodeficiency

states,CKD3b-5,anddiabetes.

• ThemostcommonpathogensareStaphylococcusaureus (including MRSA),

Streptococcusspp.,andNeisseriagonorrhoeaeinadults.

• The clinical features and natural history of gonococcal and non-gonococcal

arthritisaresufficientlydistincttodiscussthemseparately(Table17.3).

• Gram-negativebacillimaybeinvolvedinpatientswithacurrenthistoryofIV

drugabuse,orthosewhoareimmunosuppressed.

• Salmonella isa commoncause ofsepticarthritisamongpatientswithsickle

cell disease, although Staph. aureus remains the most common organism in

thisgroup.

Presentation

• Themostcommonlyaffectedjointistheknee(>50%).

• Wrists,ankles,andhipsarealsocommonlyinvolved.

• Intravenous drugusers(IVDUs) are predisposedtoseptic arthritisinvolving

theaxialjoints,e.g.sternoclavicularjoint.

• Transientsynovitis,particularlyofthehip,isnotuncommoninchildren,and

generallyoccursinthesettingafterupperrespiratorytractinfection.

• Patients with septic arthritis usually present with joint pain, swelling, and

restrictedrangeofmovementoftheaffectedjoint(s).Mostpatientsarefebrile;

however,theelderlydonotalwaysshowasystemicresponse.

Investigation

Every attempt should be made to undertake joint aspiration prior to starting

antibiotics.

• The aspirate should be sent for Gram stain, cell count and differential,

microscopy,culture,andsensitivity,andbloodcultures.

• A fluid sample should be analysed with polarized light microscopy for

crystals.

• Dependingonlikelysourceofinfection,skin,oral,andgenitalswabsshould

beconsidered.

• For a septic joint, the leucocyte count (predominantly neutrophils) in the

aspirateisusually>50,000cells/mm

• Routinebloodtestsshouldbedone:FBC,ESR,CRP,renalfunction,andliver

functiontests.

• Plain radiographs are a useful baseline investigation for assessing for

osteomyelitis or alternative pathology. In untreated septic arthritis, patchy

lucencies in periarticular bone and evidence of articular cartilage loss (joint

spacenarrowing)canbeseen.

• UScanconfirmajointeffusionandaiddiagnosticaspirationofsmalljoints.

• Ifosteomyelitisissuspected,MRIistheinvestigationofchoice.

Management

Seealso Chapter25.

Three principles determine outcome: (i) prompt diagnosis; (ii) immediate

institutionofappropriateantibiotics;and(iii)adequatejointdrainage.

• Thejointshouldbeaspiratedtodryness.

• Surgicaldrainage/washout,ordailyarthrocentesismayberequired.

• An affected joint should be rested and non-weight-bearing until the

inflammation and pain have subsided enough to allow passive mobilization.

Mobilizationshouldbeencouragedassoonaspossible.

• Empiric therapy should be started while awaiting culture results. See local

guidelines, but common regimensincludeflucloxacillin2 g IV four times a

day±gentamicinIV,oranoralthird-generationcephalosporin.

• In casesofsuspectedMRSAinfection, discussionwith amicrobiologistand

considerationofvancomycinisadvised.

• Pseudomonasspp.shouldbesuspectedinIVDUs.

• IVantibioticsareusuallycontinuedfor2weeksfollowedby4weeksoforal

antibiotics. Prolonged courses of up to 6 weeks of IV antibiotics may be

required in severe cases until swelling subsides, inflammatory markers

normalize,andculturesbecomenegative.

• Therearenostudiescomparinglongandshortcoursesofantibiotics.

• Infection of a prosthetic joint is a challenging surgical problem, and the

management should only be undertaken by specialist arthroplasty surgeons,

ideallyaspartofaprostheticjointinfectionMDT.

• Infectionofaprosthesissoonaftersurgeryorwithinashortperiodfollowinga

bacteraemicepisodecansometimesbemanagedwithprosthesisretention,but

oftenrevisionoftheprosthesisisrequired.

• Prosthesisrevisioniseitherasingleoperationordoneinastagedmanner,with

an interval period during which an antibiotic impregnated cement spacer

replacestheprosthesis.

• A joint should not be injected with glucocorticoid (GC) if intra-articular

infectionissuspected,orifthereissuperficialinfectionovertheskincovering

ajoint(e.g.cellulitisorpsoriasis).

• There is no benefit from intra-articular antibiotics. Indeed, antibiotics can

causeachemicalsynovitis.

Septicbursitis

Thetwomostcommonsitesaretheolecranonandprepatellarbursae.

• Septic bursitis should be managed with serial fluid aspiration and oral

antibiotics.

• Non-responders will need IV antibiotics, and will probably need surgical

incisionanddrainage.

• Chronicallyinfectedbursitiscanleadtoosteomyelitis.

Gonococcalarthritis

GonococcalarthritisiscausedbyNeisseriagonorrhoea.

• May present as an acute monoarthritis but is more commonly a migratory

polyarthritiswithtenosynovitisanddermatitis.

• Thepolyarthritisisusuallyasymmetric.

• Patientsareusuallyafebrile.

• Investigations should include synovial fluid analysis, blood cultures,

skin/urethral/rectal/pharyngealcultures.

• If patients are found to have gonococcal infection they should be tested for

othersexuallytransmittedinfections.

• There is increasing resistance, including multidrug resistance, of N.

gonorrhoeatoawiderangeofantibiotics.

• Treatment should be guided by local policies but a common regimen is

ceftriaxone1gIMorIVevery24hours,withasingledoseofazithromycin1

gorallyforpotentialChlamydiatrachomatisco-infection.Anoralswitchcan

beconsideredafter24–48hourswhenclinicalimprovementisseen.Treatment

shouldcontinuefor7days.

Table17.3Comparisonofclinicalfeaturesofgonococcalandnon-gonococcalsepticarthritis

Gonococcalarthritis Non-gonococcalsepticarthritis

Causativeagent:

Neisseriagonorrhoeae

Causativeagents:

Staph.aureus(50%ofcases)

Staph.epidermis(15%ofcases)

Strep. pyogenes/pneumonia (20% of

cases)

Gram-negative bacteria (10% of

cases)

Anaerobes(5%ofcases)

Mostofteninyoungadults Mostcommonintheelderly,or

underlyingjointormedicalcondition

Women>men Men>women

Hipdiseaseuncommon Hipdiseasecommon(20%ofcases)

Migratorypolyarthritiscommon Polyarthritisuncommon

Monoarthritisverycommon

Rash,skinblisters/pustules,

tenosynovitiscommon

Extra-articularmanifestations

uncommon

Synovialfluidanalysis:

Gram stain-positive in 25%, culture

positivein50%,lactatenormal

Synovialfluidanalysis:

Gram stain-positive in 60%, culture

positivein90%,lactateraised

Rapidresponsetotherapy Oftenslowresponsetotherapy.May

requiresurgery

Fullrecoveryinmostcases 10%mortality;one-thirdhaveresidual

jointdamage

Mycobacteriumtuberculosis

Epidemiology

• Until 1985, the number of tuberculosis (TB) cases in the USA and Europe

declined. More recently, the recurrence of TB has become an important

complicationofnewbiologicDMARDs.

• Itisthoughtthat30%oftheworld’spopulationisinfectedwithTB.

• Inindustrializedcountries,<5%ofcasesofTBdevelopinfectionofboneor

joints.

Pathology

• TBcanaffectanyMSKstructure.

• Predisposing factors for MSK TB infection include pre-existing arthritis,

alcoholism,useofGCs,andimmunosuppression.

Presentation

• TBofboneisusuallyalow-gradeandslowlyprogressiveinfectionassociated

withavariabledegreeoflocalandsystemicsymptoms,suchasfatigue,weight

loss,ornightsweats.

• Onsetisinsidiousandusuallymono-articularormonostotic.

• The spine is the commonest site, whether within a vertebral body (Pott’s

disease),disc,oraparavertebralabscess.

• Spinal cord compression due to vertebral destruction and/or soft tissue

swelling due to an abscess is a serious complication and must be treated

urgently.

• Spinal stabilization procedures carry a good prognosis in preventing

neurologicalsequelae.

• Monoarticulardiseaseisseenmostofteninweight-bearingjoints(hip,knee,

ankle,sacroiliacjoint—inorder).Thewristandshoulderarelesscommonly

affected.

• Osteomyelitismayaffectanylongboneandisassociatedwitheithersolitary

ormultifocalcysts.

• InTBarthritis,typicalfeaturesofsepticarthritis(e.g.warmthanderythema)

areoftenabsent.

Investigation

• ThediagnosisofTBismadebyidentifyingacid-fastbacillifromalesionor

byhistopathologicalchangesinexcisedtissue.

• Synovialfluidanalysisisnotusuallydiagnosticandasynovialtissuebiopsy

mayberequired.

• Ahighlevelofclinicalsuspicion,intheabsenceofotheridentifiedpathology,

mightleadthecliniciantotreatempirically.

Management

• Standardanti-TBregimensshouldbeusedforprophylaxisortreatment,and

surveillancefor1yearaftertreatmentisrecommended.

• Treatment is usually continued for 6–9 months, or 9–12 months for more

advanceddisease.

• Surgical intervention may be necessary—tissue biopsy, debridement of

necrotictissue,orstabilizationofajointorlongbone.

• Owing to an association between biologics therapy (particularly anti-TNFα)

anddisseminatedTB,theidentificationoflatentTBhasbecomeincreasingly

importantinpatientsbeingtreatedforchronicarthritis.

• Insuchpatients,atuberculinskintest(PPD)isuseful.Indurationof>5mm

shouldbeconsideredpositiveinpatientswhoareimmunosuppressed.

• Quantiferon-TBgold,whichisablood-basedIFNγreleaseassay,isalsouseful

forthediagnosisoflatentTB.

Atypicalmycobacterialinfections

• Patients with autoimmune rheumatic or connective tissue diseases who are

taking immunosuppressant medications are at risk of developing atypical

infections.

• Theseinfectionsareusuallychronicinnatureandcanmimicaninflammatory

flareofrheumaticdisease,thusmakingadiagnosiscanbedifficult.

• Atypicalinfectionsshouldbeconsideredinpatientswithautoimmunediseases

who present with MSK symptoms that do not respond to conservative

treatment.

• Mycobacterium malmoense has been described causing tenosynovitis and

septicarthritisoftheknee.

• M.aviumcomplexand M.chelonae osteoarticular infections have also been

described.

Osteomyelitis

Osteomyelitisreferstoanyinfectioninvolvingboneorbonemarrow.

Pathology

• Staphylococcus aureus is the most common cause of osteomyelitis. Other

importantpathogenstoconsider,particularlyintheimmunosuppressedpatient,

areTB,Pseudomonas,andSalmonella.

• Thelongbonesaremostcommonlyaffectedinchildren,andthevertebraein

adults.

Investigations

• Nosinglelaboratoryinvestigationisreliableenoughtobeusedroutinelyfor

thediagnosisofosteomyelitis.AnelevatedwhitecellcountandESRmaynot

beseen.

• Imagingisimportantinestablishingthediagnosis.Whichimagingtechnique

is successful at identifying osteomyelitis depends partly on the stage of the

infectiveprocess.

• Once the pathogen has reached bone, a suppurative reaction and marrow

oedemaoccurs.ThiscanbeseenusingMRI.

• The next stage—vascular congestion, ischaemia, thrombosis, and soft tissue

swelling—isreadilydetectedbyCT.After2–3weeks,bonereactionincluding

newperiostealboneformationanddecalcificationcanbeseenonradiographs.

• Radiographs should be requested as routine as they provide a point of

reference,andassessforotherdisease.

• Vertebral osteomyelitis is often seen early on radiographs. There may be

erosionofthevertebralbodyordisc,andparavertebralabscessesandvertebral

collapsearecommoncomplications.

• Bone scintigraphy can help localize an area of abnormality.

99m

Tc-

bisphosphonate scans, however, are not specific and the negative predictive

valueisoftengreaterthanthepositivepredictivevalue.

• 

111

In-labelledleucocytescintigraphyisanalternative.

• Bonebiopsyisthegoldstandardinvestigationtoconfirmlocationofinfection,

identifyspecificorganisms,toinformtreatmentchoices.

Management

Several general, local, and systemic factors need to be considered in the

managementofosteomyelitis(Table17.4).

• Initialtreatmentintheacutephaseisthesameasthatforsepticmonoarthritis.

Ingeneral,antibioticsareneededfor6weeks,althoughchronicinfectionmay

requirelong-term(>3months)low-dosetreatment.

• Antibiotic choice should be guided by tissuemicroscopyandculture results

andlocalantibiotictherapypolicy.

• Surgery may be required early in the acute phase especially if there is an

abscessorspinalinvolvementwithneurologicalcompromise.

• Chronic osteomyelitis implies that dead bone is present, and will require

surgicaldebridement.

• Hyperbaric oxygen has also been used successfully in the treatment of air

embolism,osteonecrosis,myonecrosis,andburnspatientswithinfection.

Table17.4Factorsrelevanttothemanagementofosteomyelitis

Factors Examples

General Age:neonatestendtoharbourS.aureus,Enterobacteriaceae,and

β-haemolyticstreptococci.Inchildren>4yrs,H.influenzaeis

common,andinadultsS.aureus.

Bone:longbones(especiallylowerlimb)aremoresusceptible

thanshortbonestoinfection.Pelvicandcranialbonesare

infrequentlyinvolved

Local Chroniclymphoedema

Venousstasis

Arterialdiseasewithpoorflow

Scars

Sensoryneuropathy

Prostheticmaterial

Systemic Malnutrition

Renalandliverfailure

Immunodeficiency

Diabetes

Malignancy

Extremesofage

Chronichypoxia

Parenteraldruguse

Lymedisease

Lyme disease is a tick-borne infection caused by the spirochaetes Borrelia

burgdorferi,B.afzeli,andB.garinii.

Epidemiology

• AllthreespirochaetesarefoundinEuropebutBorreliaburgdorferiistheonly

speciesidentifiedincasesofLymediseaseintheUSA.

• Cases of Lyme disease have been reported from most statesintheUSA, as

wellasthroughoutEurope,China,andJapan.

• Highestincidenceisinchildren<15yearsandmiddle-agedadults.

• Seasonalvariation:commoninthesummermonthsofJuneandJuly.

• ThetickvectorIxodesisfoundonrodents,boarordeer—animalsinhabiting

wooded,brush,orgrassyareas.

• Ahistoryofpotentialexposureinanendemiccountrywithinthelast30days

isanimportantfacttoestablishinconsideringthediagnosis.

Presentation

• The diagnosis is made on epidemiological history and presenting features

(Table17.5),andisconfirmedwithlaboratorytests.

• Aclearhistoryofatickbiteisnotnecessarytomakethediagnosis.

Investigations

• Diagnosisismadeby eitherisolationof thespirochaetefromtissue orbody

fluidordetectionofdiagnosticlevelsofIgMorIgGantibodiesintheserumor

cerebrospinalfluid(CSF)andchangesinantibodylevelsbetweenacute-phase

andconvalescentpairedsera.

• False-positiveresultsoccurinotherinfections(e.g.syphilis),RA,andSLE.

• Western blotting is available as a confirmatory test, distinguishing between

trueseroreactivityandfalse-positiveserology.

• If the serological status is negative, then the diagnosis is unlikely and an

alternativediagnosisshouldbesought.

Management

The management of Lyme disease is primarily with antibiotics with choice of

therapyvaryingdependingonorganaffected.

• Erythemamigransistreatedwithdoxycycline100mgtwicedailyfor3weeks,

orwithcefuroxime500mgtwicedailyfor3weeks.

• Septic arthritis is treated similarly but antibiotic treatment may need to be

continuedfor30days.

• The choice of antibiotics for neurological or cardiac disease includes IV

penicillin,cefotaxime,orceftriaxone/imipenem.

• Lyme disease can cause a post-infective inflammatory (‘reactive’) arthritis

which is typical migratory (differential: sarcoid, post-streptococcal,

palindromicRA).

Table17.5ThepresentationofLymediseases

Organ

affected

Symptoms

Skin Erythemamigrans(EM):beginsasaredmacule/papule

expanding,overdaysorweeks,tobecomealargeround

lesionoftenwithpartialcentralclearing.Thelesionusually

measures5cmormore.Theremaybesmallersecondary

lesions

Anexpandinglesionisoftenaccompaniedbygeneral

symptoms:fever,fatigue,arthralgia,myalgia,headache

Monthslaterachroniclesion,acrodermatitischronicum

atrophicans(AChA),canappear.Itisaviolaceous

infiltrativerashformingplaquesornodules)

MSK Recurrent, brief attacks of joint swelling in one or a few

joints (may become chronic in 60% of untreated cases

weekstoyearsafterinfection).

A post-Lyme syndrome of fatigue, arthralgia, and myalgia

hasbeenreported.Ongoinginfectionhasbeendifficultto

prove.Itmaybefibromyalgiasyndrome

Neurological

(mayoccur

weeksto

monthsafter

tickbite)

Lymphocyticmeningitis

Cranialneuritis(especiallyfacialnervepalsy)

Radiculoneuropathy(differentialGuillain–Barrésyndrome)

Encephalomyelitis

Cardiovascular Acutesecond-orthird-degreeatrioventricularconduction

(mayoccur

weeksto

monthsafter

tickbite)

defectsoftenassociatedwithmyocarditis.Resolvesindays

toweeks.

Carditis—rareandremitsspontaneously

*Asimilarlesionoccurringwithinhoursofatickbiteisusuallyahypersensitivityreactionanddoesnot

qualifyasEM.

Rheumaticfever

Rheumatic fever is a delayed, non-suppurative sequelae to a pharyngeal

infectionwithLancefieldgroupAβ-haemolyticStreptococcus.

Epidemiology

• Although there has been a dramatic decline in incidence in Europe and the

USA, rheumatic fever still occurs, and remains common in developing

countries.

• There are an estimated 10–20 million cases per year worldwide, with an

annualincidenceof100–200per100,000ofthepopulation.

Pathology

• AssociationshavebeendescribedwithHLA-DR2,-DR3,and-DR4.

Presentation

• Thereisalatentperiodof2–3weeksaftertransmissionbeforetheappearance

oftheillness.

• Asymptomaticpharyngitisisseenin60%ofcases.

• Patients can present with migratory arthritis (typically of the large joints),

myocarditis,orvalvulitis,thoughwithchoreaisunlikely.

• Diagnosisfollowstherevised‘Jones’criteria(Table17.6)

• Patients who have had previous acute rheumatic fever are at risk of repeat

episodes following reinfection with group A β-haemolytic streptococci. In

repeat episodes, 2 major, or 1 major and 2 minor or 3 minor criteria are

sufficientfordiagnosis.

Arthritis

Joint involvement is more common and often more severe in teenagers and

youngadults.

• Arthritis tends to start in the large weight-bearing joints and tends to occur

early.Thepaincanbesevere.Oftenthereisanabsenceofobjectivesignsof

inflammation.Itlasts2–3weeksandisself-limiting.

• NSAIDsaretherecommendedfirst-linetreatment.

• Discriminating post-streptococcal reactive arthritis (seen in the absence of

carditis) from rheumatic fever can be difficult. Most patients will fulfil the

Jonescriteriaand,therefore,shouldbeconsideredashavingrheumaticfever.

Cardiacdisease

• Rheumaticheartdiseaseisthemostsevereoutcomeofacuterheumaticfever.

Itremainsthemajorcauseofacquiredvalvularheartdiseaseintheworld.

• Rheumaticheartdiseaseusuallyoccurs10–20yearsaftertheinitialinfection.

Themitralvalve(stenosis)ismostfrequentlyinvolved.

• When left untreated, cardiomegalyandcardiac failure secondary to valvular

diseasemayensue.

• Carditismayalsooccurandisassociatedwithcardiomyopathyandconduction

defectsincludingsecond-orthird-degreeheartblock.

Table17.6TherevisedJonescriteriaforthediagnosisofacuterheumaticfever

Thediagnosisrequires2major;or1majorand2minorcriteria

Majorcriteria Carditis

Arthritis

Chorea

Erythemamarginatum

Subcutaneousnodules

Minorcriteria

Fever(≥38.5°C)

Arthralgia

Previousrheumaticfeverorrheumaticheartdisease

RaisedESRorCRP

ProlongedPRintervalonECG

Supportingevidence RaisedASOtitre*

PositivethroatculturesforgroupAstreptococci

Recentscarletfever

Normochromicnormocyticanaemia

ASO,anti-streptolysinOantibodies.Titrespeakatabout4weeks,whichisabout2weeksintothe

clinicalillnessthentitresfallrapidlyoverthefollowing2–3months.

Chorea

• Sydenham’s chorea (St Vitus’ dance) consists of abrupt, purposeless

movements,muscleweakness,andemotionaldisturbance.

• The hands and face are usually the most obviously affected parts. The

movementsarenotpresentduringsleep,butdooccuratrestandmaybemore

markedononesideofthebody.

• Choreamaybethesolefeaturesuggestingrheumaticfever(beyondobserving

new cardiac murmurs) and may occur weeks to months after onset of an

arthropathy.

Skin

• Subcutaneous nodules of rheumatic fever are firm and painless. They range

fromafewmmto2cminsize.Theyarelocatedoverbonysurfacesornear

tendons.Lesionsare presentfor 2–4weeksonly, andmoreoften inpatients

withcarditis.

• Erythema marginatum is an evanescent, non-purpuric rash, usually affecting

thetrunkandproximalpartofthelimbs,butsparingtheface.Becausetherash

oftenappearstomakearing,itisalsocalled‘erythemaannulare’.Thelesions

comeandgoinamatterofhours,heatcanmakethemappearworse,andthey

aremorecommoninassociationwithcarditis.Theyresolvespontaneously.

• Erythemanodosumisrare.

Investigation

• Thereisnodiagnostictest.

• DiagnosisisbasedondetectionofgroupAstreptococcalinfectionfollowedby

thetypicalclinicalmanifestations.

• Raisedinflammatorymarkersandmildanaemiaareoftenseen.

• Serial rises in ASO antibody (or anti-DNAaseB) titres may be seen if

measuredevery14days.

• CXRandECGtolookforconductiondefects/cardiomegaly.

Management

• The three goals of management include symptomatic relief, eradication of

group A β-haemolytic streptococci, and prophylaxis against future infection

withgroupAβ-haemolyticstreptococci.

• NSAIDsshouldbegivenuntilallsymptomshaveresolved.

• Heartfailureshouldbetreatedwithconventionalmedications.

• Penicillinisgivenfor10days,evenintheabsenceofpharyngitis.

• Chorea is treated with haloperidol 1–2 mg/kg/day. GCs are sometimes also

given,thoughthereislittleevidenceofaddedbenefit.

• Recurrencecanoccurwithinthe first2years.However, recurrenceratesare

low,andtheriskofrecurrencedeclineswithageoffirstattack.Recurrenceis

associatedwithincreasedriskofcardiacdisease.

• Prophylaxisshouldbestartedassoonasantibiotictreatmenthasfinishedwith

oralphenoxymethylpenicillinorbenzylpenicillin1.2millionunitsIMevery3–

4 weeks. Duration of prophylaxis depends on severity of disease.

Erythromycin250mgdailycanbeusedinpatientsallergictopenicillin.

Chapter18
Rareautoinflammatoryandmiscellaneous
diseases
Rareautoinflammatorydiseases
Behçet’sdisease
Sarcoidosis
Miscellaneousskinconditionsassociatedwitharthritis
Relapsingpolychondritis
Amyloidosis
Adult-onsetStill’sdisease
Eosinophilicfasciitis
ImmunoglobulinG4-relateddisease
Raredisordersofsynovium
Rareautoinflammatorydiseases
Introduction
Rare autoinflammatory diseases (RAIDs) are mostly rare monogenic
immunological disorders that typically present in childhood with recurrent
fevers,highinflammatorymarkers,andsystemicfeatures.
• The typical presentation is with bouts of fever, and associated symptoms
betweenwhichthepatientiswell(‘periodic’fever).
• The term ‘autoinflammatory’ arose from the understanding that gene
mutationsresultinswitchingonofinnateimmunitythathasasecondaryeffect
on adaptive immunity. This differs from autoimmunity where failure of
recognition between self and non-self is caused by self-reactive T cells,
involvesMHCclassIIandleadstocirculatingantibodies.
• Since the discovery of the gene for familial Mediterranean fever (FMF),
MEFV (pyrin innate immunity regulator), the genes of many other RAIDs
have been identified and collectively have proven extremely valuable in

understandinginflammatorypathways.

• AlthoughRAIDsarenotgenerallylife-threatening,earlydiagnosismayavoid

repeated hospital visits, unnecessary investigations and treatment, reduced

qualityoflife,andmorbidityfromAAamyloid.

Pathogenesis

• RAIDsaredisordersoftheinnateimmunesystem.Innateimmunityisthefirst

line of defence against pathogenic microbes and mediates host responses

against cellular stress (e.g. against lipopolysaccharide or peptidoglycan

constituents).

• Highly conserved molecular processes, known as pathogen-associated

molecularpatterns(PAMPs),aredetectedbyintracellularpattern-recognition

receptors (PRRs) such as Toll-like (TLRs) and nucleotide-binding

oligomerizationdomain(NOD)-likereceptors(NLRs),whichareexpressedby

macrophages,monocytes,neutrophils,andlymphocytes.

• PRR signalling drives (the ‘inflammasome’) cytokine production such as

interleukin-1β(IL-1β).

• Genotype-influencedinflammasomefunctioncancauseRAIDsandcontribute

to other diseases (e.g. NOD2 mutations can causes Blau syndrome and

contributetoIBDphenotypealso).

Epidemiology

• FMF, the commonest RAID, has a carrier frequency in Middle Eastern

populationsof30–50%.

• Fewerthan200familieshavebeenreportedwithtumournecrosisfactor(TNF)

receptor-associated periodic syndrome (TRAPS) and there are 100 reported

casesoffamilialcoldautoinflammatorysyndrome(FCAS)andMuckle–Wells

syndrome(MWS).

• AsanexampleofotherRAIDs,therearefewerthan10familiesreportedto

haveMajeedsyndrome,mostlyarisingfromJordan.

Table18.1Thespectrumofrareautoinflammatorydiseases

Mainfeatures Diagnosis;moleculardefect Inheritance;gene;

genelocation

Periodicfever,

macularorpapular

rash,abdominal

pain

MKD(MVAandhyperIgD

syndrome(HIDS));MVK

deficiency

AR;MVK;

12q24.11

FMF;pyrindeficiency AR;MEFV(pyrin

innateimmunity

regulator);16p33.3

TRAPS;TNFreceptorsignalling AD;TNFRSF1A;

12p13.31

Feverandurticarial

rash

CINCA,MWS,andFCAS;

aberrantcryopyrinproduction

andinflammasomeresponses

AD;NLRP3;1q44

Granulomatous

diseasewithlow-

gradefever

Blausyndrome AD;CARD15;

16q12.1

Early-onsetIBD AR;IL-10R

Pyogenicrash PAPA AD;PSTPIP1;

15q24.3

Majeedsyndrome AR;LPIN2;18p11

CAMPS;abnormalactivationof

NFκB

AD;CARD14;

17q25

DIRA;uncheckedIL-1α

activation

AR;IL-1RN;

2q14.1

DITRA;asforDIRA AR;IL-36RN;

2q14.1

CANDLE;defectinIFN

signalling

AR;PSMB8;

6p21.3

Skeletaldisorders Majeedsyndrome/DIRA Seeabove

CNO Notknown

Caffey’sdisease AD;COL1A1;

17q21.33

Cherubism AD;SH3BP2;

4p16.3

MultisystemRAID Behçet’sdisease Notknown

Systemic-onsetJIA Variousgenes

AD,autosomaldominant;AR,autosomalrecessive;CANDLE,Chronicatypicalneutrophilicdermatosis

withlipodystrophyandelevatedtemperatureCAMPS,CARD14-mediatedpsoriasis;CINCA,chronic

infantileneurologicalcutaneousandarticularsyndrome;CNO,chronicnonbacterialosteomyelitis;

DIRA,deficiencyofIL-1receptorantagonist;DITRA,deficiencyofinterleukin36receptorantagonist;

FCAS,familialcoldautoinflammatorysyndrome;FMF,FamilialMediterraneanfever;IBD,

inflammatoryboweldisease;MKD,mevalonatekinasedeficiency;MVA,mevalonicaciduria;MVK,

melavonatekinase;MWS,Muckle–Wellssyndrome;PAPA,pyogenicarthritis,pyodermagangrenosum

andacne;SAPHO,synovitis,acne,pustulosis,hyperostosis,osteitis;TRAPS,tumournecrosisfactor-

associatedperiodicsyndrome;TNFRSF,tumournecrosisfactorreceptorsuperfamily.

Approachtodiagnosis

Diagnosisisbasedonclinicalsuspicion,mostlyinchildren,attimesofrecurrent

feversormultisysteminflammationofunknownaetiology.

• Treatable causes of fever such as infection, neoplasia, and autoimmune

diseasesshouldbeexcluded.

• Familyhistory,ethnicity,ageofonsetoffever,especiallywithinfirstyearof

life, characterizationofthefever, and rash and manifestations are important

cluestodiagnosiswithRAIDs.

• Characterization of the fever includes its duration and periodicity. This also

helpstounderstandtheburdenofdiseaseonqualityoflife.

• High inflammatory markers and a neutrophilia are typical during febrile

episodesandnormalizeduringdisease-freeintervals.

• Associatedfeaturesalsoincludeabdominalorlimbpainand:

• Diarrhoea—presentin75%ofcaseswithMVKdeficiency.

• Uveitis.

• Sensorineuralhearingloss.

• Inflammatoryepisodesprovokedbyvaccination.

• Arthritis.

• ConfirmationofaRAIDcanbesoughtwithgenetictesting;however,>50%of

RAIDpatientshavenegativegeneticresults.

• IntheUK,genetictestingisundertakenbytheNationalAmyloidosiscentreat

UniversityCollegeHospital,London( http://www.ucl.ac.uk/amyloidosis).

• InformationaboutthelatestgeneticabnormalitiesisavailableontheIn-Fever

websiteat http://http://fmf.igh.cnrs.fr/ISSAID/infevers/.

• Urinalysis should be requested to screen for proteinuria which raises the

possibilityofsecondaryAAamyloidosis.

CutaneousmanifestationsofRAIDs

• Urticarialeruptions—typicalofpatientswiththecryopyrinopathies—areoften

indistinguishablefromthemorecommonmastcell-mediatedchronicurticaria.

The latter is usually asymmetric with itchy recurrent wheal and flare and

angio-oedema.

• Urticarial vasculitis, which is fixedinshapefor >24 hours and also seen in

cryopyrinopathies.

• Multiple sterile abscesses—seen in pyoderma gangrenosum, acne and

pyogenic arthritis (PAPA) syndrome, SAPHO syndrome, Majeed syndrome,

DIRA,early-onsetIBD,andseveralotherRAIDs.

• Psoriaform rashes: seen in congenital forms of psoriasis (e.g. CAMPS) and

pustularskinlesionsasinSAPHOsyndrome.

• Ichthyosiform rash:tan-colouredand scalyisseen in~90%of patients with

Blausyndrome.

RAIDpresentations

RAIDs might be considered in a differential diagnosis on the basis of age of

presentation,familial inheritance(seeTable18.1), and typical clinical features

commontocertaingroupingsofRAIDs.

Neonatalandinfantileperiodicfevers

• ARAIDisconsideredininfancywhenafeverisunresponsivetoantibioticsor

recurrent, when an associated rash is persistent or unusual, and there are

atypicalfeatures,suchasboneoedema.

• Alternative diagnoses for consideration include neonatal lupus (NLE; see

Chapter10),Kawasakidisease,Behçet’sdisease,andsystemic-onsetJIA.

• ARAIDinthefirstyearoflifeincludes:

• chronicinfantileneurologicalcutaneousandarticularsyndrome(CINCA),a

cryopyrinopathy also known in the USA as NOMID (neonatal-onset

multisysteminflammatorydisease).

• FCAS.

• Majeedsyndrome.

• deficiencyofIL-1receptorantagonist(DIRA).

• Blausyndrome.

• chronic atypical neutrophilic dermatosis with lipodystrophy and elevated

temperature(CANDLE).

Childhoodperiodicfevers(cryopyrin-associatedperiodicsyndromes)

CAPS are a group of autosomal dominant RAIDs that share the same gene

mutation(NLRP3)butpresentatdifferentageswithvariationsofphenotypethat

includesanurticarialrash.

• NLRP3geneencodestheproteincryopyrin.Cryopyrinisakeycomponentof

the inflammasome (an intracellular multi-protein complex), which regulates

theprocessingofIL-1β.

• CAPS result in excess IL-1β and respond to anti-IL-1 therapy (anakinra,

canakinumab,andrilonacept).

• AAamyloidosisoccursin~25%generallyinallCAPS.

• InCINCA,feversareusuallyshortlived,lowgrade,orabsent.

• Typical features in CINCA are frontal bossing, saddle nose, midface

hypoplasia;arthritisandbonyovergrowthofknees,handsandfeet,clubbing,

CNSandophthalmicinvolvement.

• Radiographs in CINCA may show irregular ossification of metaphyses and

epiphyses.

• FCASisalsoknownasfamilialcoldurticariaandassociatedwithlow-grade

feverandarthralgia.Itpresentswithinthefirst6monthsoflife.

• TypicallyinFCAS,coldprecipitatessymptomswithin1–2hoursandattacks

last<24hours.

• MWS typically presents in an older child with high fever, typically in the

afternoon.

• InMWS,feverattackslast1–2daysalthoughtherashcanbepersistentand

sensorineural deafness is common usually appearing in childhood or even

earlyadulthood.

FamilialMediterraneanfever(FMF)

FMFismostcommoninnon-AshkenaziJews,Arabs,Turks,andArmeniansasa

result of a mutation in the gene which encodes pyrin. Pyrin is expressed in

myeloidcellsandregulatestheinflammasome.

• Diagnosisisbasedonthepresenceof:

• short,intense,self-limitingepisodesoffever(1–3days)withaleucocytosis

andhighESR.

• serositis(peritonitisandlesscommonlypericarditisorpleuritis).

• comprehensive response to oral colchicine, which achieves remission in

65% of patients and 20–30% experience a reduction in the severity and

numberoffeverattacks.

• Less common features include large joint lower limb arthritis, meningitis

headache,orchitis,vasculiticrash,andmyalgia.

• Geneticanalysisisnotalwayshelpful.

• Therecommendeddoseofcolchicineis0.5mg/dayforchildren<5yearsof

age,1mg/dayforchildren5–10years,and1.5mg/dayforchildren>10years.

Dosesaretitratedupwardsforlackofefficacyanddownwardsforabdominal

pain/diarrhoea in 0.25 mg steps (max. 2 mg/day). Colchicine virtually

eliminatestheriskofAAamyloid.

• Anti-IL-1 (e.g. anakinra) may be effective in colchicine-resistant FMF

patients.

TNFreceptor-associatedperiodicsyndromes(TRAPS)

Previously known as Hibernian fever, TRAPS affects 1 per million in Europe

andiscausedbymutationsinthep55TNFreceptor1(TNFR1).50%haveno

familyhistory.

• Presentation is often by 4 years with prolonged, although milder, periodic

fevers,lasting1–3weeks.In30%,symptomsarealmostcontinuous.Feveris

alwaysassociatedwithhighESR.

• Common features are myoarthralgia, tender macular rash on the extremes

and/or torso, and abdominal pain, headache, pleuritic pain, conjunctivitis,

periorbitaloedema,andlymphadenopathy.

• Genotypingishelpfulbuttwopolymorphismsarepresentin4%ofthenormal

population(andmaybeassociatedwithmildsymptoms).

• Acuteflaresaretreatedwithglucocorticoids(GCs)andflaresbestprevented

withanakinraorcanakinumab.Etanercept(notinfliximab)maybeeffective.

• Withouteffectivelong-termtreatment25%developAAamyloid.

Mevalonatekinasedeficiency(MKD;mevalonicaciduria(MVA)/hyper-IgD

syndrome(HIDS))

• Thecondition(s)wasfirstidentifiedin1984insixpatientsofDutchancestry

withalonghistoryofrecurrentattacksoffeverandhighserumIgDlevels.

• AnARcondition,mutationsinthemevalonatekinase(MVK)generesultina

deficiency of mevalonate kinase, essential in cholesterol biosynthesis.

Complete absence of MVK activity results in mevalonic aciduria (MVA)

associated with developmental delay, progressive ataxia, visual loss, and

failuretothrive.

• MKDstartsinearlychildhoodandpresentswithfeverslasting3–7days.

• Characteristicallytheconditionisprecipitatedbyvaccination.

• Other features include abdominal pain, diarrhoea, lymphadenopathy,

arthralgia,aphthousulcers,andpolymorphicrash.

• DiagnosisissupportedbyanIgDconcentration>100IU/mLduring/between

attacksandincreasedurinemevalonicacidduringfever.

• MVKgenemolecularanalysisisusedtoconfirmthediagnosis.

• Treatmentissymptomaticduringaflarewhichmayalsorespondfavourablyto

GCs.TheremaybearoleintreatmentforinhibitorsofIL-1orTNFα.

• SymptomsimprovewithageandAAamyloidosisisrare.

Periodicfever,aphthousstomatitis,pharyngitis,adenitis(PFAPA)syndrome

PFAPAsyndromeisincludedhereasitisthecommonestsyndromeassociated

withrecurrentfever,althoughitisnotaRAID.

• Itisdefinedbydebilitatingepisodesofabruptonsetoffeverlasting3–6days

withrecurrenceevery2–6weeks.

• Otherfeaturesincludesorethroat,smallmouthorlipulcers,tenderswellingof

thecervicallymphnodes.

• The syndrome usuallypresentsbeforethe age of 5yearsandspontaneously

resolvesduringtheseconddecadeoflife.

• CRP/ESR and neutrophils are elevatedduringattacksand normal (or settle)

betweenthem.

• 1–2daysofprednisolone(1–2mg/kg)maybegivenatthestartofanattack,

whichmaybepreventedbycolchicine,anti-IL-1therapy,orevencimetidine

insomecases.

Late-onsetFMF

ThisformofFMFisamildervariantoftheconditioninchildren.

• Itoccurstypicallyinmenandwithabdominalattacks.

• Chronicmanifestations(e.g.amyloid)rarelyoccur.

Late-onsetTRAPS

OfallpatientswithTRAPS,9%presentinadulthoodwithmeanageofonsetof

35yearsandasimilarphenotypetopaediatriconset.

Schnitzler’ssyndrome

Veryrareandusuallyfrom50yearsofagewithurticarialrashandfatigue.

Whendiagnosisisunclear

Thereisconsiderableoverlapinfeaturesoftheinheritedperiodicfeversmaking

diagnosischallenging.

• Insomecasesgeneticanalysisisinconclusive.Thismaybebecauseofasingle

mutation in an AR disorder or identification of variants of unknown

significance (e.g. low-penetrance mutations, functional polymorphisms, and

novelvariantsofunknownfunctionalimpact).

• As a guide to diagnosis in general, the Eurofever Project has produced a

validatedevidence-basedtool(Table18.2).

Table18.2TheEurofevertoolforindicationformolecularanalysisorclinicalclassification*ofpatients

withsuspectedRAIDsaftercarefulexclusionofothercauses.

FMF MKS CAPS TRAPS

Presence Score Presence Score Presence Score Presence

Durationof 9 Ageofonset<2 10 Urticarialrash 25 Periorbital

episodes<2

days

years oedema

Chestpain 13 Aphthous

stomatitis

11 Neurosensorial

hearingloss

25 Duration

episodes

>6days

Abdominal

pain

9 Generalized

enlargementof

lymphnodesor

splenomegaly

8 Conjunctivitis 10 Migratory

rash

†

Eastern

Mediterranean

‡

ethnicity

22 Painfullymph

nodes

13 Myalgia

North

Mediterranean

‡

ethnicity

7 Diarrhoea

(sometimes/often)

20 Relatives

affected

Diarrhoea

(always)

Absence Absence Absence

Absence

Aphthous

stomatitis

9 Chestpain 11 Exudative

pharyngitis

25 Vomiting

Urticarialrash 15 Abdominal

pain

15 Aphthous

stomatitis

Enlarged

cervicallymph

nodes

Durationof

episodes>6

days

Cut-off ≥60

Cut-off ≥42 Cut-off ≥52 Cut-off

*Theclinicalfeaturesshouldberelatedtothetypicalfeverepisodes(i.e.exclusionofintercurrent

infectionorothercomorbidities).

†Centrifugalmigratory,erythematouspatchesmosttypicallyoverlyingalocalareaofmyalgia,usually

onthelimbsortrunk.

‡EasternMediterranean:Turkish,Armenian,non-AshkenaziJewish,Arab.NorthMediterranean:

Italian,Spanish,Greek.

CAPS,cryopyrin-associatedperiodicsyndromes;FMF,familialMediterraneanfever;MKD,mevalonate

kinasedeficiency;TRAPS,receptor-associatedperiodicfeversyndrome.

ReproducedfromFederici,Silviaetal,Evidence-basedprovisionalclinicalclassificationcriteriafor

autoinflammatoryperiodicfevers,AnnRheumDis2015;74:799–805,withpermissionfromtheBMJ.

RAIDswithprominentskinmanifestations

Pyodermagangrenosum,acne,andpyogenicarthritis(PAPA)syndrome

PAPAsyndromeischaracterizedbymultiplesterileabscessesorpyodermawith

severecysticacneandpainfulhotarthritis.

• PAPAisattributabletomutationsofthePTSTPIP1genethatencodesaprotein

whichinteractswithpyrin.

• PAPAmayberesponsivetoanti-TNFαorIL-1blockade.

DeficiencyofIL-1receptorantagonist(DIRA)

DIRApresentsintheneonatalperiodwithapustularrash,arthritis,periostitis,

and osteolytic lesions of ribs and long bones. An excellent response to IL-1

inhibition(e.g.anakinra)isseen.

Chronicatypicalneutrophilicdermatosiswithlipodystrophyandelevated

temperature(CANDLE)syndrome

CANDLE syndrome is AR with increased IFN-γ expression. It appears to be

responsive to drugs inhibiting Janus kinases (JAKs), which mediate IFN-γ

signalling.

Blausyndrome

Blausyndrome isan ADRAID characterizedbyatan-colouredichthyosiform

rash (90%) and non-caseating granulomas. Blau syndrome is indistinguishable

fromsarcoid,similarlyaffectingthejoints,skin,anduvealtract.

CARD14-mediatedpsoriasis(CAMPS)

InCAMPs,severegeneralizedpustularpsoriasispresentsbefore3yearsofage.

Feversareuncommonhowever.

Furtherreading

GattornoM,FedericiS,PelagattiMA,etal.Diagnosisandmanagementofautoinflammatorydiseasesin

childhood.JClinImmunol2008;28:S73–S83.

Koné-PautI,PiramM.Targetinginterleukin-1βinCAPSsyndromes.Whatdidwelearn?AutoimmunRev

2012;11:77–80.

Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-

associatedperiodicsyndrome.NEnglJMed2009;360:2416–25.

Behçet’sdisease

Epidemiologyandpathophysiology

Behçet’s disease (BD) is a systemic inflammatory disorder of unknown

aetiology.ItismostcommonintheMediterraneanbasin,theMiddleEast,and

Asia.

• Prevalenceisestimatedat80–370cases/100,000inTurkey.

• Theusualonsetofthedisorderisinthethirdtofourthdecades.Onsetisrare

beforepubertyorafterthesixthdecade.

• TheM:Fratioisequal,butthediseasetendstorunamoreseverecoursein

menandtheyoung.

• PatientsfromEasternAsia,MiddleEast,andMediterraneancountriesshowa

higherprevalenceofHLA-B51;InIsraelisthereisanassociationwithHLA-

B52,andintheUKHLA-B57.

• BD is considered to have a strong angiopathic basis and considerable

morbidityoveralliscausedbythrombosisinadditiontoinflammation.

• Mildanaemiaofchronicdiseaseandneutrophiliaisseenin15%ofpatients.

ESR and CRP are often only moderately raised with episodes of arthritis,

erythemanodosum(EN)andthrombophlebitis.

• Autoantibodiesarecharacteristicallyabsent(i.e.ANCAnegative).

Clinicalfeaturesandtheirmanagement

Full-blownBDmightbeeasytoidentify,butthereareconditionsthatmimicthe

incomplete picture, including reactive arthritis, antiphospholipid syndrome

(APS), multiple sclerosis, IBD, erythema multiforme, and neutrophilic

dermatoses.TheInternationalStudyGroup(ISG)criteriapublishedin1990are

the most widely accepted diagnostic and classification criteria (see  Table

18.3).Forclinicalmanifestationfrequencies,see Table18.4.

Skinandmucosalinvolvement

• Skinlesionsmaybenodular(likeEN),acneiform,orvasculitic.

• The pathergy reaction, a hyper-reactivity of the skin to a needle prick, is a

nonspecificphenomenon, butmaybehelpfulin diagnosisof BD(note: also

positiveinIBDandSweet’sSyndrome).Afterskinpuncturewithaneedle,a

papuleorpustuleformsin24–72hours.Thereactionisthoughttobeunusual

inpatientsfromNorthernEuropeortheUnitedStates,butispositivebetween

60–70%ofpatientsfromJapanandTurkey.

• Painful oral aphthous ulcers may precede other features by several years.

Idiopathicoralaphthousulcersarecommon,andalonedonotimplyBD.The

ulcers may resemble ordinary aphthae, but tend to be more frequent and

multiple,andmayhealwithscarring.

• Genital ulceration in men is most prominent over the scrotum (90%).

Urethritisis notseen unlessthereisameatalulcer. Inwomen, thelabia are

commonlyaffected.

Table18.3InternationalStudyGroupcriteriaforthediagnosisofBehçet’sdisease

Clinical

feature

required

for

diagnosis

Definedas:

Recurrent

oral

ulceration

Minoraphthous,majoraphthousorherpetiformulcers,observed

byaphysicianorreportedreliablybythepatient,recurrentat

least3timesinone12-monthperiod

Plus,any2ofthefollowing:

Recurrent

genital

ulceration

Recurrentgenitalaphthousulcerationorscarring,observedbya

physicianorreportedreliablybythepatient

Eye

lesions

Anterioruveitis,posterioruveitis,orcellsinvitreousonslitlamp

examination;orretinalvasculitisobservedbyan

ophthalmologist

Skin

lesions

Erythemanodosum-likelesions,observedbyaphysicianor

reportedreliablybythepatient,pseudofolliculitisor

papulopustularlesions;oracneiformnodulesobservedbya

physicianinpost-adolescentpatientsnotreceivingGCs

Positive

pathergy

test

Testinterpretedaspositivebyaphysicianat24–48hrs,done

withanobliqueinsertionofa20-gaugeorsmallerneedleunder

sterileconditions

Skinandmucosalinvolvementtreatment

• MildoralandgenitalulcerationmayrespondtotopicalGCpreparationsorGC

inhalers.

• Colchicine 1.5 mg/day (0.5mg tds) can be used to treat frequent attacks of

aphthousulceration.

• More resistant cases may respond to azathioprine (AZA) 2.5 mg/kg/day,

mycophenolate mofetil (MMF) and/or brief courses of prednisolone 20

mg/day.

• Anti-TNFα(etanerceptandinfliximab)havebeenshowntobebeneficialfor

mucocutaneousdisease.

• Ciclosporin and interferon alfa have been shown to be effective in RCTs.

NSAIDsarefrequentlyusedforpaincontrol.

• Thalidomidehas modestbenefitsinmucocutaneousBD,butitisdifficultto

obtain and carries a significant risk of peripheral neuropathy and

teratogenicity. Itisgenerally reservedforhighly resistantdisease inpatients

whowillfollowstrictcontraception.

Eyedisease

• Eyediseaseisaseriouscomplicationandapoorprognosticfactor.

• Itismorecommoninmen,inthe<25yearsagegroup,isusuallyseenduring

thefirst2yearsofhavingBD,andisbilateralin70–80%.

• The most frequent eye involvement is chronic relapsing panuveitis. The

presence of a hypopyon occurs in ~20% of patients and is almost always

associated with severe posterior retinal vasculitis. Recurrent bouts of

inflammationresultinstructuralchange,andtotallossofvisionoccursin20%

ofcasesdespitetreatment.

Eyeinvolvementtreatment

Topical GC and mydriatics with close supervision may be sufficient in mild

disease, but severe disease requires AZA 2.5 mg/kg/day, ciclosporin, up to 5

mg/kg/day, anti-TNFα therapy (especially infliximab), and cyclophosphamide

(CYC)forrefractorycases.

Musculoskeletalinvolvement

Arthritisorarthralgiaisseeninabout50%ofpatients.

• MSKsymptomsmayprecedetheotherfindingsbymonthsoryears.

• Arthritis might commonly involve knees, ankles, hands, and wrists, or

occasionallysymmetrical.Itisusuallyaself-limitingsynovitis,andtendstobe

non-erosiveandnon-deforming.

• Back painis rare.However,asubgroupofpatientshave areactive arthritis-

like features, presenting with acne, arthritis and enthesopathy (see main

differential:SAPHOsyndrome, Chapter16).

Musculoskeletalinvolvementtreatment

PainmayrespondtoNSAIDsandcolchicine(e.g.0.5mgthreetimesaday).

• Inflammatorydiseaseoften requirestheintroductionof AZA2.5mg/kg/day.

OthertherapiesincludeSSZ2–3g/dayorMTX10–20mgweekly.Infliximab

couldalsobeconsidered.

Table18.4FrequencyofclinicalmanifestationsinBehçet’sdisease

Lesion Prevalence(%)

Aphthousulcers 97–100

Genitalulcers ~85

Skinlesions

Papulopustularlesions

Erythemanodosum

Pathergyreaction

~80

~60%(Mediterraneancountries,Japan)

Eyelesions/uveitis 50

Arthritis 30–50

Subcutaneousthrombophlebitis 25

Arterialocclusion/aneurysm ~4

Gastrointestinallesions 1–30(moreprevalentinJapan)

Epididymitis ~5

Deepveinthrombosis 5–20

Neurologicaldisease ~5

Secondaryamyloidosis 0.04–3

Cardiovascularandpulmonaryinvolvement

• BD can affect both arteries and veins. In spite of the thrombotic episodes,

thereisarelativeabsenceofembolicphenomena.

• The heart is rarely involved in BD, but may manifest as endocarditis,

myocarditis, pericarditis, coronary vasculitis, and ventricular aneurysms.

Right-sided endomyocardial fibrosis with intracardiac thrombi is an unusual

manifestationthathasbeenobservedinyoungmaleswithwidespreadvascular

disease.

• Thrombophlebitisoccursin25%ofpatients.Lowerlimbvenousthrombosisof

the deep veins is often seen. Occlusion of suprahepatic veins (Budd–Chiari

syndrome)isararecomplicationofBDthatcarriesahighdeathrate.

• Artery involvement (1.5–7.5%) carries significant associated mortality.

Lesions are typically aneurysmal with a risk of rupture, or uncommonly,

occlusive. The abdominal aorta is the most frequently affected resulting in

abdominalpain.Peripheralarterialinvolvementmayresultinreduced/absent

pulseswithintermittentclaudication,coldextremities,orevengangrene.

• The pulmonarypathologyofBDisrelatedtoarterialvasculitis. Aneurysms,

thromboses,andinfarctsarefound.Pulmonaryembolismisraredespitehigh

ratesofthrombophlebitis.

Cardiovascularandpulmonaryinvolvementtreatment

• AspirinandNSAIDscanbeusedforphlebitis.

• Aneurysms and arterial occlusion can be treated with endovascular surgery

including intra-arterialembolization if combination immunosuppressantsfail

orareconsideredinappropriate.

• Thereremainsdebateastowhethertouseheparinororalanticoagulantsfor

BD thrombophlebitis. Most physicians will choose to treat with

anticoagulation in addition to immunosuppression. If patients have BD-

associatedaneurysms,anticoagulationincreasestherisksofhaemorrhage.

Neurologicalinvolvement

Neurologicalinvolvementisseenin5%ofpatientswithBD.Itusuallyoccurs

after the first 5yearsofthedisease,and is almost never a presenting feature.

Patternsofinvolvementareeithervascularorparenchymal.

• Parenchymal disease is usually manifested by bilateral pyramidal signs,

unilateralhemiparesis,behaviouralchanges,andheadaches.

• Themostcommonlyaffectedsiteisthebrainstemandbasalganglia.Cerebral

corticesseemtobespared.Meningealirritationanddementiamayalsooccur.

As is the case with eye disease, central nervous involvement is often more

severeinmen.

• Cerebrospinal fluid (CSF) changes such as pleocytosis and increased

cellularityoccurin60%ofpatientswithparenchymalinvolvement.

• MRI is more sensitive than CT for imaging. Signal changes, with contrast

enhancement in the brainstem and basal ganglia regions, occur but are not

specific(considerMS,sarcoid,APS).

• Dural sinus thrombosis is a feature characterized by headache, sixth nerve

palsy, papilloedema, and raised CSF pressure.Ithasabetterprognosisthan

parenchymalinvolvement.Anassociationbetweenduralsinusthrombosisand

deepveinthrombosisexists.

• Incontrasttoothervasculitides,peripheralneuropathyisunusual.

Neurologicalinvolvementtreatment

• Thrombosisoftheduralsinusesandincreasedintracranialpressureshouldbe

treatedwithIVmethylprednisolone1gfor3–5days.

• ParenchymalinvolvementisusuallytreatedwithCYCorAZAcombinedwith

GCs.

• AsmalltrialhasfoundMTXmaystoptheprogressionofchronicneurological

involvement,butlargerstudiesareneeded.

• A few case reports suggest infliximab may be beneficial in refractory

parenchymaldisease.

Gastrointestinalinvolvementanditstreatment

• Whileseeninuptoone-thirdofpatientsinJapan,gastrointestinal(GI)disease

israreinpatientsfromtheMediterraneanbasin.

• Thepathologyismucosalulceration,mostlyinileumandcaecum.

• The course is one of relapse and remission, and a tendency for bowel

perforation.ItcanbedifficulttodistinguishthefindingsofGIBDfromthose

ofCrohn’sdisease.

• IntreatingGIBD,ulcerationmayrespondtoprednisolone0.5–1mg/kg/day,

SSZ2–3g/day,orinfliximab.AZAisanalternative.

• Surgicalevaluationmaybenecessarytomanageseveresequelae.

• Largeulcers,highCRPandperforationarepredictorsofrecurrence.

Renalinvolvementanditstreatment

Renaldiseaseisseenmuchlessthanmightbeexpectedwithsystemicvasculitis.

• There are occasional reports of glomerulonephritis, ranging from IgA

nephropathytorapidlyprogressiveglomerulonephritis.

• Secondary amyloidosis AA usually presents with nephrotic disease, and has

beenreportedinabout1%ofpatients.

• Epididymitisisseeninupto20%ofmales.Otherurologicalproblemsinclude

cystitisanderectiledysfunction.

• Treatmentfocusesonsymptomcontrol.PatientswithAAamyloidosisrequire

therapyforBD.

• ColchicinecanbeusedtotreatbothBDandamyloidosis.

Sarcoidosis

Sarcoidosisisamultisystemdiseaseofunknownaetiology,characterizedbythe

presenceofmultiple,non-caseatinggranulomas.

Epidemiologyandpathophysiology

• Sarcoidosis is found worldwide but the prevalence, clinical features, and

outcomevariesconsiderably.

• Itmaypresentatanyage,butprevalencepeaksinthe20–40yearsagegroup

withasecondpeakinwomen>50yearsold.

• Itisseenmoreoftenindevelopedvsunderdeveloped,WesternvsEastern,and

inNorthernvsSouthernEuropeancountries.

• SwedenandDenmarkhaveprevalenceratesof60per100,000,TheUK20per

100,000. In the USA, sarcoidosis is 10–15× more prevalent in African

American people than in Caucasians, and in this ethnicity, disease is often

severe. Studies have suggested a link between HLA-B8, HLA-DR3, acute

sarcoidosis,andarthritis.

• Granulomata and associated tissue inflammation can occur in virtually any

tissueinthebodyandcanmanifestlocalsymptomsalone.Systemiceffectsare

notalwayspresent.

Generalpatternsofdisease

Acutesarcoidosis(Lofgren’ssyndrome)

• Thispresentswithrapid-onsetfever,acutearthritis/arthralgias,EN,andhilar

lymphadenopathy.

• LÖfgren’ssyndromehasahighrateofremissionandagoodprognosis.

• TreatmentusuallyrequiresNSAIDsonly.

• Ithasbeenreportedtooccurinseasonalclusters,especiallywinterandearly

spring,suggestingenvironmental/infectioustriggers.

• Thechestradiographclearswithin1yearin60%ofcases.

• Around15%ofpatientswithLÖfgren’ssyndromehave araisedangiotensin

convertingenzyme(ACE)levelatpresentation.

Chronicsarcoidosis

• Chronic sarcoid is less common than LÖfgren’s syndrome and has an often

subtle, insidious, progressive, and highly variable clinical course. Clinical

manifestationscanbeextensive(Table18.5).

• Granulomata can occur in virtually any tissue in the body and can manifest

localsymptoms.Systemiceffectsarenotalwayspresent.

Early-onset(childhood)sarcoidosis

EOS refers to disease onset in the first 5 years of life and has a clinical

phenotypedistinctfromadult-onsetdiseaseandverysimilartoBlausyndrome

(seeearlierinthischapter).

• A typical presentation is with rash, polyarthritis (typically a ‘boggy’

tenosynovitis),anduveitis(littlepulmonaryinvolvement).

• The rash occurs in 77%andisoften unusual including a soft yellow-brown

papillomatouslesion,hypopigmentation,andulceration.

• Eye disease is often asymptomatic and uveitis requires screening withaslit

lamp.Lacrimalhypertrophyandconjunctivalgranulomamaybefound.

• Other organ involvement is rare but may include parotids glands, testes,

vasculitis,lungs,andrenalinvolvementfromhypercalciuria.

• Treatmentisasdescribedlaterinthissection.Thereisaguardedprognosisfor

EOSasnearlyalldeveloplong-termmorbiditydespiteintervention.

• Olderchildrenhaveaclinicalphenotypesimilartoadult-onsetdisease.

Musculoskeletalmanifestationsofsarcoid

Joints

• Distinctive patterns of arthropathy are seen in both acute and chronic

sarcoidosis. In acute disease, migratory arthralgias may precede other

symptoms.

• Acutesarcoidarthritisismainlyoligoarticular,occasionallypolyarticular,but

rarely monoarticular. It commonly involves the lower limb joints, often

resultinginsymmetricaleffusionsaffectingthekneesandanklejoints.After

recovery,recurrenceratesarelow.

• Chronic polyarthritis is uncommon. It is more frequent in women and in

associationwithpulmonarydisease.

• Different forms of chronic arthritis can occur: non-deforming with

granulomatous synovitis, non-erosive deformity (Jaccoud’s), dactylitis, and

tenosynovitis.Kneesandanklesareofteninvolved.

• Rheumatoidfactorispositivein10–47%ofchronicarthritis.

Bone

• Bone involvement is estimated to occur in up to 15% of all patients with

sarcoidosis,andisusuallyaccompaniedbyskindisease.

• Approximately50%ofaffectedpatientsareasymptomatic.

• Different types of bone involvement are seen: cystic (most common), lytic,

scleroticfocallesions,andosteopenia/osteoporosis.

• Bonecystsareoftenfoundincidentallyonplainfilms,andseenmostoftenin

phalangesbutmayalsooccurintheskull,facialbones,ribs,spine,pelvisand

longbones.

• Bonecystsarefrequentlyseenwithpersistentdiseaseand/orlupuspernio(i.e.

erythematousindurationoftheskinacrosstheface).

• Dactylitisappearsas‘sausage-like’swollendigits.

• Otherradiologicalfeaturesincludethickeningofcorticalbone,acrosclerosis,

andjointdestruction.

• Lyticlesionswhichappearinvertebralbodiescanleadtobackpain,andbea

causeofvertebralfractures.

Table18.5Clinicalmanifestationsinchronicsarcoidosis

Organ/system Clinicalfeatures

Lung Parenchymaldiseasein>90%ofcases

Skin Lupuspernio,plaques,nodules,vascularpurpura

Ocular Uveitis,conjunctivitis,xerophthalmia

Lymphatics Lymphadenopathy,splenomegaly

Bonemarrow Infiltration

Hepatic Failure,granulomas,portalhypertension

Renal Nephrocalcinosis,granuloma,glomerulardisease

Gastrointestinal Granulomas(alsoinsalivary,lacrimalglands,nose,

tonsilsandlarynx),xerostomia

Cardiac Arteritis,cardiomyopathy,conductionabnormalities

Nervoussystem Centralandperipheralneuropathy.Intracerebral

lesions.Meningealinflammation.Seizures

Endocrine/reproductive

organs

Granulomas

Muscles

• Skeletalmuscleinvolvementoccursin~50–80%ofpatientswithsarcoidosis,

but is often asymptomatic. Itmaypresentasproximalpain, tenderness, and

weakness.

• Myopathymaybefocalwithpainfulnodulargranulomatousmasses,insidious

withasymmetricaldiffusepattern,oracutewithelevatedmuscleenzymes.

• Muscleweaknessisoftenmorepronouncedthaneitherthesymptomsofpain

orthelevelofraisedCK.

• Acutesarcoidmyopathymayinvolvetherespiratorymuscles.

• Electromyographyisabnormalasforpolymyositis.

Diagnosisandinvestigations

Diagnosis relies on the combination of clinical and radiographic findings,

histologicalproofofnon-caseatinggranulomas,andexclusionofotherdiseases

withsimilarpresentation.

• All patients with suspected sarcoidosis should undergo the following

investigations: electrocardiogram (ECG), pulmonary function tests, PA chest

radiograph, slit-lamp examination, tuberculin skin test, urinalysis, 24-hour

urinarycalciumandbloodtests(urea,electrolytes,creatinine,FBC,ESR,bone

profile, vitamin D, PTH, LFTs, CRP, ACE, CK) in addition to a thorough

physicalexaminationandsymptom-drivenevaluation.

• ACTchestwillalso benecessaryto assessthedegree ofparenchymallung

involvement.

• Leucopenia can be seen in around 30% of cases, and eosinophilia in 25%.

Thrombocytopeniaisalsorelativelycommon.

• TheESRmaybeelevatedintheacutephase,particularlyifENispresent(see

laterinchapterforEN/panniculitis).

• Hypercalciuria and/or hypercalcaemia is seen in 10–20%, secondary to

increased 1α-hydroxylation of 25-hydroxyvitamin D to active 1,25-

dihydroxyvitamin D (1,25(OH)

D) by inflammatory cell-derived 1α-

hydroxylase. Hypercalciuria can exist without there being (supra-reference

range)hypercalcaemia(butPTHwillbesuppressed).

• Liverfunctiontestsmaybederangedandathirdofpatientshavesignificant

proteinuria.

• GranulomaepithelialcellsproduceACE.SerialmeasurementsofACEmaybe

usefulinmonitoringthecourseofthedisease.

• The distribution of inflammatory tissue in sarcoid and guidance to site of

potentialbiopsycanbeidentifiedusingeitherGa-67orsomatostatinreceptor

scintigraphy.

• Other causes of granulomatous disease include tuberculosis and other viral,

parasitic, bacterial, or fungal infections, lymphomas, Crohn’s disease,

granulomatosiswithpolyangiitis,anddrugreactions.

• Sincesarcoidosiscanresembleotherdiseases,thediagnosisshouldideallybe

confirmedbyhistology.

• Bronchoalveolarlavage(BAL)maydemonstratelymphocytosisandisuseful

in excluding other diagnoses. Transbronchial lung biopsy or mediastinal

lymphnodebiopsymayalsoberequired.

Treatment(seealsopp.662–80)

• Acute, transient disease may resolve spontaneously, and require only

supportive care. NSAIDs alone may be effective, and should be used in

conjunctionwithprotonpumpinhibitors.

• More severe disease may require treatment with GCs, either alone or in

combinationwithMTX.

• Addition of HCQ may also help the skin and joint manifestations. Several

reports also describe its use in pulmonary and neurological disease, and in

hypercalcaemia.

• AZA is most often used as second-line drug therapy in patients with

progressivediseasedespiteGCs.

• CYChasbeenusedinneuro-andcardiacsarcoidosis.

• Infliximab may be effective for refractory forms of this disease, including

lupus pernio; however, relapse of sarcoidosis has been observed upon

discontinuation.

• Colchicinehasbeenusedinpatientswithsarcoidarthritisatdosessimilarto

thoseusedingout.

• No therapy is required for asymptomatic osseous or cystic bone disease, or

asymptomaticmuscledisease.TheplaceforGCsinchronicsarcoidmyopathy

remainsuncertain.

• Mortality is <5% and mainly results from respiratory failure secondary to

pulmonaryfibrosisandrefractoryneurologicalorcardiacdisease.

Miscellaneousskinconditionsassociatedwith

arthritis

Panniculitis

Panniculitisisinflammationinfattissue.Itisaninflammatoryprocessinvolving

neutrophils,leucocytes,andhistiocytesthatcausesfibrosisandgranulomas.

• The categories of panniculitis, based on histopathology are septal, lobular,

mixedtypeseptalandlobular,panniculitiswithvasculitis.

Septalpanniculitis

• This includes erythema nodosum (EN) and Vilanova’s disease (subacute

nodular migratory panniculitis). EN is a common, acute, and self-limiting

condition (typically in lower legs). It usually heals in 4–6 weeks without

scarring.Arareformcancauseulcerationandamigratoryformcanoccurfor

severalyears(women40–50yearsold).

• AssociationsofENarenumerous(seeTable18.6).

Lobularpanniculitis

Numeroussyndromeshavebeendefined:

• Weber–Christian disease: a relapsing, febrile, nodular non-suppurative

disorder. Multiple recurrent nodules and fever, arthralgia, myalgia, and

abdominal pain. Any area of the body containing fat can be involved, e.g.

mesentery, heart, lung, liver, kidney. There is a 10–15% mortality.

Investigationsmayshowtypicalhistologicalfeaturesonbiopsy,elevatedESR,

anaemia,leucopenia,orleucocytosis.

• Lipogranulomatosis: this group of conditions tends to occur in children.

Multiplelesions,oftenontheextremities,resolvewithsubcutaneousatrophy.

• Post-GC use: the pathogenesis of this rare condition is not understood. It

seemstobelimitedtochildren.ItoccursonwithdrawalofGCs,andmayclear

uponGCre-administration.

•  α1-antitrypsin deficiency: may predispose to panniculitis in many types—

worth checking genetic status if severe, recurrent, or family history of

panniculitis.

• Calcifyingpanniculitis:afeatureofchronicrenalfailure.Itisnotthesameas

metastatic calcification. The prognosis is poor even with good calcium–

phosphatebalance.Parathyroidectomymayhelp.

• Lipodermatosclerosis: may be a result of venous insufficiency and

thrombophlebitis. It should be treated with compression stockings.

IntralesionalGCsorlow-doseaspirinmayalsohelp.

• LupusprofundusisararemanifestationofchroniccutaneousSLE,occurring

in<3%ofcases.Thelesionsareusuallytenderandmayulcerateandcalcify,

commonlyoccurontheface,upperarms,andbuttocks,andmayunderliean

area of discoid lupus. The lesions do not seem to follow the course of the

systemicdisease.ItmayrespondtoGCs.

• Associatedwithacutepancreatitisandacutevasculitis.

Table18.6Causes/associationsoferythemanodosum

Cause Examples

Infections Streptococcal,TB/leprosy,Yersinia,Salmonella,histoplasmosis,

blastomycosis,psittacosis

Drugs Penicillin,sulfonamides

Pregnancy

Diseases Sarcoidosis,IBD,SLE,SScl,dermatomyositis,malignancy,

Sweet’ssyndrome

Neutrophilicdermatoses

• The neutrophilic dermatoses are a group of non-infectious disorders

characterized by the presence of an angiocentric, primary neutrophilic

inflammatorycellinfiltrate(Table18.7).

• The disorders can be divided into those that cause vessel wall destruction

(vasculitis)andthosethatdonot.

Sweet’ssyndrome

• Thisconditionisrareandoccursmoreinwomenthanmen(4:1),between30

and70years.Ithasoccasionallybeenreportedinchildren.

• It is otherwise known as acute febrile neutrophilic dermatosis and was

originally described following respiratory infection, but is more commonly

seen in patients with malignancy. It is also caused by drugs, especially

granulocyte-colonystimulatingfactor.

• The characteristic features are fever, neutrophilia, and tender erythematous

cutaneouslesions(plaques,nodules,andpapules).

• Lesionscanresemblevasculitis,especiallyinafebrileillpatient.

• Skin biopsy shows intense infiltrate of mature neutrophils, typically in the

upperdermis.

• Untreated,thelesionsresolveover6–8weeks,butnewlesionswillcontinueto

appear.

• The condition is usually an acute, GC-responsive self-limiting disorder. If

longer-termtreatmentisrequired,GCdosagemaybereducedbytheaddition

ofanNSAID,dapsone,colchicine,orpossiblyMTX.

• Asecondarycausefortheconditionshouldbesought(Table18.8).

Table18.7Non-infectiousneutrophilicdermatoses

Group Examples

Non-

angiocentric

Psoriasis,reactivearthritis,acnefulminans

Angiocentric

andvessel

destruction

Leucocytoclasticvasculitis,polyarteritisnodosa

Angiocentric,

novessel

destruction

Sweet’ssyndrome,pyodermagangrenosum,bowel-associated

dermatosis–arthritis,Behçet’sdisease,rheumatoidarthritis,

ulcerativecolitis,familialMediterraneanfever

Table18.8AssociationsofSweet’ssyndrome

Associations Examples

Haematological

malignancy

Leukaemia,lymphoma,myelodysplasticdisorders

Solidtumours Breast,gastric,bladder,colon

Infectiousdiseases HIV,hepatitisB/C,TB,salmonella

Inflammatorybowel

disease

Ulcerativecolitis,Crohn’sdisease

Autoimmunediseases Rheumatoidarthritis,SLE,Sjögren’ssyndrome,

Behçet’sdisease

Pyodermagangrenosum

• This is an uncommon, ulcerative, cutaneous lesion associated with AAVs,

SLE,severeRA,andIBDsandrarelyspondyloarthritis.

• Thelesionischaracterizedbyanerythematous,violaceousborderoverhanging

acentralareaofulcerationandnecrosis.

• The lesions start as discrete pustules, most often on the legs, and are often

extremelypainful,healingwithscars.

• There is no specific treatment. An underlying disease should be excluded.

Treatmentsincludetopicalsodiumcromoglicateor5-aminosalicylicacid,oral

sulfonamides,dapsone,andGCs.

Multicentricreticulohistiocytosis

• Thisisararesystemicdisease,occurringinadultsintheir50s.Itsrecognized

clinicallybythecombinationofpapularandnodularskinlesionsandasevere

destructivepolyarthritis.

• Itisassociatedwithmalignancy(25%).

• ThearthritismimicsRAbutnotablyinvolvesDIPJs.Thedestructionmaygive

apicturesimilartoarthritismutilans.See Plate7c.

• Theskinlesionsoccurin~90%ofcases.Histologically,theinfiltrateconsists

of multicentric giant cells and histiocytes from the monocyte-macrophage

lineage. The lesions are often numerous, non-pruritic, skin coloured (or

yellow/brown),sizemm–cmindiameter,andoccurmostonthedorsumofthe

hands and face (nose, corner of the mouth, and ears). Extensive facial

involvementmayleadtoa‘leonine’facies.

• About25%ofcaseshavexanthelasma.

• The differential diagnosis includes RA, PsA, sarcoid dactylitis, xanthoma,

histiocytosis X, histiocytoma or tendon sheath giant-cell tumour—usually

solitary.

• Theconditionwaxesandwanes.Spontaneousremissionscanoccur.

• Forpatientswithmilddisease,MTXmaybesufficient,buttheconditioncan

beaggressivesomanypatientsrequiretreatmentwithCYCorchlorambucilto

preventprogressivedamage.

Relapsingpolychondritis

Relapsing polychondritis (RP) is a rare multisystem disorder of unknown

aetiology,characterizedbyepisodicandsometimesprogressiveinflammationof

cartilageleadingtodestructionandfibrosis.

• Commonsitesofinvolvementincludetheear,nose,larynx,joints,heart,and

eyes.Characteristically,thecartilaginouspartofthepinnaisinvolved,sparing

thenon-cartilaginouslobe.

• Arthralgiainvolveslargeandsmalljoints.

• SimilarpatternsofdiseasemaybeseeninPR3-positiveAAV.Somepatients

withrelapsingpolychondritisareANCApositive.

• ThediseasepredominantlyaffectsCaucasians,withpeakincidenceinthefifth

decade(M=F).

• 50paediatriccaseshavebeenreportedworldwideandthereappearstobean

associationwith(monogenetic)autoinflammation.

• ThereisalsoanassociationwithHLA-DR4.

• Approximately 30% of cases are associated with other inflammatory or

autoimmune diseases, such as systemic vasculitis, RA, SLE, Sjögren’s

syndrome,thyroiditis,andIBD.

• Therearenospecificlaboratorytests.Diagnosisismadeonclinicalgrounds.

Thecourseofthediseaseisgenerallynotlife-threateningunlessitinvolvesthe

laryngotrachealcartilageormajorarteryroots.

• MAGICsyndrome(MouthAndGenitalulcerswithInflamedCartilage)might

represent a distinct condition but is exceptionally similar to BD with

secondaryRP.

Treatment

• Treatmentisbasedonanecdoteandconsensus.TherearenoRCTs.

• Ifinvolvementislimitedtoexternalearandnasalcartilagewithnoapparent

destructionorarthritis,symptomsmaybecontrolledwithNSAIDsalone.

• Dapsone(50–200mg/day)mayalsobeofvalueandsomeprefersmalldoses

ofGCs(10–20mg/day)formilddiseasealso.

• For destructive disease in the cartilage or laryngotracheal, vestibuloneural,

lung,eye,heart,kidneyinvolvement,orsystemicvasculitis—highdoseGCs

areused(prednisolone~60mg/day).

• CYC at 1–2 mg/kg/day has been considered in severe life-threatening lung,

heart,orrenaldisease.

• PersistentorseverecasesmayalsobetreatedwithAZA,MTX,orciclosporin

(withdueattentiontorenalfunction).

• Patientsshouldbeassessedfortrachealinvolvement(e.g.stridor).Somecases

may require temporary or permanent tracheostomy and stents if laryngeal

involvementissevere.Othermeasuresmayincludecontinuouspositiveairway

pressureatnight.

• There have been a few case reports regarding the use of biologic therapies

includinganti-TNFα,andbothIL-6andIL-1inhibitors,butclinicaloutcomes

havebeenvariable.

Table18.9Featuresofrelapsingpolychondritis

Organ Clinicalfeatures Prevalence

(%)

Externalear 95

Arthritis Non-deformingandnon-erosive 85

Nose Cartilagedestruction,saddle-nose 48

Eye Episcleritis,uveitis,retinalvasculitis 57

Respiratory

tract

Dysphonia,dyspnoea,stridor 67

Innerear 53

Skin Erythemanodosum,vasculitis,Behçet’s-like

ulceration

Kidney Glomerulonephritis(poorprognosis) 8

Heart Pericarditis,aorticvalveincompetence,heart

block

Bloodvessels Aneurysms(aorticrootandabdominalaorta). 12

ReproducedfromTrenthamDE,LeCH.RelapsingPolychondritis.AnnInternMed1998;129:114–22

withpermissionfromWoltersKluwer.

Amyloidosis

Amyloid—a proteinaceous, fibrillar material—is associated with many

conditions. The low solubility of amyloid and its relative resistance to

proteolyticenzymescontributestotheirreversibleandoftenprogressivecourse

ofamyloidosis.

• Despite morphological similarities (including the formation of a β-pleated

sheet),amyloidisaheterogeneousgroupofproteins(atleast20).Alltypesof

amyloidfibrilshaveacarbohydratemoietyintheformofglycosaminoglycans

and proteoglycans. Most forms of amyloid also contain the extrafibrillar

protein,amyloid-P.

• Twoformsareimportantasmanifestationsofaresponsetochronicsystemic

inflammation:amyloid-L(AL)andamyloid-A(AA).

• AL consists of monoclonal immunoglobulin light chains and is seen in

idiopathicandmyeloma-associatedamyloidosis.Itisthecommonestsystemic

amyloidosisinWesterncountries.

• AAisderivedfromserumamyloidA(SAA),anacutephaseapolipoprotein,

andissecondary‘reactive’amyloidosis.

• It is unclear whynotall chronic inflammatory disordersareassociated with

amyloidosis and how various precursor proteins are converted to insoluble

amyloidfibrils.

• Inthecontextofrheumaticdisorders,AAamyloidosisismainlyseeninadult

RAandAS.

• SeveralconditionsarerarelyassociatedwithAAamyloidosisduetorelatively

lowlevelsofacute-phaseSAAprotein.TheseincludeSLESScl,andSjögren’s

syndrome(SS).

• Other conditions associated with AA include chronic infections, periodic

fevers,IBD,andlessfrequentlymalignancies.

Investigations

Thediagnosisofamyloidosisismadebytissuebiopsy.

• Althoughspecimenscanbeobtainedfromtheliver,heartorkidneys,increased

bloodvesselfragilityassociatedwithamyloiddepositioncarriesanincreased

bleedingrisk.Thereforereadilyaccessibleabdominalsubcutaneousfatisthe

standardaspiration (ASFA),withasensitivity of57–88%, andspecificity of

100%.

• If the ASFA is negative, or contraindicated, biopsy of the salivary gland or

rectalmucosamaybeuseful.Peripheralnervebiopsiesvaryintheirdiagnostic

valueandcancauseresidualdysaesthesia.

• AlkalineCongoredstainshowsamyloiddepositsasapplegreen/yellowunder

thepolarizingmicroscope.

• Immunofixation of serum and urine, as well as an Ig free light chain assay

should be done to confirm AL amyloidosis. If the diagnosis is uncertain, a

bonemarrowbiopsycouldbeconsidered.

• If ALandAA amyloidosesare excludedon immunofixation,furthergenetic

testingmayhelpidentifyotherweaklyamyloidogenicproteinsknowntomake

upthehereditaryamyloidoses.

• Inpatientswithchronicinflammatorydiseaseandproteinuriaand/orchronic

renalfailure,increasedSAAconfirmsAAamyloidosis.

• Echocardiogramisthegoldstandardfordiagnosingcardiacamyloid.Cardiac

MRIisalsohighlysensitiveforheartinvolvement.

• Theserumamyloidproteincontributestostabilityofamyloiddepositsinvivo.

This property is used diagnostically in radiolabelled serum amyloid protein

scintigraphy to detect amyloid in the body and is of value in assessing

responsetotreatment.

Treatment

• Theconditionisprogressiveandthereisnocure.Markedheterogeneityofthe

hereditaryamyloidosesmakescounsellingdifficult.

• The processes by which the disorder may be controlled include liver

transplantationforlysosomalamyloidosisandbonemarrowtransplantation.

• In the rheumatic diseases, the main goal is to control underlying disease to

suppressSAAproduction.VariousimmunosuppressiveagentsincludingMTX,

chlorambucil,LEF,andCYC(oftenincombinationwithGCs)haveimproved

theprognosisinRAandJIApatients.

Table18.10TheclinicalfeaturesofALandAAamyloidosis

Organ/condition Comment

AL Heart Deathoccursin50%ofcasesfromrestrictive

cardiomyopathy,congestiveheartfailure,

conductiondisturbances

Lungs 90%developcoughanddyspnoea

Skin 40%ofcases:papules,nodules,tumours

Neuropathy 10%ofcasesdevelopcarpaltunnelsyndrome

Macroglossia

Vasculopathy

Amyloid

arthropathy

Autonomic

disturbance

and

Weakness

Fatigue

Weightloss

Renal Nephroticsyndrome/renalfailure—majorcauseof

deathinAA*,causeofdeathinone-thirdofAL

patients

Gastrointestinal

tract

Malabsorption,obstruction,diarrhoea,

hepatosplenomegaly

*InAAamyloidthespleen,liver,andkidneysareofteninvolvedfirst.

Adult-onsetStill’sdisease

Epidemiologyandpathogenesis

• Adult-onsetStill’sdisease(AOSD)isararesystemicinflammatorydisorderof

unknownaetiology,characterizedbydailyspikingofhighfeversaccompanied

byafleetingrash,arthritis,andsystemicmanifestations.

• Menandwomenareequallyaffectedwithbimodalpeaksatages15–25and

36–46yearsthoughcaseserieshavesuggestedanassociationwithpregnancy

andinthepost-partumperiod.

• Theremaybeageneticpredisposition.ACanadianstudyfoundapossiblelink

with HLA-B17, -B18, -B35, and -DR2, but this has not been confirmed in

otherstudies.GeneticpolymorphismsoftheIL-18genemayalsobelinkedto

AOSDsusceptibilityand/orseverity.

• Variousinfectioustriggershavebeenpostulated,suggestingAOSDmaybea

reactive syndrome. These include EBV, echovirus, CMV, parvovirus 19,

coxsackievirus, influenza, and bacteria including Mycoplasma pneumoniae,

Chlamydiapneumonia,Brucellaabortus,andBorreliaburgdorferi.

• Thelper1(Th1)cytokinespresentinbloodandtissuesarethoughttoplaya

roleinthepathogenesisofAOSDinadditiontoIL-1,IL-6,IL-18,TNFα,and

IFN-γ.

Clinicalfeatures

Severalsetsofclassificationcriteriahavebeenproposedandarewelldeveloped

fromretrospectivedata.TheYamaguchicriteria(Box18.1)providethehighest

sensitivity(93.5%).

• Fever:acuteonsetofdailyspikinghighfeverexceeding40°Cisoftenthefirst

symptom. Typically peaks once daily in late afternoon or early evening

(quotidian), lasting <4 hours, and normalizing in 80% without antipyretics.

Theremaybeadoublequotidianpattern,withhighestspikesoccurringinlate

afternoon.

• Rash: evanescent salmon-pink, macular or macular papular eruption,

predominantlyinvolving proximallimbs andtrunk.Theoverallincidenceof

therashinAOSDis~70%.Therashusuallyappearsinconjunctionwithfever,

and may exhibit Koebner phenomenon. There may be pruritus and

appearancesconfusedwithdrugallergy.

• Musculocutaneousdisease:arthritismay initiallybemild,oligoarticular,and

transient, and may evolve gradually into a more severe, destructive, and

symmetrical polyarthropathy—affecting mainly knees, wrists, and ankles.

Elbows,shoulders,hipsinterphalangealjoints,andtemporomandibularjoints

mayalsobeinvolved.Generalizedmyalgiaswithfeverspikesareseeninthe

majorityofpatients,butinflammatorymyopathyisrare.

• Pharyngitis:estimatedtooccurin~70%ofAOSDcases.

• Liver: hepatomegaly occurs in 50–70%, partly influenced by NSAID use.

Casesoffulminantliverfailurehavebeendescribed.

• Tender cervical lymphadenopathy and splenomegaly occur in 50%. Lymph

node biopsy may resemble lymphoma on light microscopy, but

immunohistochemistrydemonstratesbenignpolyclonalB-cellhyperplasia.

• Cardiopulmonarydisease:serositisoccursin30–40%(pleuritis,pericarditis),

transientpulmonaryinfiltrates.ILDprogressingtoARDS,cardiactamponade,

andmyocarditishavebeendescribed.

• Haematological disease: is rare, but pancytopenia secondary to macrophage

activationsyndrome(MAS)mayoccur(~40%ofpatients),whichcanbelife-

threatening (see  Chapter 25). There have been reports of pure red cell

aplasia,thromboticthrombocytopenicpurpura(TTP),andhaemolyticuraemic

syndrome(HUS).

Laboratoryandradiographicfindings

• ThereisnospecificdiagnostictestinAOSD,andnoassociationwithRFor

positiveANA.

• ESRisraisedinvirtuallyallcases,andCRPmaybeelevated.

• Marked elevations in serum ferritin occurin~70%,correlating with disease

activity. A threshold of greater than fivefold the upper limit of normal as a

diagnostic tool for AOSD is thought to have a sensitivity of 80%, but a

specificity of 45%. Levels of 3000–30,000 ng/mL are not uncommon,

normalizingwithdiseaseremission.

• Aferritinlevelof>1000ng/mLwithaglycosylatedfractionof20%orless,

hasdiagnosticspecificityof>90%.

• There is leucocytosis (>10 × 10

/L), with a granulocyte predominance.

Normocyticnormochromicanaemiaandreactivethrombocytosisiscommon,

especiallyduringactivedisease.

• ThereisincreasedriskofelevatedintravascularcoagulationinAOSD,andthis

maybeassociatedwithhaemophagocytosis(macrophageactivationsyndrome)

resultinginpancytopenia,requiringpromptimmunosuppression.

• Elevated liver transaminases, lactate dehydrogenase, and bilirubin levels are

seenin75%ofcases,rangingfrommildtofulminant.Liverbiopsychanges

arenon-specific.

• VeryhighlevelsofIL-18havebeendemonstratedinanumberofstudiesof

AOSD.

• Pregnancyandthepost-partumperiodmaybefacilitativeonthedevelopment

ofAOSD(highIL-18responsescanoccurinassociationwithpregnancy).

• Secondary haemophagocyticsyndrome(HS) can occur:diffuse intravascular

coagulation (DIC), hepatosplenomegaly, pancytopenia, a decrease in ESR,

hypofibrinogenaemia,markedhyperferritinaemia,andraisedtriglyceridesand

liverenzymes.

• EarlysuspicionofHSiscrucialasthereishighmorbidityandmortality.The

goldstandarddiagnostictestisbonemarrowaspiratetoidentifythepresence

of haemophagocytosis, but appearances may be visible on a blood film, in

additiontofeaturesofhaemolysis.

• Therearenospecificradiographicfindings.Classically,thereisbilateralnon-

erosiveintercarpalandcarpometacarpaljointspacenarrowingonradiographs,

whichmayprogresstoankylosisoverseveralmonths.Rapiddestructionofthe

hipandkneejointscanoccurinsomecases,requiringtotaljointarthroplasty.

Box18.1TheYamaguchicriteriaforAOSD

Diagnosis requires the presence of ≥5 criteria, including at least 2 major

criteria,withoutthepresenceofanyexclusioncriteria.

Majorcriteria

• Feverof>39°C,intermittent,≥1week.

• Arthralgiasorarthritis,≥2weeks.

• Typicalrash.

• Leucocytosis(>10×10

/L)with≥80%granulocytes.

Minorcriteria

• Sorethroat.

• Recentsignificantlymphadenopathy.

• Hepatomegalyorsplenomegaly.

• AbnormalLFTs(includinglactatedehydrogenase).

• NegativetestsforANAandRF.

Exclusioncriteria

• Infections.

• Malignancies.

• Otherrheumaticdisease,i.e.vasculitis.

InformationfromYamaguchiMetal.PreliminarycriteriaforclassificationofadultStill’sdisease.J

Rheumatol1992;19:424–30.

Treatment

Treatment strategies are based on organ involvement and disease severity,

aimingtocontrolfever,arthritis,andsystemicdisease.

• NSAIDs can beused first line,andoften a highdoseof aspirin isrequired.

AlthougheffectiveforMSKsymptomsandfever,efficacyratesarelow,~20%

inAOSDpatients

• GCsremainfirst-linetreatment,regardlessofpresentation.Theusualdoseis

0.5–1 mg/kg/day of prednisolone. Pulsed methylprednisolone is helpful in

severediseaserefractorytooralGCs.GCscontroldiseaseactivityin~60%,

butefficacyseemshigherforsystemicratherthanarticularsymptoms.

• ForrefractoryAOSD,MTXisacommonlyusedGC-sparingagent,inducing

remissionin~70%.

• There is also reported efficacy of AZA, HCQ, D-penicillamine, ciclosporin,

andtacrolimus.

• Intravenousimmunoglobulin(IVIg)seemstohaveasuspensiveeffect,butis

welltolerated andsafetouseifconcomitantinfection. Usualdose is2g/kg

over2–5days.Tworandomizedopenlabeltrialshavedemonstratedefficacy

ofIVIgifusedearlyinthecourseofAOSD.Itshouldalsobeconsideredin

the context of macrophage activation syndrome, life-threatening

complications,andinthecaseofAOSDflareduringpregnancy.

• BiologicDMARDsusedincludeanakinra(IL-1antagonist),tocilizumab(IL-6

inhibitor)withbeneficialeffectsonsystemicandarticularfeatures,andanti-

TNFαespeciallyinchronicpolyarticulardisease.

• Adalimumab and etanercept may have led to macrophage activation in two

reportedcasesof AOSD,and have beenassociated withparadoxicaldisease

flares.Furtherprospectiveevidenceisrequiredontheiruse.

Courseofdiseaseandprognosis

Therearethreemainpatternsofdisease,with~1/3ofpatientsfallingintoeach

category.

• Self-limitingormonophasicpatterncharacterizedbyasinglediseaseepisode.

Mostachievecompleteremissionwithin1year.

• Intermittentorpolycyclicsystemicpatternconsistingofrecurrentattacks,with

remissionbetweenflares. Subsequent diseaseflaresare often less severe,of

shorterdurationandmaybeyearsapart.

• Chronicarticularpatternassociatedwithpoorprognosis.Diseaseispersistent

with predominantarticular symptoms resulting inseveredestructive arthritis

andarthroplastyfrequentwithin2years.

• Predictors of a chronic disease course include rash, polyarthritis, and

involvement of shoulders and hips. Patients with systemic disease generally

haveafavourablediagnosis.Seriouscomplicationsfromdiseaseortreatment

arerare,butamyloidosisisthoughttobeacommoncauseofdeath.

Furtherreading

JamillouxY,Gerfaud-ValentinM,HenryT,etal.Treatmentofadult-onsetStill’sdisease:areview.Ther

ClinRiskManag2015;11:33–43.

Eosinophilicfasciitis

Eosinophilicfasciitisisanuncommonidiopathicconditionthatischaracterized

bytherapidspreadofskinchangesovertheextremities.

• Skin—usuallyinthelimbs—initiallytakesona‘peaud’orange’ appearance,

whichisreplacedbyinduration.

• LikeSScl(see Chapter13),flexioncontracturesandRaynaud’sdiseasemay

bepresent.UnlikeSScl,theepidermisisspared(i.e.superficialwrinklingis

intact)andnailfoldcapillaroscopyisnormal.

• Other localized scleroderma conditions (see  Chapter 13) will be in the

differentialdiagnosisinearlydisease.

• Theconditionmayresolvespontaneously.Otherwise,70%ofcasesrespondto

GCs.

• Theconditionmaybeaparaneoplasticphenomenon.

• Itisover-representedinwomenandinthehaematologicalmalignanciesinthis

respect. The paraneoplastic condition often fails to respond to GCs and

resolvesonsuccessfultreatmentoftheunderlyingmalignancy.

• MTX and MMF may be effective and are used as GC-sparing

immunosuppressants.

ImmunoglobulinG4-relateddisease

Epidemiologyandpathophysiology

Immunoglobulin G4-related disease (IgG4-RD) is a rare systemic fibro-

inflammatorydisorderofunknownaetiology.

• ThepathophysiologyandroleoftheimmunesysteminIgG4-RDisnotwell

understood.ThereisTh2cellinvolvementwithnumerousTh2cytokines(IL-

4,IL-5,andIL-13)presentalongsideT-regs(IL-10andTGF-β).Circulating

plasmablastlevelscorrelatewithdiseaseactivity,suggestingtheimportanceof

Bcellsinpathogenesis.

• Characteristichistopathologicalfindingsarealymphoplasmacyticinfiltration

withIgG4-positiveplasmacells,storiformfibrosis(irregularlywhorledpattern

offibrosis),andobliterativephlebitis.

• Itcanaffectmultipleorgansites(seelaterinsection)andmaybelocalizedor

systemic,butmostcommonlyaffectstheextra-pancreaticbileducts,lacrimal

orsalivaryglands,orpancreas.

• IgG4-RD often presents with a tissue mass and so may mimic a solid

malignancyorlymphoma.

• It is more common in males and appears to predominantly affect patients

betweentheageof50–70years.

Clinicalmanifestations

• Multiple organs can be affected: extra-pancreatic bile ducts, lacrimal or

salivaryglands,orpancreas(Table18.11).

• Disease is often incidentally identified on imaging or histopathology

examinationofatissuespecimen.

Investigations

• Tissuebiopsyisdiagnostic.

• SerumIgG4levelsmayberaised,althoughthesecanbenormal.

• ESRandCRPmaybeelevated.

• Hypergammaglobulinaemiaisoftenseen.

• Lowserumcomplementlevelsoccurinaroundone-thirdofpatientswithrenal

involvement.

Treatmentandprognosis

• There areno RCTstoguidetreatment.GCsareeffective,particularlyin the

inflammatoryphasebutlesssointhefibroticphase.

• Though frequently used, there is a lack of consensus as to whether a GC-

sparingagentshouldbeused.

• RTXhasbeenshowntobeeffectiveinacaseseriesandarecentprospective

open-labeltrial.

• MMF, MTX,and AZA aresuggested astreatment options,butthereislittle

evidencebasefortheiruse.

• The natural history and prognosis are poorly described. Significant organ

dysfunction may result from uncontrolled and progressive inflammationand

fibrosis in involved tissues. Relapses are common on weaning GCs,

particularlyinsystemicdisease.

Table18.11OrganinvolvementinIgG4-relateddisease

Organ/system Pathologies

Hepatobiliary Pancreatitis,sclerosingcholangitis,andcholecystitis

Salivaryand

lacrimalglands

Sialadenitis,submandibularglanddisease,

dacryoadenitis,parotitis

Endocrineglands Thyroid(Riedel’sthyroiditis)

Ophthalmic Orbitalmyositis,pan-orbitalinflammation,orbital

pseudo-tumour

Vascularand

cardiac

Aortitisandperiaortitis(retroperitonealfibrosis),

pericarditis

Pulmonary Pleuritis,lungmass/nodules,mediastinitis

Lymphaticsystem Lymphadenopathy

Neurological Pachymeningitis,hypophysitis

Renaland

genitourinary

Membranousglomerulonephritis,tubulointerstitial

nephritis,renalpyelitis,prostatitis

Skinand

cutaneous

Papulo-nodules,plaques,maculopapularrash,purpura,

urticarial,psoriatic-likelesions

Raredisordersofsynovium

Pigmentedvillonodularsynovitis(PVNS)

• PVNS is a rarenon-malignantcondition (2 per million)characterized by an

uncontrolledproliferationofsynoviocytes.

• Itisassociatedwithironandfatdeposition.

• Repeatedsmallhaemorrhagesandlipiddepositsstainthesynoviumred-brown

andyellow,respectively.

• Thecauseoftheconditionisunknown,althoughsomestudieshaveproposeda

linkwithchronicrepetitivetraumaorhaemarthroses.

• Anyagemaybeaffected(mainlythirdtofourthdecade;bothsexes).

• Theclassicpresentationiswithmonoarthritis.

• The knee is the most commonly affectedjointand‘diffuse’ disease is more

aggressiveandmorelikelytorecur.

• PVNScausesaninsidiousonsetofpainandswelling,blood-stainedsynovial

fluidaspirate,withcharacteristicsynovialbiopsyfindings.

• Differential diagnosis: malignant synovioma, TB arthritis, synovial

haemangioma,synovialchondromatosis,amyloidosis,haemophilia.

• Radiographs are often normal. Calcification is not a feature of PVNS and

might suggest another cause (e.g. malignant lesion, chondromatosis, gout,

CPPD,trauma,etc.).

• Erosions and subchondral cysts (also on non-articular surfaces) can occur.

Lossofjointspaceoccurslate.MRIisdiagnostic.

Treatment

• Monoarticular PVNS is treated by excision of the lesion with or without

precedingYttrium-90(Y-90)radiationsynovectomy(RS).

• Y-90RSisessentiallyonlysuitablefortheknee.

• Y-90RScanbecoadministeredwithintra-articularsteroid.

• Re-186HEDPRScanbegivenformid-sizejoints(e.g.elbow,ankle).

• DiffuseformsofPVNStendtobeprogressiveandrecurrent.

• There are no robust treatment trials of PVNS. Treatment is based on

radiologicalstagingandtechnicalfeasibility.

Synovialchondromatosis

• Synovial chondromatosis is a chondrometaplasia of the sub-synovial

connectivetissue.Thejointcontainsthickened,white-bluenodularsynovium.

• The cause is unknown, the disorder uncommon, and the process non-

malignant. It tends to occur more often in middle-aged men and has never

beenreportedinprepubertalchildhood.

• Clinically thecondition resemblesPVNSbut tendsto beslowlyprogressive

andsometimescanbeself-limiting.

• Radiographsmayshowpunctatecalcificationatthejointmargin.

• The diagnosis should be confirmed on synovial biopsy. In rare cases, there

maybetransformationtoachondrosarcoma.

• Treatmentissurgicalandusuallymanagedwitharthroscopy,removingloose

bodiesand/orthesynovialmembrane.

Chapter19
Hereditarydisordersofconnectivetissue
Background:molecularabnormalitiesofcollagenandfibrillin
Osteogenesisimperfecta
Distalarthrogryposes
Marfansyndromeandrelateddisorders
Ehlers–Danlossyndrome
Hypermobilityspectrumdisorderinadults
Hypermobilityinchildrenandadolescents
Sticklersyndrome
Background:molecularabnormalitiesofcollagen
andfibrillin
Collagen and fibrillin are major connective tissue proteins with important
mechanicalfunctionsparticularlyintissuesrelevanttoMSKintegrity,strength,
and flexibilityintendons,ligaments, and bone. In thischapter, we outline the
conditions manifest by abnormalities in collagen and fibrillin: osteogenesis
imperfecta(OI),Marfansyndrome(MFS),Ehlers–Danlossyndrome(EDS),and
hypermobilityspectrumdisorder(HSD)—themostcommonhereditarydisorders
ofconnectivetissue(HDCT).
Osteogenesisimperfecta
Osteogenicimperfecta(OI)isacollectionofgeneticdisorderscausedbyalack,
or deficiency, of type I collagen historically known as brittle bone disease.
Variedgenotypescanresultinrelatedbonephenotypes.
Epidemiology
• OIisuncommon—about1:20,000livebirths.

Genetics

• OI occurs, in >90% of cases, because of mutations in the COL1A1 or

COL1A2gene.

• In most cases of OI type I there is a ‘functional null’ allele of COL1A1 on

chromosome17orCOL1A2onchromosome7leadingtoreducedamountsof

normalcollagenI.

• Historicallyfourmaintypeshavebeendefinedonclinicalcriteria(Table19.1)

thoughatleast17distinctgenotypesarenowrecognized.

• OI may exhibit considerable interfamilial and intrafamilial variability in the

numberoffracturesanddegreeofdisability.

Pathophysiology

• PathologyarisesasaresultofdefectsinstructureorquantityoftypeIcollagen

foundinbone,ligaments,teeth,sclerae,andskin.

Clinicalfeatures

Fractures, bone deformity, ligament laxity, joint hypermobility, easy bruising,

poordentition,andhearingdeficitarecommonfeatures.

• Generalized osteopenia and fractures early in childhood are common.

Fractures are rare in the neonatalperiod;fracturetendencyis constant from

childhood to puberty, decreases thereafter, and often increases following

menopauseinwomenand>60yearsinmen.

• OIcanpresentinyoungadultswithlowBMDorfragilityfracturesincluding

recurrentinsufficiencyfractures.

• FracturesinOIare treatedwithstandard orthopaedicproceduresappropriate

forthe typeoffractureandthe age,andhealrapidlywith evidenceofgood

callusformation(sometimeswithhypertrophiccallusformation)andwithout

deformity.

• Using clinical, radiographic, and genetic criteria, Sillence developed the

classificationcurrentlyinuseintoOItypesItoIV:adominantformwithblue

sclerae, type I; a dominant form with normal sclerae, type IV; a perinatally

lethalOIsyndrome,typeII;andaprogressivelydeformingformwithnormal

sclerae,typeIII.

• Hearing loss of conductive or mixed type occurs in about 50% of families,

beginning in the late teens and leading, gradually, to profound deafness,

tinnitus,andvertigobytheendofthefourthtofifthdecade.

• Individuals with OI type I have blue sclerae which remain intensely blue

throughoutlife,incontrasttothescleraeinOItypeIIIandOItypeIVwhich

mayalsobeblueatbirthandduringinfancy.

• Theintensityofbluescleraefadeswithtimesuchthattheseindividualsmay

havescleraeofnormalhuebyadolescenceandadultlife.

• Adifferentialdiagnosistoconsiderinyoungchildrenisnon-accidentalinjury

(NAI) and depending on the time of presentation, idiopathic juvenile

osteoporosis,Cushing’s,andhomocystinuria.

Table 19.1 The clinical and collagen abnormalities in the (historically clinically defined) four main

osteogenesisimperfecta(OI)phenotypes(Sillenceclassification)

Type Clinicalfeatures Inheritance Defect

I Normalbonegrowth.Normaldentition.

Hearinglossin50%.Bluesclera

AD Decreased

productionof

typeI

procollagen

(nullallele)

II Lethal.Stillbirths AD

AR(rare)

Rearrangement

ofcollagen

IA/2Agenes

III Oftendeformedgrowthatbirthand

worsens.Poordentitioncommon.

Hearinglosscommon.Mayhaveblue

sclera

ADorAR Mutationsin

α1andα2

collagen

chains

IV Oftenbonedeformityandshortstature.

Poordentitioncommon.Hearingloss

uncommon.

AD Mutationsin

theα2chains

AD,autosomaldominant;AR,autosomalrecessive.

Management

• Fractures heal rapidly with evidence of a good callus formation, and, with

goodorthopaediccare,withoutdeformity.

• Short-term use of bisphosphonates in children and adults with type I OI is

associatedwithBMDgainsandfractureriskreduction.

• In children, IV bisphosphonate is favoured over oral treatment—mostly

pamidronatehistoricallybutnowzoledronicacidisbeingincreasinglyused.

• Treatmentwithbisphosphonatescanreducebonepainandfractures,increases

BMD,resultsinmorenormalskeletalgrowth,andiswelltolerated.Greatest

gainsareprobablyinthefirst2–4yearsoftreatment.

• Inchildren,pamidronateisgivenat1mg/kgbodyweightover4hourson3

successivedays;infusioncyclesarerepeatedevery4months.

• Some evidence for a positive effect on BMD, bone pain, and fracture

prevention from teriparatide exists anecdotally. Intuitively teriparatide may

offer a better ‘treatment fit’ for OI compared with bisphosphonate in low

collagenproductionOI.

• Thelong-termskeletaleffectsofanti-resorptiontherapyinadultswithOIare

unknown.

• ThereareanecdotalreportsoftheuseofteriparatideinadultswithOIwhere

gainsinBMDaredocumented.

• RCTsofteriparatideandabaloparatideareinplanning.

• Regular hearing evaluations after adolescence and early stapedectomy or

stapedotomyarerecommended.

• Patient information is available at:  http://www.brittlebone.org and

http://www.oif.org.

Distalarthrogryposes

Case reports of congenital contractural arachnodactyly (CCA; Beal’s

syndrome/distalarthrogryposistypeIX)highlightthewidevariationinclinical

features representing variable genetic expressivity in the distal arthrogryposes

(DAs).

• In the DAs, the MSK features of joint contractures, arachnodactyly,

camptodactyly,andkyphoscoliosispredominateinCCA.

• The DAs types 1–10 are a groupofdisordersthatmainly involve the distal

partsofthelimbsmanifestbycongenitalcontracturesoftwoormoredifferent

body areas without primary neurologic or muscle disease. The prototypic

distalarthrogryposisistype1(DA1)—characterizedlargelybycamptodactyly,

clubfoot,andheterozygousmutationintheTPM2geneonchromosome9p13

(thegeneencodingbeta-tropomyosin).

Marfansyndromeandrelateddisorders

Marfan syndrome (MFS) is due to heterozygous mutations (numerous) in the

fibrillin1gene(FBN1)onchromosome15q21.1.

• MFS is an autosomal dominant condition with complete penetrance and

prevalenceof1in25,000;criteriafordiagnosisareshowninTable19.2.

• MFS is characterized by long extremities (span/height ratio >1.05), long

fingers and feet (arachnodactyly) with a hand/height ratio >11% and

foot/heightratio>15%, tallstature(with uppersegment/lowersegment ratio

<0.89), pectus deformity of the chest wall, high-arched palate, mandibular

hypoplasia,lensdislocationsandmyopia,andjointlaxity.

• Othercommonorpeculiarmanifestationsincludestriaedistensae,pulmonary

blebs(whichpredisposetospontaneouspneumothorax),andspinalarachnoid

cystsordiverticula.

• AllfeaturesarelistedinTable19.2.

• Mitral valve prolapse, mitral regurgitation, dilatation of the aortic root, and

aortic regurgitation are cardiovascular features. Aneurysm of the aorta and

aorticdissectionarelife-threatening.

• About35%ofaffectedpersonshaveMVprolapse,aorticrootenlargementor

both on echocardiography, despite normal auscultatory findings on cardiac

examination, thus all MFS patients should have an echocardiogram and

thoracicCT/MRtoassesstheaorticvalveandarch.

• Betablockadehasbeenusedonthepremiseitwilldecreasetherateofaortic

dilatationandimprovesurvival.

• IncomparingMFSwithnon-MFSchildren,heightisadiscriminantcriterion

when>3.3standarddeviationsabovethemeanforage.

Beal’ssyndrome

• MFSshowspleiotropismandclinicalvariability.Itsharesoverlappingfeatures

withcongenitalcontracturalarachnodactyly(alsotermedBeal’ssyndromeand

distal arthrogryposis type IX), which is caused by a mutation in the FBN2

gene(chromosome5q23–q31).

Loeys–Dietzsyndrome(LDS)

LDShassimilaritiestoMFS.

• LDScharacteristicsincludecraniofacialdysmorphism(craniosynostosis,cleft

palate, hypertelorism), arachnodactyly, camptodactyly, scoliosis, joint laxity,

talipes equinovarus, translucent and hyperelastic skin, umbilical hernia, and

vascularlesions,e.g.dilatationoftheascendingaorta.

• LDS1iscausedbyamutationintheTGF-βR1gene.

• LDS2iscausedbyabymutationintheTGF-βR2gene.

• LDS3, which is associated with early-onset osteoarthritis, is caused by a

mutationintheSMAD3gene.

• LDS4iscausedbyamutationintheTGF-β2gene.

• LDS5iscausedbyamutationintheTGF-β3gene.

Table19.2TheGhent1996criteriaforMarfansyndrome(MFS)

Majorcriteria

1.Skeletal—

fourormore

of:

Pectuscarinatum

Pectusexcavatum(requiringsurgery)

Marfanoidhabitus

Arachnodactyly

Scoliosis>20°

Reducedextensionattheelbow(to<170°)

Pesplanus

Protrusioacetabulae

2.Cardiovascular:dilationoftheascendingaortainvolvingatleastthe

sinusesofValsalvaordissectionoftheascendingaorta

3.Ocular Ectopialentis

4.Dura LumbosacralduralectasiaonCTorMRI

5.Genetic Parent,child,orsiblingmeetingthecriteriaorpresenceofa

mutationinfibrillingeneknowntocauseMFS

Minorcriteria

1.Skeletal Mild–moderatepectusexcavatum

Jointhypermobility

High-archedpalate

Facies:dolichocephaly,malarhypoplasia,enophthalmos,

retrognathia

Cardiovascular

Mitralvalveprolapse

Dilatationofpulmonaryarterybelowage40years

Dilatationordissectionofthedescendingthoracicor

abdominalaortabelowage50years

Calcificationofthemitralannulusbelowage40years

3.Ocular Flatcornea,myopia

4.Skin Striae;recurrentincisionalhernia

5.Pulmonary Spontaneouspneumothorax;apicalblebs

Intheabsenceofgeneticconfirmation,2majorcriteriaand1othersysteminvolvementarerequiredfor

thediagnosis.Inacasewheregeneticmutationsareknowninthefamily,1othermajorcriterionis

requiredwithinvolvementofoneotherorgansystem.

Ehlers–Danlossyndrome

Ehlers–Danlos syndrome (EDS) is a clinically heterogeneous condition

characterized by skin fragility, ligament laxity, short stature, spinal deformity,

vascularfragility,and(rarely)retinaldetachment.

Classification

TheVillefranchenosologyforEDShas beenupdated.Villefrancherecognized

nine subtypes based on the severity of the clinical features, the underlying

biochemicalandgeneticdefect,andthepatternofinheritance.The2017updated

classification (Table 19.3) lists 13 subtypes and is available online at:

https://ehlers-danlos.com/wp-content/uploads/2017-EDS-

Classification_March_2017.pdf

Table19.3The2017classificationofEDS

NameofEDSsubtype Inheritance Geneticbasis

Classical(cEDS) AR COL5A1,COL5A2

Classical-likeEDS(clEDS) AR TNXB

Cardiac-valvularEDS(cvEDS) AR COL1A2

VascularEDS(vEDS) AD COL3A1(rarelyCOL1A1)

HypermobilityEDS(hEDS) ?? Unknown

ArthrochalasiaEDS(aEDS) AD COL1A1,COL1A2

DermatosparaxisEDS AR ADAMTS2

KyphoscolioticEDS AR PLOD1,FKBP14

Brittlecorneasyndrome(BCS) AR ZNF469,PRDM6

SpondylodysplasticEDS

(spEDS)

AR B4GALT7,B3GALT6,

SLC39A13

MusculocontractualEDS

(mcEDS)

AR CHST14,DSE

MyopathicEDS(mEDS) ADorAR COL12A1

PeriodontalEDS(pEDS) AD C1R

AD,autosomaldominant;AR,autosomalrecessive.

Genotypingandclinicaldiagnosis

• Thereisconsiderableoverlapbetweensubtypes.

• Diagnosis is increasingly though genotyping—available on blood or saliva

DNAsequencinganalysis.

• ForthosewhomeettheminimalclinicalrequirementsforanEDSsubtype,but

whohavenoaccesstomolecularconfirmation;orwhosegenetictestingshows

one(ormore)genevariants ofuncertain significancein thegenes identified

foroneoftheEDSsubtypes;orinwhomnocausativevariantsareidentifiedin

anyoftheEDS-subtypespecificgenes,thena‘provisionalclinicaldiagnosis’

ofanEDSsubtypecanbemade.

• If no diagnosis is made by genotyping and if there is an extreme clinical

phenotype,thenexpandedmoleculartestingcanbeconsidered.

• Embryonic testing can be done either by pre-implantation genetic diagnosis

(PGD) and pre-natal testing in utero. PGD is only approved for use in the

vascularandclassicalEDStypes.

ClassicalEDS(cEDS)

• cEDS is often predominantly initially manifest by disability. It affects skin,

woundhealing,andjoints.Theeffectsoftenworsenovertimeashypermobile

joints can be unstable, causing painful dislocations, subluxations, arthritis,

bursitis,tendonitis,and(later-adult)painfulOA.

• Hyperextensibleskiniseasilytornanddoesn’trepairitselfwell,causingpain

anddisfiguringscarring.

• Difficulties may arise during pregnancy: joint pain from increased body

weight, early rupture of membranes and premature birth, cervical

incompetence and spontaneous abortion, excessive tissue trauma during

delivery, and MSK complications in the post-natal period due to lifting and

caringforthenewborn.

• Patientsareoftenpartlyresistanttolocalanaesthetic—causeunclear.

• PhysicaltherapyforEDSshouldfocusongradedexerciseandjointandskin

protection.Someindividualsrequirejointsplints.Spinaldeformitymayneed

bracingorsurgery,andretinaldiseaserequiresophthalmicexpertise.

HypermobileEDS(hEDS)

The1997criteriafordiagnosinghEDSwereupdatedin2017.Formerly,criteria

for diagnosis were met if there was either hyperextensibility (and/or smooth

velvety skin) and/or generalized joint hypermobility and the presence of ≥1

minorcriteria(recurringjointdislocations,chronicjoint/libpain,positivefamily

history.

• The2017criteriasupercedetheBrightoncriteria.SeeareTable19.4.

• hEDS evolves over time. Contortionism and propensity for sprains and

dislocationsoccursinhEDSbutisnotspecifictothediagnosis.

• Paininitiallyisoftenlimitedtolowerlimbs.

• Theremaybeeasyfatiguabilityandvoidingdysfunction.

• The‘pain’phase(whichstartsinthesecondtofourthdecadeoflife)includes

more widespread and progressively worsening MSK pain, pelvic pain in

women,andheadache.

• The ‘stiffness’ phase (observed in a few adults and elderly only) results in

general reduction of joint mobility, significant reduction in function due to

disabling pain and fatigue, and limitations from reduced muscle mass and

weakness,priorinjuriesandarthritis.

• Patients with all types of EDS, may be at risk of developing postural

orthostatictachycardiasyndrome(PoTS)—anabnormalincreaseinheartrate

thatoccursaftersittinguporstanding,causingdizziness,fainting,andother

symptoms.

• However, the EDS-PoTS association is disputed as PoTS can be a benign

conditionaffectingmostcommonlygirlsandwomenaged15–50years.

• PoTScanbetreatedwithsaltandfluidsupplementation.

VascularEDS(vEDS)

Uterine,arterial,orvisceralruptureandahistoryofspontaneousbleedingraises

thepossibilityofvascular(typeIV)EDS.

• Thereisanexpectedshortenedlifespan(median49yearsformenand53years

forwomen).Acrogeriaiscommon.

• Appearance is often characteristic: translucent skin, increased visibility of

veins,thin lips,small chin,thin nose,largeeyes, recedinggums. Alsooften

seen:recedinggums,easybruising,congenitalclubfoot.

• vEDS can cause massive bleeding (e.g. intracranial aneurysm, arterial

dissection,uterineandGIbleeding).

• In vEDS, operative therapy is reserved for compelling indications in which

benefitclearlywarrantsriskbecauseofbleedingrisk.

Table19.4The2017criteriafordiagnosinghypermobileEDS(hEDS)

Criteria1

Thereisgeneralizedjointhypermobilitybasedona‘positive’Beightonscore

(seeTable19.6)of:

• ≥6inprepubertalchildrenandadolescents.

• ≥5inmenandwomen,post-pubertyuptoageof50years.

• ≥4inmenandwomenolderthan50years.

Criteria2

Twoormoreofthefollowingfeaturesapply.Thereis/are:

A.Atleast5systemicmanifestationsofamoregeneralizedconnectivetissue

disorderarepresent(fromfollowinglist).

B.Apositivefamilyhistory(≥1first-degreerelativesindependentlymeeting

criteriaforhEDS).

C.Musculoskeletalcomplications(≥1fromfollowinglist)

A:anunusuallysoftorvelvetyskin,mildskinhyperextensibility,unexplained

striaewithoutahistoryofsignificantweightchange,bilateralpiezogenic

papules of the heel, recurrent or multiple abdominal hernias, atrophic

scarring involving at least 2 sites and without the formation of truly

papyraceousand/orhaemosidericscarsasseenincEDS,dentalcrowding

andhighornarrowpalate,pelvicfloor,rectaland/oruterineprolapsein

childrenmenornulliparouswomenwithoutahistoryofmorbidobesityor

other predisposing condition, arachnodactyly defined by bilateral

Steinberg and/or Walker signs, arm span to height ratio ≥1.05, mitral

valveprolapse,aorticrootdilatationwithZ-score>+2.

C: MSK pain in ≥2 limbs, recurring daily for at least 3 months, chronic

widespread pain for ≥3 months, recurrent joint dislocations or frank

instability, in the absence of trauma (requiring both ≥3 atraumatic

dislocations in same joint or more atraumatic dislocations in 2 different

joints occurring at different times and medical confirmation of joint

instabilityat≥2sites,unrelatedtotrauma.

Criteria3

Allthefollowingarerequired:

• Absence of skin fragility, which should prompt consideration of other

typesofEDS.

• Exclusion of other heritable and acquired connective tissue disorders

includingautoimmunerheumaticconditions.

• In patients with an acquired/autoimmune connective tissue disorder

additionaldiagnosis ofhEDSrequiresmeetingbothfeaturesAandB of

criterion2.FeatureCofcriterion2cannotbecountedtowardsadiagnosis

ofhEDS.

• Exclusionofotherdiagnosesthatmayalsoincludejointhypermobilityby

meansofhypotoniaand/orconnectivetissuelaxity.

AdiagnosisofhEDSismadewhenallthreecriteriaaremet.

Hypermobilityspectrumdisorderinadults

Hypermobilityisnowcharacterized through theterm‘hypermobility spectrum

disorder’(HSD).Generalizedandlocalizedforms arerecognized(Table19.5).

Notably, havinganHSDcan be an advantage ifitis not severe; for example,

flexibility/hypermobility may present greater opportunity for enhanced motor

competence and sporting prowess through increased agility, as with gymnasts

andsomedancers.

• Associated features of HSD include chronic widespread pain, fatigue,

cardiovascular autonomic dysfunction, bowel dysfunction, pelvic organ

prolapse.

• Inadults,thediagnosisofbothhEDSandanHSDrequiresknowledgeofthe

Beightonhypermobilityscale(Table19.6).Thescalehasbeenvalidatedacross

somebutnotallethnicgroupswheretherangeofconnectivetissuelaxitymay

vary.

• ThegeneticsoftheHSDsispoorlyunderstood.

• Althoughhypermobilitydiminisheswithage,thesymptomstendtocontinue

andmayworsen.

• Itisimportanttorememberthatolderpatientsmayhavebeenpreviouslymore

mobile and that the Beighton score may not be an appropriate measure. A

historyofjointlaxityshouldbesought.

Table19.5Thespectrumofjointhypermobility(JH)inadditiontohEDS

Type Beighton

score

MSK

involvement

Notes

Asymptomatic

generalizedJH

Positive Absent

Asymptomatic

peripheralJH

Usually

negative

Absent JHtypicallylimitedto

handsandfeet

Asymptomatic

localizedJH

Negative Absent JHlimitedtosinglejoints

orparts

Generalized-HSD Positive Present

Peripheral-HSD Usually

negative

Present JHtypicallylimitedto

handsandfeet

Localized-HSD Negative Present JHlimitedtosinglejoints

orparts

Historical-HSD Negative Present HistoricalpresenceofJH

Table19.6Beighton(‘Bye-ton’)adulthypermobilityscore

Subjecthastheabilityto: Right Left

1 Passivelydorsiflexthefifthmetacarpophalangealjointto90° 1 1

2 Opposethethumbtothevolaraspectoftheipsilateralforearm 1 1

3 Hyperextendtheelbow10° 1 1

4 Hyperextendtheknee10° 1 1

5 Placehandsflatonthefloorwithoutbendingtheknees 1

Possibletotalscore 9

Treatmentofjointhypermobilitysyndromeinadults

• It is importanttode-medicalize simple situations offlexiblejoints and mild

hypermobilitywherepossible.

• Patients should be reassured that unlike other forms of heritable connective

tissue disease, there are often no serious long-term complications of most

HSDs and the mainstay of treatment is a combination of conservative

measuressuchasphysiotherapyandpainrelief.

• Analgesicsareoftenunhelpfulforchronicpain,buthavetheirplaceinacute

symptoms.Painandfatiguecausesignificantmorbidity.

• Joint stabilizing exercises withparticularreference to core stability, posture,

and proprioception are beneficial, as may be advice on avoiding overuse

injuries and practical ways of managing day-to-day activities. A global

approach to joint stability and function, as opposed to just treating regional

symptoms,iseffective.

• ‘Pain management’ should be considered in chronic pain cases. This might

include for example, cognitive behavioural therapy and management plans

similartothoseusedinfibromyalgia.

• The role ofserotonergic/noradrenergic agents inthesepatients is unclear. In

parttheremaybeeffectivecontrolofdepression;however,theremayalsobe

directanalgesicpropertiestotheseagents.

• Neurolepticagentsforneuropathicpainhavenotbeenstudiedinthisgroupof

patients.However,gabapentinorpregabalinandothersimilaragentsmayhave

arole.

• Cardiovascular autonomic dysfunction requires specialist assessment and

advice.

• Pregnancyisoftenaconcern.UnliketherarerformsofEDS,hEDSandthe

HSDsarenotassociatedwithanymajorvascularhazardduringpregnancyand

labour. However, in hEDS, and generalized HSD there are a number of

considerations:

• Jointpain/dislocationmayincreaseduringpregnancy.

• Positioning during delivery should be carefultoavoidexcessivestrain on

joints.

• Labourmayberapid.

• Membranesmayruptureprematurely.

• Thereisanapparentresistancetotheeffectsoflocalanaesthetics.

• Healingmaybeimpairedandsurgicaltechniquemayneedtobemodified

accordingly.

• Thereisnoabsoluteindicationforcaesareansection.

• Severe pelvic floor problems (uterine prolapse, etc.) May occur than

otherwiseanticipated.

Hypermobilityinchildrenandadolescents

A robust definition of the HSDs in children and/or adolescents has not been

established,sodistinguishing‘themorehypermobileoftherangeofnormal’(i.e.

familialconnectivetissuelaxity)from‘pathological’ischallengingifbasedon

hypermobilityalone.

• Historically,useofthediagnosticterms‘benignjointhypermobilitysyndrome’

andEhlers–Danlossyndromehypermobilitytype(EDStype3)hadatendency

to draw attention to a heterogeneous population of children and adolescents

with widespread pain and other clinical features whose level of stress and

disabilitywaspoorlyserved.

• InconsideringmakingadiagnosisofhEDSoranHSDinachildoradolescent

itisimportanttoconsiderthat:

• Beightoncriteriahaveneverbeenvalidatedinchildren.

• in the past, diagnostic labels such as EDS type 3 have been over- and

misusedwithoutreferencetovalidatedcriteria.

• thatjointhypermobilityandconnectivetissuelaxityisamanifestationofa

numberofdisorders—see Box19.1,p.592.

Box19.1Childhoodconditionsassociatedwithjointhypermobility

• Osteogenesisimperfecta.

• Ehlers–Danlossyndrome(e.g.classical,vascular).

• Marfansyndrome.

• Loeys–Dietzsyndrome.

• Sticklersyndrome.

• Distalarthrogryposis/Beal’ssyndrome.

• Trichorhinophalangealsyndrome(TRPS).

• Meier–Gorlinsyndrome(OMIM613805).

Epidemiology(ofasymptomatichypermobility)

• Hypermobility is present at high levels in the normal paediatric population.

ThereareracialvariationsandaBeightonscoreof≥4isespeciallycommonin

preschoolchildren.

• Inteenagegirlsandboys(mean14years),alargeUKstudyfoundgeneralized

joint laxity in 27.5% and 10.6%, respectively, using a cut-off of four

hypermobilejoints.

• Hyperextensibilityatthelittlefingerhasbeenfoundin>40%girlsand>30%

scored positively for thumb apposition. One explanation of this is that

hypermobilitymaybenormalinateenagepopulation.

Therelationshipofhypermobilityandchronicpaininchildren

• A theoretical basis for problems with hypermobility is that individuals with

hypermobility require greater muscular control to avoid stress, and possible

damage,ofthejointcapsuleorassociatedligaments.Asaresult,ithasbeen

inferredthathypermobilitymaybeariskfactorforchronicMSKpain.

• However,althoughthereissome,ifinconsistentevidence,thathypermobility

inchildrenandadolescentsisassociatedwithanincreasedriskofMSKpain,

thetruevalueofadiagnosticlabelofHSDasthecauseofpainisunclearand

mayevenbeharmfulinassertingalife-longconditionwhenthisisunproven.

• Painassociatedwithhypermobilityshouldalsobeseeninthecontextofthe

generalprevalenceofMSKpain.SeveralstudieshaveshownMSKpaincan

occurinathirdofpeoplefromthegeneralpopulation.

• Itisprudenttoconsiderthatifthereislong-termpaininachildwhohassome

featuresofhypermobility,thepainandhypermobilitymaynotnecessarilybe

linkedthroughacausalmechanism:

• A prospective study of the relationship between hypermobility (Beighton

score≥6)andMSKpaininthesamepopulationfoundatwofoldincreased

riskofpaininshoulders,knees,feet,andankles,butnototherjoints.

• In the same study, the impact of pain on daily activities was found to be

unrelatedtohypermobility.

• The lack of association between chronic widespread pain, hypermobility,

andpainintensityisconsistentacrossstudies.

• Inastudyofjuvenilefibromyalgia,painscoresweresimilarinthosewith

andthosewithouthypermobility.

• Asaresultoftheabove-listedpoints,inachildwithchronicpainwherethere

issomeevidenceforhypermobility,rehabilitationandfunctionalrestorationis

bestachievedbya‘needs’ratherthan‘diagnostic’focus.

Reference

1.VanLaerL,DietzH,LoeysB.Loeys-Dietzsyndrome.AdvExpMedBiol2014;802:95–105.

Sticklersyndrome

Sticklersyndromeisaclinicallyvariableandgeneticallyheterogeneousdisorder

characterizedbyocular,auditory,skeletal,andorofacialabnormalities.

MostformsofSticklersyndromearecharacterizedbytheeyefindingsofhigh

myopia,vitreoretinaldegeneration,retinaldetachment,andcataracts.Additional

findingsmayincludemidlineclefting(cleftpalateorbifiduvula),PierreRobin

sequence, flat midface, sensorineural or conductive hearing loss, mild

spondyloepiphysealdysplasia,andearly-onsetosteoarthritis.

TherearefivegeneticsubtypesofStickersyndrome:

• Type I is caused by heterozygous mutation in the COL2A1 gene on

chromosome12q13.

• SticklersyndrometypeII(STL2),sometimescalledthebeadedvitreoustype,

iscausedbymutationintheCOL11A1geneonchromosome1p21.

• SticklersyndrometypeIII(STL3),sometimescalledthenon-ocularform,is

causedbymutationintheCOL11A2geneonchromosome6p21.STL1–3are

ADinherited.

• ARformsincludeSticklersyndrometypeIV(STL4),causedbymutationin

theCOL9A1geneonchromosome6q12–q14,andtypeV(STL5),causedby

mutationintheCOL9A2geneonchromosome1p33–p32.2.

Chapter20

Commonupperlimbmusculoskeletallesions

Subacromialimpingement

Adhesivecapsulitis

Lateralhumeralepicondylitis

For a detailed view on the differential diagnosis of the entire range of upper

limblesions,see Chapter3

Forsteroidinjectionofupperlimblesions,see Chapter24

Subacromialimpingement

Subacromialimpingement(SAI)isimpingementoftissuesbetweenthehumeral

head(oftenthegreatertuberosity)andanarchofoverlyingtissuesformedbythe

acromion, coracoacromial ligament, and coracoid. The tissue most frequently

affectedispartoftherotatorcufftendon,thesupraspinatustendon.

Clinicalfeatures

Impingementcausesshoulderpainwhenthepatientreachesuporbehindtheir

back,orrollsoverontheshoulderatnight.

• SAIisthemostcommontypeofpresentationofshoulderpaininadults.

• Painisoftenreferredtotheupperarm.

• Causesareacuterotatorcufftendonitis(whichmaybecalcific),subacromial

bursitis, rotator cuff tear with cuff instability and impingement, and

glenohumeral(GH)instabilityduetoanumberofdifferentlesions(e.g.labral

tear,synovitisduetocrystalarthritis).

• Inferior acromial osteophytes/acromioclavicular joint (ACJ) osteoarthritis

(OA)canaccompanyanysubacromiallesion,andoftenprecedethemandthus

areriskfactorsforrecurrentrotatorcuffdisease.

• Weaknessandlossofrangeofmotionoccurparticularlyifthetendontears.

• Long-termrotatorcuffdiseasecanleadto‘cuffarthropathy’,withOAofthe

GHjoint(GHJ)andsignificantchronicmorbidity.

• In children or young adults with SAI, consideration of an underlying GH

(instability)lesionismandatory.

Makingadiagnosis

• Exclude alternative causes of shoulder pain, including rotator cuff tear,

adhesive capsulitis, and referred pain from the neck or abdomen (e.g.

cholecystitiswithpainreferredtotheshoulder).

• Signs:painfularconactivearmelevation,painonactivereachbehindback,

positiveNeerorKennedy–Hawkinstest(see Fig.3.5p.91;Table20.1).

• An AP radiograph can show changes identifying GH or bony pathology,

calcifictendonitis,andchronicchangesatsupraspinatusinsertiononhumeral

head.

• ConsiderrequestinganAPviewwith30°externalrotationatthearm,anoutlet

Yview,andanaxillaryview.

• In manycases,USisthemainstayof furtherclarifyingthenatureofrotator

cuff pathology, detecting structural damage, and identifying alternative

explanationsforshoulderpain.

• MRIalsocharacterizessitesofcuffinflammationandismoresensitivethan

USinidentifyingcufftearsandcanprovidemoreinformationaboutthewhole

shouldercomplexincludingGHJlesions,deeperlyingenthesitis,theACJ,and

bonelesions.

• Thegoldstandardfordiagnosingcufftearsisdirectvisionatarthroscopy.

Management

• Avoidoverheadarmactivities.

• Trialafull-doseregularNSAIDfor2weeks.

• If the rotator cuff is convincingly not torn (feasible to tell only for

supraspinatusbytestingshoulderabductionagainstsubmaximalresistanceat

position of downward vertically held arm), consider steroid (e.g.

methylprednisolone40mg;see Plate5)withlocalanaestheticinjection(e.g.

5 mL 1% lidocaine). Approach laterally or posteriorly under acromion—see

also Chapter24.

• Follow-upinjectionwithcuffphysiotherapy2weekslater.Physiotherapycan

addressrotatorcuffmuscle(s)weaknessandimbalanceandabnormalposture.

• Patients should be given realistic expectations that physiotherapy may take

severalmonthstoproviderelief,andmuchself-motivationisneeded.

• Considerasecondinjectionnotbefore6weeksafterthefirst(Fig.20.1;see

also Chapter24forinjectionprocedure/technique).

• Refer for surgical opinion if symptoms persist, as some are amenable to

arthroscopicdebridementofimpingingacromialosteophytes.

• A full-thickness tear that is identified early and not fully retracted, can be

amenabletosurgicalrepair.

Table 20.1 The range of disorders presenting with subacromial impingement pain. Clinical testing,

thoughit canbe elaborate,has beenshown repeatedlyin studiesnot to be asspecific as the original

literatureappearedtosuggest

Condition Diagnosismadeby

Supraspinatus/cufftendonitis MRIorUSor

arthroscopy

Subacromialbursitis(e.g.trauma,gout,CPPD) US/MRI

Rotatorcufftear(partialorfull) MRI

Longheadofbicepstendonitis Clinical,US/MRI

OAACJ(impingementofosteophytesoncuff) Clinical,

radiographs,MRI

GHinstabilityduetolabraltrauma(e.g.SLAPlesion),

arthritisGHJ

MRI

Enthesitis(e.g.deltoidoriginatacromion)inSpAs

(see Chapter8)

Clinical,US,MRI

Lesionatsuprascapularnotch(e.g.cyst,tophus) MRI

Fig.20.1Pragmaticalgorithmformanagingsubacromialimpingement.

*Use20–40mgtriamcinoloneacetonideormethylprednisoloneacetate.LH,longhead.

Adhesivecapsulitis

Adhesivecapsulitis(AC)—aetiologyunknown,thoughitinvolvescapsularand

coracohumeralligamentcontractures—issuggestedbyagradual,painfullossof

bothactiveandpassiverangeofmovementoftheGHJ(seealso Chapter3for

clinicalassessmentanddifferentialdiagnosisonpresentation).

Epidemiology

• ACismorecommoninfemalesthanmales,andisfourtimesmorecommonin

diabeticsthanthegeneralpopulation.

• Femalesaretypicallyaffectedbetweentheagesof40and60years.

• ACoccursbilaterallyin15%ofpatients.

• Recurrenceisunusual.

• Withoutintervention,thepainusuallyresolvesin<2years,butthepatientmay

beleftwithlong-termrestrictionofshouldermovement.

Presentationandinvestigations

• AC should not be confused with SAI, though the two lesions can co-exist.

With SAI, passively induced GHJ movements remain intact and are less

painfulthanactivemovements. WithAC,passiveandactivemovementsare

equallyimpaired.

• Cluestothediagnosisfromexaminationincludemarkedrestrictionofexternal

rotation, early scapular abduction (normally the scapula doesn’t move until

30°ofabductionhasbeencompleted).

• If the presentation is delayed (e.g. >6 months), a secondary SAI may have

evolvedandisexposedassomerangeofmotionbeginstoreturn.

Management

• Rule out associated conditions: diabetes, hypothyroidism, lung carcinoma,

myocardial infarction, stroke, and protease inhibitor use for human

immunodeficiencyvirus(HIV)infection.

• Control pain during the initial painful/stiff phase of the condition. Consider

NSAIDs,IAsteroidinjection(e.g.40mgmethylprednisolonewith5mL1%

lidocaine), suprascapular nerve block, or a short course of prednisone 30

mg/dayfor3weeks.

• Ifrotatorcuffintact(confirmwithUS),considerimage-guidedhydrodilatation

ormanipulationunderanaesthesia(MUA),early.

• Hydrodilatation improves pain and function to a greater degree than MUA

whencomparedinRCTs.

• Mobilizewithphysicaltherapyearly,butbeawarethismaybelimitedbypoor

paincontrol.

Lateralhumeralepicondylitis

Lateralhumeral epicondylitis(LHE)—oftencalled tenniselboworapophysitis

of the common extensor tendon origin—is essentially an enthesitis. It is

common,andaffects 1–3%oftheadultpopulation,typicallyage40–60years.

Thedominantarm ismostaffected.It is rarein elitetennisplayers, butupto

40%ofsocialplayersgetitatsometime.Enthesitisatthesiteiscommonandis

typically associated with the SpA conditions (see  Chapter 8). For clinical

assessmentanddifferentialdiagnosis,see Chapter3.

Pathophysiology

LHE is thought to be due to either cumulative trauma overuse disorder from

mechanical overloading or typical SpA-related pathophysiology if an

inflammatorycause.

• Ifchronic,itcanleadtotendondegenerationandbonechanges.

• Trueinflammationoftheenthesiscanoccurbutpaincanexistwithoutthere

beinganyidentifiableinflammation.

• Poorprognosisisassociatedwithmanualwork,highlevelphysicalstrain at

work,andhighbaselinepainanddistress.

• Consider that the lesion may be part of SpA if bilateral, recurrent without

traumaorassociatedwithotherSpAfeatures.

Presentationanddiagnosis

(Seealso Chapter3.)

• Painiselicitedbyresistedforceinforearm/wristpronation(e.g.handshakes,

turningdoorknobs,carryingbags)orresistanceoffingerorwristextension.

• Pain often extends from the LHE down the extensor compartment to the

forearm.

• Enthesitis,tendontears,andjointlesionsmaybediagnosedbyanexperienced

MSKultrasonographer.

• MRImaymissmildLHE/enthesitisandappearancesarenotspecific.MRIis

moreusefulforrulingouttendontearsandjointlesions.

• IflesionsarebilateralthenspecificallyconsiderSpA.

• The main differential diagnoses are elbow joint lesions, referred neck pain,

andenthesitis(e.g.DISHorenthesitislinkedtoSpA,particularlyPsA;see

Chapter8).

Management

(Seealso Chapter24.)

• During the acute phase, LHE can be treated with activity restriction, pain

control,anelbowclasp,andimmobilization.

• NSAIDs and gabapentin/pregabalin may help in some cases. Employ a

treatmenttrialforalimitedperiodoftimeandreview.

• Injection around the epicondyle with methylprednisolone 20 mg should be

considered if conservative therapy fails—see Chapter 3 for details (see

Plate6).

• Isometricgripexercisesandstretchingforearmextensortissues(gradedwrist

flexionmobilisations)mayalsohelpwithrecovery.

• IfotherinflammatoryMSKlesionsareevidentthenexaminingforwidespread

enthesitislesionsandotherfeaturesofSpAisindicated.WithsubstantialSpA-

related enthesopathic disease then DMARDs may be considered (e.g.

sulfasalazineormethotrexate).

• Surgery is rarely indicated, and should be considered for patients with

persistentsymptomsdespiteothertherapies(Fig.20.2).

• Unproven therapies include autologous blood injection of tendon origin,

lithotripsy,andtherapeuticUS.

Fig.20.2Pragmaticalgorithmformanaginglateralepicondylitis(LHE).

Chapter21
Spinaldisordersandbackpain
Introduction
Acategorizationofbackpain
Acuteandsubacutebackpain(adults)
Chronicbackpain(adults)
Backpaininchildrenandadolescents
Introduction
Forareviewofspinalanatomyandfunctionalanatomy,see Chapter3under
relevantsectionsforthoracicorlumbarspineinadults.
• The differential diagnosis of symptoms located to the neck and back is
includedintherelevantpartof Chapter3.
• Relevant review of issues and tables on spinal conditions include the
following:
• Painful neurological and MSK conditions of the thoracic spine and chest
wall.See Table3.12,p.132.
• Commonand/orseriouscausesofneckpaininadults.See Table3.1,p.
75.
• Testingnerveroottensioninpatientswithlowbackpainandassociatedleg
pain.See ‘Testingnerveroottension’,p.146.
• Testingmusclestrengthinthelowerlimbs(inpatientswithneurogenicleg
painassociatedwithlowbackpain).See Table3.15,p.147.
• Principal combinations of signs used for identifying lumbar nerve root
lesions.See Table3.16,p.148.
• Commonly reported patterns of radiographic abnormality in adults with
spinal symptoms: the interpretation, and suggested reaction. See  Table
3.17,p.149.
• Reviewofchoiceofimaging:radiographsandCTorMRI?See Chapter3,

p.150)

Acategorizationofbackpain

Non-spinalbackpain

Painmayradiatetothebackfromlesionsinotherstructures,e.g.renal,aortic

aneurysmal, pleuriticorpancreatic disorders, and periaortitis. Forsummaryof

conditionscausingspinalpainsee ‘Thoracicbackandchestpaininadults’,p.

132and‘Lowbackpain:adults’,p.140).

Acutenon-specificbackpain

• Thisaccountsfor80–85%ofallacutebackpain.

• Typically, 90% of cases will recover in <6 weeks (the threshold for

reassurance).

• Most causes will be ‘mechanical’ in origin but some causes will be

neuropathicandothersinflammatoryinnature.

Chronicbackpain

• Describespainthathasbeenpresentfor>12weeks.

• Some causes will be neuropathic, others inflammatory in nature, but the

majoritycanbecategorizedas‘mechanical’.

Neuropathicpain

• This typeof painaccounts forapproximatelyone-thirdofacuteandchronic

lowbackpain.

• ThepainDetect

questionnaireisausefulassessmenttool,aswellasanaide

memoire for the typical symptoms of neuropathic pain: burning, prickling,

hot/colddysaesthesia,sensitivitytotouchandpressure,numbness,andsudden

‘electricshock’-likesymptoms.

‘Redflags’and‘yellowflags’

Thisterminologyisusedtoidentifypotentiallyserioussecondaryphysical(red)

andpsychosocial(yellow)pathologies(Table21.1).

Table21.1Warningsignsforsinisterpathologycausingbackpain

‘Redflags’ ‘Yellowflags’

• Ageofonset<20years

• Ageofonset>55years

• Recenttrauma

• Beliefthatpainandactivityareharmful

• Abnormal ‘sickness behaviour’, e.g.

extendedrest

• Pain constant, progressive,

andnoreliefwithrest

• Intensenight-timepain

• Thoracicpain

• Pasthistoryofmalignancy

• Osteoporosisrisk

• Infection risk

(immunosuppressed)

• Systemically unwell—

weightloss/fever,etc.

• Progressive neurological

signs including bladder

dysfunction

• Structuraldeformity

• Low/negativemood

• Work environment (low

support/satisfaction conflicting evidence

forhighpace/demand)

• Seekingtreatmentsthatseemexcessiveor

inappropriate

• Inappropriateexpectations

• Lack of social support in private life

(moderateevidence)

• Compensationclaims

Acuteandsubacutebackpain(adults)

Acutemechanicalbackpain

• Mostcasesinaprimarycaresettingareduetolumbarmusclestrainorsprain

presenting with diffuse pain in the lower back to buttocks, which resolves

spontaneously.

• Ifpainisrelatedtopostureormovement,especiallyofthethoraciccage,and

local tenderness is felt at the lumbosacral junction then the pain is highly

likelytobeMSKinorigin.

• Withinthegravid population,two-thirds ofthepregnant womensufferfrom

lowbackpain,typicallyincreasingwithgestationalstage,impactingonsleep,

work,andday-to-dayfunction.

• ‘Red flags’ merit more thorough investigation. Although far less common

(<15%ofallcases),thefollowingshouldbeconsidered(%ofcasesinback

painpopulation):

• Fracture.

• Symptomaticherniateddisc(4%).

• Spinalstenosis(3%).

• Malignancy(0.7%).

• Axialspondyloarthritis(axSpA)/ankylosingspondylitis(0.3%).

• Caudaequinasyndrome(0.04%)causingsaddleanaesthesia,legweakness,

bilateralsciatica,andbladderdysfunction).

• Spinalinfectionorinflammatoryradiculopathy(0.01%).

• Herniateddiscsaccountfor4%oflowerbackpain.Discherniationpresents

withlegpainradiatingpasttheknee,andismostcommoninpatientsbetween

20and50yearsofage.

• Degenerative causes of backpain,includingdegenerative disc disease, facet

joint OA, and lumbar canal spinal stenosis, are more common in older

patients.

• The immediate management is a combination of adequate and regular

analgesia, titrating as per patient response, as well as encouraging gentle

mobilizationandnormalizationofactivities.

• Intheshortterm,asdiazepammaybeconsideredtodecreasemusclespasm

andaidsleep.

• The clinician should explore patient fears (‘yellow flags’) and, where

appropriate,reassurethatseriousillnessisunlikely,thattestsarenotusually

needed,andseverepainisoftenshort-lived.

• Radiographsarelikelytobeunhelpfulformanagementinmostcasesunless

redflagsignsarepresent.

• MRI of the lumbar spine, for example, frequently demonstrates abnormal

findingsinasymptomaticpatients;therelationshipbetweensuchfindingsand

clinicalsymptomsisnotalwaysclear.

• Arehabilitationapproachshouldbeconsidered(Table21.2).Theevidencefor

therapies is variable. Adherence may be augmented by providing patient

educationliterature.

Table21.2Therapiesusedinfacilitatingrehabilitationafteracutemechanicallowbackpain

Manipulation Eitherdonebyanosteopath,chiropractor,orphysiotherapist.

Cochranereview(2012)demonstratedlackofefficacy

comparedtoinerttreatmentorshammanipulation.Smaller

studiessince2015demonstrateaslightbenefit,however

McKenzie

exercises

Passive extension exercises designed to improve pain and

stiffness associatedwith discand anteriorspinal structure

pathology. May aggravate pain from posterior spine

structures,e.g.facetjoints,spinousprocesses.

A systematic review in 2011 has demonstrated a modest

benefit in patients undertaking directional preference

exercisewithintheMcKenzieframework

Hydrotherapy

Poorlystudied,butwarmthcaneasemovementandaugment

land-basedexercises.Mightbeconsideredafterinitial

balneotherapy

painfulphasetoregainnormalmovementsandmobility.May

onlysuitafewpatientsandresourcesmaybelimited

Graded

activity

programmes

Usefulforpatientswhorequireguidanceandwouldbe

unabletogainoptimallyfromhomeexerciseregimen.Aplan

forrehabilitationwithmilestonesisusefulforsomepatients

Behavioural

programmes

Focusesonpsychologicalaspectsofpain,involvesmoderate

supervisionandplannedwithdrawaloftreatment.Differs

fromsomeotherapproachesinthatthetherapisttakesover

the‘control’ofthebackpain.Limitedresourcesmayrestrict

provisionofthisapproach

Backpainandnerverootlesions

See also  ‘Low back pain: adults’, pp. 144–147 for review of anatomy and

functionalanatomy.

• Nerve root compression occurs mostly because of acute or subacute disc

prolapseorforaminalstenosis.Thepeakincidence isage 30–50years. 70%

resolvewithin3monthsand90%within6months.

• Nerverootcompressionshouldbesuspectedifacuteorsubacutebackpainis

associatedwithsegmentalnerveorsciaticlegpain.

• Acute sciatic pain (‘sciatica’ affecting the outer and posterior leg) is often

sharporburninginnature,andmostfrequentlyarisesfromacutediscprolapse

ofeitherL4/5orL5/S1(>90%ofcases).

• Sciaticaischaracterizedbylegpainprojectingpasttheknee, whichmaybe

moreseverethantheassociatedbackpain.

• Apatientwithaherniateddiscmaypresentwithsciatica.

• Evidence of disc herniation may be elicited by straight leg raise or crossed

straightlegraise(i.e.elevationofunaffectedleg).Thesetestsarepositiveif

painisfeltinthebuttockorinthebackatalegangleof30–60°.Painelicited

atalegangle<10°isconsistentwithMSKbackpain.

• L5 nerve root lesions give decreased strength of the foot and great toe

dorsiflexion,standingonheel,anddecreasedanklereflexandsensationover

greattoe.

• S1 root lesions give decreased strength in plantar foot flexion, difficulty in

weight-bearingontoes,anddecreasedanklereflexandsensationonthesoleor

outerpartoffoot.

Principlesofmanagement

• Thenaturalhistory:30–60%ofpatientsrecoverin1week.

• Analgesia such as paracetamol (acetaminophen) and NSAIDs should be

consideredfirst.

• Useofdiazepammaybeofbenefitintheshorttermtolessenmusclespasm.

Some patients may need opiate therapy for pain control, e.g. codeine

phosphate, tramadol, buprenorphine, and short- or long-acting morphine

sulfate.

• Bedrestshouldbediscouraged:prolongedbedrestleadstoworseoutcomes.

Gentlemobilizationshouldbeencouraged.

• Anepiduralsteroidinjectioncanimprovepainintheshortterm,butdatafrom

RCTsdoesnotshowbetterlong-termoutcomeat3monthsorlongercompared

withcontrols.

• A meta-analysis showed that 1 in 7 patients having a steroid epidural

experienced >75% improvement in pain in the short term, and 1 in 13

experienced>50%symptomimprovementinthelongterm.

• Physicaltherapyandsupervisedrehabilitationusinglumbarextensorexercise

regimensmaybeofbenefit.

• MRI can characterize lesions, but 25% of asymptomatic people have frank

disc protrusions; so MRI gives poor specificity. MRI should be used to

confirmadiagnosis,nottoreachforone.

• Theabsoluteindicationsforsurgery(Table21.3)arecaudaequinasyndrome,

progressivemuscleweakness,andneuropathycausingfunctionaldisability.

Facetjointarthritis/syndrome

• Lumbar spine facet joint (FJ) osteoarthritis (OA) is common in middle

aged/elderlyadults,andcanbepartofgeneralizedOA.

• FJOA is associated with degenerativeandspondylolyticspondylolistheses—

forwardslippageofavertebraeonthevertebraebelowit.

• Psoriatic arthritis (see  Chapter 8) and calcium pyrophosphate disease

(CPPD; see  Chapter 7) can also affect FJs and are under-recognized as

causesoflowbackpain.

• Typicalsymptomsincludepainonextensionorrotationofthelowerback.The

painisoftenreferredtotheupperbuttocks,isworsewhilestandingstill,and

easedbyforwardlumbarflexion.

• Facethypertrophyitselfcannotbefelt,buttrueFJsyndromeisaccompanied

bymusclespasmandsuperficialsofttissuetenderness.

• ArthriticFJsmaybeseenonobliquespinalradiographs;however,imagingin

generalcannotreliablyidentifysymptomaticFJs.FJinjectionwithanaesthetic

mayconfirmthediagnosisifthisresultsinsignificantpainrelief.

Table21.3Surgicalapproachesforlumbardiscprolapse

Discectomy Essentialfordiscscausingcaudaequinasyndromeand

progressiveneurologicaldeficits.Excludingabove

indications,comparedwithconservativetherapy,ina

randomizedcontroltrial(RCT)66%vs33%patients

weresatisfiedfollowingsurgeryat1year,and66%vs

51%weresatisfiedat4years;thus,benefitofsurgeryin

thelongtermissmall.Adverseeventswithsurgery

includemortality(<0.2%),duraltears(4%),and

permanentnerverootinjuries(<1%).70%successratein

shortterm.Riskoffailurefromsurgeryrelatestohysteria

orhypochondriasisscoresonMMPI*andpresenceof

litigationclaims

Microdiscectomy Smallersurgicalfieldresultsinearliermobilizationand

lesspostoperativedisability.Outcomessimilartothose

ofconventionaldiscectomyfromCochranereview,2014

Percutaneous

discectomy

Suctioningofcentraldiscmaterialcausingdisc

decompressionandrelievingnerverootpressure.

Associatedwithlowcomplicationrateandrapid

rehabilitation.SmallRCTstudiessuggestsimilar

efficacytodiscectomyandmicrodiscectomy

Chemonucleolysis Injectionofproteolyticenzymeintodisc.RCTssuggest

standarddiscectomyissuperior.Rare,butdevastating

neurologicalcomplications;riskofanaphylaxis(0.3%)

Laserlumbar

discectomy

Vaporizingofpartofdiscbylaserthroughaneedle

probe.Efficacysimilartodiscectomy.NoRCTdata

Prosthetic

intervertebraldisc

replacement

Also,indicatedfordegenerativediscdisease,post-

laminectomysyndromeandnon-specificpersistentlow

backpain.Artificialdiscsconsistoftwoend-plates

separatedbypliableinnercore.RCTcomparativestudies

haveshownashort-termbenefitinamelioratingback

painandlong-termbenefitinreducinglegpain,

comparedwithdiscectomy.Complicationratemaybe

high(upto45%)andserious:discitis,re-herniation,

haematoma

*MMPI=MinnesotaMultiphasicPersonalityInventory.

ManagementofFJarthritis/syndrome

• Patients can be treated according to principles applied for all patients with

acutemechanicalbackpainexceptthatextensorexercisesarecontraindicated

astheywillaggravatesymptoms.

• Shortcoursesofanalgesicsand/orNSAIDsasforOA.

• Generally,adviseminimalbedrest.

• Steroid injection of FJs is frequently used, although studies have failed to

demonstratebenefitoverplaceboinjection.

• RadiofrequencydenervationofmedialbranchesofdorsalramisupplyingFJs

can help, but the procedure should only be considered if local anaesthetic

blockworksfirst.

Lumbarcanalspinalstenosis

• Thediagnosisisfrequentlymissedintheelderly.

• Itpresentsmainlywithachy,stiffpainsinthelegsincreasedonwalkingand

easing if the patient stops walking, sits, or leans forward (neurogenic or

pseudo-claudication).

• Pain, numbness/tingling, and weakness are the most common symptoms.

Neurologicallegsignscanbeaccentuatedafterexercise.

• ThediagnosisismadeusingMRIofthelumbarspine.

• Non-surgical management (including pain control and physical therapy) is

oftenadequate.

• Decompressive laminectomy is required for progressive neurological

symptoms,bladderdysfunction,orcaudaequinasyndrome.

Non-traumaticvertebralfracture

• A fragility (minimal or not) trauma vertebral fracture is usually due to

osteoporosis,collapseofanabnormalvertebra(e.g.vertebralhaemangioma),

orsecondarytomalignancyorinfection.

• Thehistoryshouldfocusonidentifyingriskfactorsfortheseconditions.Post-

menopause or hypogonadism, previous fracture history, steroid use, and

alcoholismmayallcontributetoosteoporosis.

• WeightlossorB-typesymptomsmayindicatethepresenceofmalignancyor

infection.

• Kyphosisandlossofheightcanoccuraftervertebralfracture.

• A full examination should be done to evaluate the possibility of cord

compressionormalignancy.

• Investigate with anteroposterior and lateral spinal radiographs, MRI, bone

biochemistry(boneprofile,PTH),morningluteinizinghormone(LH)andfree

testosterone,25-OHvitaminD,CRP,thyroidfunctiontests(TFTs),serumand

urineelectrophoresis.

• MRIisgoodatdiscriminating infectionandtumoursfromosteoporosis,and

candatefractures,butbiopsyforhistologyandcultureisessentialiftumouror

infectionhasnotbeenruledoutbyMRI.

Managementofnon-traumaticvertebralfracture

• The patient should be carefully monitored for evolving neurological deficits

withalowthresholdforMRIwholespine.

• Pain control often requires long-acting narcotics, with short-acting narcotics

forbreakthroughpainasparacetamol(acetaminophen)andNSAIDsaloneare

unlikelytobesufficient.

• Calcitonin 100–200 IU twice-dailySCor 200 IU/day by nasal spray hasan

analgesiceffectandreducesboneturnoverinosteoporosis.

• Osteoporosisshouldbetreatedaggressivelyinduecourse(see Chapter16)

but bisphosphonates should not be regarded to have/relied on to provide an

analgesiceffect.

• Discuss any pathological malignancy-related fracture with a clinical

oncologist.

• Considervertebroplastyorballoonkyphoplastywherepainisuncontrolledby

analgesia.

Post-surgicalbackpain

• Therearenumerouscausesandnosingleentity(Table21.4).

• Post-surgicalbackpainpresentsamanagementchallenge.Amulti-disciplinary

approach is often need in providing optimization of analgesia, physical

therapy, behavioural modification via psychotherapy, use of nerve blocks,

epidurals, and spinal cord stimulators, radio-frequency ablation as well as

consideringtheneedforre-operation.

• Somepreoperativefactorssuchasnerverootexitforaminalstenosis,smoking,

obesity,andpre-morbidpsychiatricconditionscanleadtohigherprevalenceof

post-surgicalbackpain.

• Imaging with gadolinium-enhanced MRI may be helpful to delineate

inflammatorytissuearoundthesurgicalsite.

• Persistentpainaftersurgerymaybeassociatedwithadversepsychologicaland

socialfactors,outstandinglitigation,orinsuranceclaims.

Non-septicdiscitis

• Inflammation of the intervertebral disc is often associated with annulus

enthesitisatthevertebralend-platesandvertebralosteitis.

• The causes include disc degeneration, CPPD disease, axSpA/ankylosing

spondylitis(‘romanus’lesions)andotherSpAs;also,SAPHO(see Chapter

16.

• The lesion should be identified with MRI and treatment should include

aggressiveanalgesiaadjustedastolerated.

• In RCTs, intradiscal steroid injections have been shown to be little help

overall.IVbisphosphonate(e.g.pamidronate60–90mg)hasanecdotallybeen

shown to help the symptoms of axSpA and SAPHO discitis

(‘spondylodiscitis’).

Table21.4Implicatedcausesofpost-surgicalbackpain

Recurrent

disease

Example:furtherdiscprotrusionandradicularfeatures.Ifre-

operationnotappropriateconsidernerverootblock,steroid

epidural,etc.

Operationfor

wronglesion

MRIcanshowlesions,whichmaynotberelevanttoclinical

features.Morethan1or2lesionscancoexist.Detailed

clinicalassessmentpriortoimagingisessential

Misdiagnosis

originally

Astructurallesiontreatedwhenaninflammatorydisease,

typicallySpA-relateddisease,waspresentandcausing

ongoingsymptoms

Altered

biomechanics

Increasedloadburdenovertheadjacentstructures,leadingto

accelerateddegenerativechangesinareasbothaboveand

belowthesurgery.Also,alteredbiomechanicsmay

potentiallyresultinincreasedtensionoverthepre-vertebral

andpost-vertebralmuscles,leadingtostiffness,spasm,and

pain

Adverse

rehabilitation

conditions

Resolutionofsymptomsandregainingfunctionalcapacityif

slowhasbeenassociatedwithsignificantpsychologicaland

socialfactors.Poorresultofsurgeryalsoassociatedwithan

outstandinginsuranceclaimorlitigation

Arachnoiditis Thoughttobeadirecteffectofsurgery.Duraltissuebecomes

inflamed.Innerveroot/discsurgeryoftenassociatedwith

sensoryrootsymptomsforsomemonthsafterwards.

Diagnosiswithcontrast-enhancedMRI.Whereassociated

withsensoryradicularsymptoms,mayrespondtosteroidroot

block,epidural.Ifradicularsymptomschronicanddisabling

considerspinalcord(implanted)stimulator

Chronicbackpain(adults)

TheGlobalBurdenofDiseaseStudy2010publishedinTheLancet delineated

howMSKdisordersarethesecondmaincauseofdisabilityworldwidemeasured

by years lived with disability (YLDs). Low back pain was the leading

contributortotheYLDsattributablefromMSKdisorders.

• Further analysis demonstrated how low back pain was the sixth out of 291

causesofglobalburdenofdiseasemeasuredbydisability-adjustedlifeyears

(DALYs).InWesternEurope,itisthefirstcause.

• In 2010, the global age-standardized prevalence of chronic back pain was

9.4%,withahigherrateinmen(10.1%)thaninwomen(8.7%).

• In WesternEurope,theprevalenceof lowback painwas 15.5%inmen and

14.5%inwomen.

• Managingchronicbackpainrequiresanemphasisonpsychologicalandsocial

management.

• Patients with chronic back pain are likely to have set beliefs about their

problem,theabilityofhealthcaresystemstohelpthem,andaremorelikelyto

have developed coping strategies than patients with acute or subacute back

pain.

• People with chronic back pain who continually seek further and different

healthcareoptionsarelikelytohavelesssuccessfulcopingstrategies.

Initialapproachtomanagingchroniclowbackpain

(SeeTable21.5.)

• Be confidentthatthere isnoundiagnosed conditionaffecting backpain and

thatnonewneurologicallesionshaveevolved.Ifexaminationraisesconcern,

useMRItoruleoutlesions.

• Establishempathyandtrust,takingtimetogetinformationaboutpatients’:

• socialsituation.

• healthandillnessbeliefs.

• intra-familydynamics.

• workandhomerole.

• perceptionoftheirroleatwork.

• viewonconventionalandcomplementarytherapies.

• viewonwhatdoesanddoesn’twork.

• specificviewofexercisetherapy.

• Plan the managementapproachwith the patient andestablishshort-to mid-

termgoals,includingwhether,andwhattypeof,supervisionisrequired(e.g.

gradedprogrammeofexercise)andhowoftenareviewisneeded.

• Consider‘domains’oftherapyunderthefollowingheadings:

• Physicaltherapy.

• Work/lifecommitments.

• Psychologicalandsocialsupport.

• Painkillersandmedications.

• Education(insightandcopingstrategies).

• Plantoreviewprogressatregularintervals.

• Evaluate patients carefully at baseline if considering long-term opiate use.

There may be an increased risk of dependency if the patient currently or

previously abused drugs, there is a high level of psychological distress, if

short-actingopiatesareused,ordrugsareprescribed‘asneeded’.

• Although many strategies, especially those that combine techniques, can be

costly, these costs to healthcare are likely to be offset by the saving in lost

wages.

Table21.5Managementoptionsforchroniclowbackpain:adults

Exercises RCTevidencesupportsuse.Greaterevidenceofeffect

whencombinedwithbehaviouralmethods.Aerobic

exercisesaugmenteffectof‘backschool’.Shouldbe

essentialpartofoutpatientphysicalretrainingprogramme.

Nodifferenceinefficacybetweenindividualorgroup

programmes

Manipulation Trialsshowefficacyonpaininthelongterm

Transcutaneous

electricnerve

stimulation

(TENS)

DisappointingresultsfromRCTsinchronicbackpain,

althoughefficacyforotherspecificdiagnosesareunknown

Posturetraining Maybemoreappropriatethancorsetuseandeasyto

combinetrainingwithsupervisedexercisetherapy

Pilates Low-levelevidenceforshort-termbenefit

Medications Paracetamol,especiallyusedinconjunctionwithopiatesto

obtainasynergisticeffect.

NSAIDsbestforacute-on-chronicpainflares,for

regulatingpainintensity,asshownbycurrentRCTs.

COX2-selectiveNSAIDsmayhavebetterGIsideeffect

profile.

Systemicreviewandmeta-analysishasdemonstrated

efficacyofopiatesintermsofpainreductionintheshort

term.Themedicationscanbedeliveredinavarietyof

ways:oral,trans-dermal,andbuccal.Chronicopiateusefor

chroniclowbackpainhasnotbeenextensivelystudied.A

mentalhealthevaluationbeforelong-termprescribingis

essentialtoavoidtriggeringdependency(seetext);short

courses,initiallyforatrialperiod,aresensible.Best

supervisedbyaspecialistwithexperienceinpain

management.

Low-dosetricyclics(e.g.amitriptyline,nortriptyline)are

usefulparticularlyifchronicneuropathicpainispresent.

Otherneuropathicagentssuchasgabapentin,pregabalin,

andduloxetinecanbeused.

Musclerelaxants:diazepamhasbeenshowntohaveshort-

termbenefitsinacute-on-chronicexacerbationsofback

pain.Evidenceforeperisoneiscurrentlylimited.

Topicallidocainecanbeusedasadjunctivetreatmentfor

neuropathicpain,thoughasyetnoclearevidencebase.

Systemicanti-nervegrowthfactoragents:limitedevidence,

experimentalphase

Backschool Regularprogrammecarryinganeducationalcomponent.

Programmesvaryfromonetomanysessions.Maybemore

effectiveinoccupationalsetting.Non-complianceand

relapseareproblems.Recentmeta-analysesshow

inconsistentresultswithregardtoefficacy

Psychology-

orientated

rehabilitation

programmes

Intensivecoursesoftenrunbypsychologistsand‘hands-

off’physicaltherapistscanhelp(highly)selectedpatients.

Focusisonlearningtocopewithpainandincreased

controlofeffectsofpainonfunctioningandpsyche.Not

suitableformanypatients.Coursesfewandfarbetween.

Cost-effectivenessofcoursesnotproved.Goodefficacy

comparedtostandardcare,especiallywithworkoutcomes

Complementary

therapies

Increasinglyused.Byconsensus,chiropractichasbeen

showntobehelpfulforchroniclowbackpain.

Acupuncturehasyettobeprovedsuccessfulinrobust

studies.Poorevidencebaseotherwise

Epiduralsteroid

injections

Goodlevelofevidenceforshort-andmedium-term

efficacyinreducingbackandradicularlegpain.

Greaterbenefitestablishedwithregimenconsistingoflocal

anaestheticandsteroid

Epidural

etanercept

therapy

Doesnotseemtohaveadverseeventscomparedtoplacebo

butfurtherstudiesneededtoestablishrobustefficacy

Intrathecal

opiates

Conflictingresultsfrom(only)non-controlledstudies.

Generally,resultsshowoverallshort-termimprovements

regardingpainperception,butnotfunction.Bestreserved

forpatientswhereallelsehasfailed

Spinalcord

stimulator

(SCS)

AnumberofgoodstudiesshowthataSCSiseffectivefor

neuropathicincludingradicularpain.Techniqueis

relativelysafe.Carefulpatientselectionisimportant.

Studiesshow50%reductioninpaininthelongterm

Percutaneous

adhesiolysis

RobustevidencefromRCTsdemonstratingshort-andlong-

termefficacyindiminishingchronicbackpainand

improvingfunctionalimpairment

Additionalsourcesofreferencesonthevalueofinterventions

ChouR,HuffmanLH;AmericanPainSociety,etal.Nonpharmacologictherapiesforacuteandchronic

lowbackpain:areviewoftheevidenceforanAmericanPainSociety/AmericanCollegeofPhysicians

clinicalpracticeguideline.AnnInternMed.2007;147:492–504.

Van Tulder MW, Becker A, Bekkering T, et al. Chapter 3 European guidelines for the management of

acutenonspecificlowbackpaininprimarycare.EurSpineJ2006;3(Suppl2):161–191.

RelevantCochranedatabaseevaluations

2003:MultidisciplinaryBio-psychosocial,Rehabilitation,Musclerelaxants.

2004:Backschools.

2005:Bedrest,Exercisetherapy,Behaviouraltherapy,Acupuncture.

2007:Herbalmedicine,Traction,Insoles,Opioids,Injectiontherapy,ProlotherapyandLasertherapy.

Backpaininchildrenandadolescents

Children with spinal problems present with deformity, back pain, limping,

systemicorneurologicalfeatures,oracombinationofeffects.

• Backpaininadolescentsiscommon—by20yofage,occursinupto80%,but

is rare in children<8years.Painina child <4y and pain requiring hospital

admissiontypicallypredictunderlyingpathology.

• Age determines the likelihood of cause, with infection and tumours being

morecommoninyoungchildrencomparedwithadolescents(Table21.6).

• Theprinciplesofhistorytakingandexaminationinchildrenarediscussedin

Chapter3,Seepp.154–155.

Non-specificlowbackpain

• Theannualincidenceis13–24%inschoolchildren.

• Adolescent back pain is linked with familial clustering, physical inactivity,

sportsinjuries,andpsychosocialfactors.

• Particular risk factors from a recent birth cohort studies includefemalesex,

muscle deconditioning previous sports injuries, sleeping problems, and

persistentfatigue.

• Mostchildrenandadolescentshaveself-limitingsymptoms.

• Management should focus on an explanation of the short natural history,

reassurance, addressing predisposing factors that remain a trigger for

recurrenceandincreasingexercisetoimprovemusclestrength.

• Back pain associatedwithhyperlordosis and pain on lumbarextensionof is

commonlyassociatedwithtighthamstringsorhipflexors,weakcoreandtense

paraspinalmuscleswithreducedforwardflexion.

• A thorough assessment of gait, posture, core stability, limb strength and

muscletightnesswillhelpdirectphysiotherapy-ledhomeexerciseplan.

Idiopathicscoliosis

Themajorformofidiopathicscoliosisisvertebralmalalignmentinthecoronal

planeassociatedwithspinalrotationaccentuatedonspinalflexion.

• Overall prevalence is reported to range from 0.5% to 5%, with the highest

prevalencewithinthe12–14yearsagegroups.

• About70%areasymptomatic.Theincidenceofbackpainisprobablyhigher

thaninthebackgroundpopulation.Progressionismorelikelyinthepresence

of pain or thoracic curve convex to the left—conditions that should be

investigatedforseriousunderlyingspinalpathology.

• Potential interventions include scoliosis specific exercises, bracing, and

surgery. There is poorqualityevidence for scoliosis-specificexercises as an

adjunctivetreatmentalongsideotherinterventions.

• Progressivescoliosis(Fig.21.1)requiresbracingorsurgery.Usuallycurvesof

25–45° are braced; rigid bracing seems to be superior compared to elastic

bracing.

• A child with a curve >40° would be considered for surgical intervention.

Similaroutcomes areachievedatshorttermfollowup forboth traditionally

opensurgeryversusminimallyinvasiveprocedures.

• An MRI to look for tumour, syrinx, neural tethering or infection should be

doneifthereisacurveconcavetotheleftandpain.

• It’simportanttodifferentiatethecauseofscoliosis(e.g.biomechanical,post-

traumatic,neuromuscular,metabolic,congenital,idiopathic).

Congenitalandneuromuscularscoliosis

Congenitalscoliosis(CS)isassociatedwithgenitourinarymalformations(20%)

and,rarely,congenitalheartdisease.Itisararecondition,occurringinabout1in

10,000 newborns. Neuromuscular scoliosis (NMS) is associated with cerebral

palsy,musculardystrophy,spinomuscularatrophy,andmyelodysplasia.

• CSisassociatedwithspinaldysraphism(20%),myelodysplasia,andKlippel–

Fielsyndrome.

• Toavoidrapidprogressionandincreasedlong-termmorbidityanddisability,

referforpromptcorrectionofprogressivecurves.

Table21.6Causesofbackpaininchildren

Developmental Painfulscoliosis,

Spondylolysisandspondylolisthesis,

Scheuermann’sdisease

Infection Discitis,

Vertebralosteomyelitis,

Spinalepiduralabscess

Inflammation Juvenilearthritis,

Osteoporosis

Mechanical Herniateddisc,

Musclestrain,

Fractures

Neoplasms Benign(osteoidosteomas,osteoblastoma,

aneurysmalbonecyst),

Malignant(leukaemia,lymphoma,sarcoma)

Visceral Pyelonephritis,appendicitis,retroperitonealabscess

Non-accidental Fractures—ribs,spinousprocesses,

Softtissueinjuries,burns

Fig.21.1MeasurementofthedegreeofscoliosisbytheCobbmethod:1,thelowestvertebrawhosebottom

tiltstotheconcavityofcurve;2,theerectperpendiculartoline1;3,thehighestvertebrawhosetoptiltsto

theconcavityofcurve;4,thedropperpendiculartoline3;α,theintersectingangle.Curveslessthan20°are

consideredtobemild,20–40°aremoderate,andabove40°aresevere.

Scheuermann’sosteochondritis

• This is perhapsthemost commoncauseof spinal deformityinchildren and

adolescents(1–8%ofalladolescentsusually13–17years).

• Theaetiologyisunknown.

• Most casesareasymptomaticandpresent withconcernsabout thekyphosis.

Pain occurs over the apex of the deformity often related to activity or

prolonged sitting. Lumbar pain occurs with a compensatory hyperlordosis.

Tightnessoccursinanteriorshouldermuscles,hipflexorsandhamstrings.

• Thetypicalradiographicpatternisofmildwedgevertebraldeformities(<10°)

ofthoracicvertebraeandirregularend-plates.

• Delayedpresentationoccursinadultseitherwith(degenerative)backpainsor

disclosedonaspinalradiographas‘vertebralfractures’(erroneously—asthe

wedgeshapedoesnotdenotefracture).

Management

• Minorkyphosisistreatedwithanexercise programtoincreaseflexibilityof

trunk, hamstring and pectoral muscles, and is monitored with radiographs,

obtainedperiodicallyuntilskeletalmaturity.

• Bracingisindicatedforakyphosis>55°orathoracolumbarscoliosis>40°and

shouldcontinueuntiloneyearafterfusionoftheiliacapophyses.Surgeryis

typically reserved for a thoracic kyphosis >70° or thoracolumbar scoliosis

>60°.

Spondylolysisandspondylolisthesis

Spondylolysisisadefectintheparsinter-articularis,mostcommonlyatL4or

L5.Aloneasalesionitiscommon(4%preschoolchildrenand6%<18years).It

occursinupto15%ofeliteadolescentathletes.

• Spondylolysis is a risk factor for asymptomatic and symptomatic

spondylolisthesis(forwardslip ofavertebra on theone below facilitatedby

thebilateralspondylolysis.(Fig.21.2)).

• Progressiveslippagemayoccurduringtheadolescentgrowthspurt.

Management

• If the slip is >25% (grade II, III, or IV), then effective physical therapy is

important, to stabilise the spine (which is at risk of lumbar hyperextension)

beforeareturntosports.

• Advice should be given on regular abdominal muscle exercises, avoiding

gainingabdominalobesity,andconsiderregularbracing.

• SurgeryisconsideredforprogressivevertebralslippageorgradeIII/IVslip.

Herniateddisc

Herniateddiscsareinfrequentinchildren<11y,butdiscprotrusionaffectsupto

20%by18yofage.

• How much pain can be attributed to the disc protrusion is often unclear.

Buttockorhippainexacerbatedbyforwardbend,coughorsneeze,orpositive

legraise,suggestspainisduetothediscprotrusion.

Management

• Withoutnerverootimpingement,managementisconservativeandincludesa

shortperiodofbedrest,adequateanalgesics,andNSAIDswithearlyexercise-

basedrehabilitationregimen.

• Over 50% improve with conservative treatment, but reported results from

surgeryforsignificantnerverootlesions,areverygood.

Spinaltumours

• Althoughrareinchildren,spinaltumourspresentwithnightpainincreasingin

intensity over time and associated with weight loss, radicular features, and

focaltenderness.

• Other typical (though not specific) features include painful scoliosis and

effectivenessofNSAIDs.

Management

• Radiographs (may be negative in early disease) and MRI are essential with

bonescintigraphy(+SPECT)orCTtoidentifyposteriorelementtumours(e.g.

osteoidosteoma).

• Adequateanalgesiaisrequired.NSAIDs:ibuprofeninrecommendedbutdoses

for weight may not be sufficient. Consider naproxen 15 mg/kg/day for

adolescents.

• Bed rest is not essential, although wise if scans suggest risk of vertebral

collapseorcordcompression.Ifthelatter,discussurgentlywithapaediatric

spinalsurgeonandradiotherapist-oncologist.

• Initiateasearchforothertumoursknowntometastasizetospine(Box21.1).

• Investigation within an adolescent unit is advisable given the specific

multidisciplinaryinputoftenneeded.

Fig.21.2Spondylolisthesismeasuredasa%slipofL4onL5(α/β).GradeI<25%,gradeII25–50%,grade

III50–75%,andgradeIV>75%.

Box21.1Primaryspinaltumoursinchildrenandadolescents

Osteoidosteoma

Benign.Notuncommon.Mainlyadolescents.Posteriorvertebralboneusually.

Paincanbesevere.Discriminatefromosteoblastomasbysize(osteomasare

<1.5cm,osteoblastomas>1.5cm)ashistologyisoftenidentical.Lesionsare

associatedwithscoliosis(63%).Surgicalexcisionistreatmentofchoice.

Aneurysmalbonecyst

Benign. Symptoms often triggered by vertebral collapse. Take care when

consideringbiopsy todiscriminate frommalignant lesions.Discuss indetail

withMSKradiologist.

Eosinophilicgranuloma

Benign—oftenoccursaround10yearsofage.Rare.Lytic.Mayoccasionally

be multiple/disseminated—staging important. Symptoms often triggered by

vertebralcollapse.Cordandradicularcompressioncanoccur.Biopsyessential

to discriminate from malignant lesions. Surgical excision or internal spine

fixation not usually needed. Consider radiotherapy if cord compression

threatened. Consider external brace fixation in all and monitor for

spontaneous resolution. Disseminated lesions can be treated with

chemotherapy.

Ewingsarcoma

Overall rarely affects spine (~10% cases). Can affect any part of spine

including sacrum (latter cases often delayed diagnosis). Suspicion of it

requiresbiopsy.Treatwithcombinationchemotherapyandlocalradiotherapy.

5-year survival ~50%. Outcome better for tumour sizes <8 cm or localized

disease.

Leukaemia

Considerinallcasesofspinalosteopeniaorsingle/multiplevertebralcollapse.

Maybereferredpainfromhipandorpelviclesions.

Notoriousassociationwithdelayeddiagnosis.Associatedsystemicsymptoms

may not necessarily be present, but normal FBC at presentation unlikely

(~10% cases only). Also look for eosinophilia and hypercalcaemia, and

considerbonemarrowaspirate.

Lymphoma

Rarelypresentswithbackpain;however,knowncauseofpersistentbackpain.

MRI is imaging of choice: can show vertebral collapse and soft tissue

paraspinal mass. Biopsy is diagnostic. Case reports of plasmacytomas

presentingsimilarly.

Secondarymalignanttumour

Neuroblastoma, rhabdomyosarcoma, Wilms tumour, retinoblastoma, and

teratoblastomaareknown to present withback pain. Positive biopsyshould

triggerasearchfortheunderlyingprimaryneoplasm.

Chapter22

Chronicpainsyndromes

Pain

Generalizedpainsyndromes

Localizedpainsyndromes

Chronicpaininchildrenandadolescents

Complexregionalpainsyndromeinchildrenandadolescents

Pain

Introduction

Acutepainisadangersignal.Painsignalsa‘threat’andstimulatesabehavioural

response and memory toenableavoidingfuture ‘threat’. By nuanced contrast,

chronicpainistypicallyamaladaptiveprocessofreportingsucha‘threat’.

• Painisdefinedby theInternationalAssociationfortheStudyof Painas‘an

unpleasant sensory and emotional experience associated with actual or

potentialtissuedamageordescribedintermsofsuchdamage’.

• Thepainneuropathwaycanbemodified—eitherbyamplificationordamped

at various levels including peripherally—at the spinal cord and centrally.

Modificationsmayoccurinresponsetoavastarrayofinterpretivesensessuch

asbeliefs,earlierlifeexperiences,emotions,andemotionalresponses.

• The physiology and pathophysiology of pain is thus complex and it is best

viewedinthe contextof aneuromatrixrather thana pain nerveor asimple

gatetheory.

• Chronicpainisconsideredamaladaptivesensationthatbothover-reportsthe

peripheralthreatsignalssotypicalofacutepain,anddirectlycontributesto,or

maybetheprincipalexplanationfor,thepatient’sdistress.

• Viewed another way, tissue damage or inflammation cannot explain the

presence or level of distress and effective pain management requires an

understandingofallfactorsthatinfluencepainperception.

• Itisnowwidelyrecognizedthateffectiveexplanationofpainprocessingthat

integratesthepatient’sownexperiencesisinitselftherapeuticandallowsthe

patienttobuildonthepainmanagementstrategiesrecommended.

• Chronicpainmanagementstrategiesrecognizethebiopsychosocialmodelof

pain interpretation and are most effective when they integrate a

multidisciplinaryapproachtargetingspecificneeds.

Foreaseofexplanation,chronicpainsyndromeshavebeensub-dividedinto

chronic widespread (or diffuse) pain (CWP) and regional (or focal) pain

syndromes. Pragmatically this helps with considerations of differential

diagnoses and targeting investigations effectively. Management strategies

oftenoverlap.

Painneurophysiology:peripheries

Noxiouspainfulstimuliaredetectedintheperipherybynociceptorsonprimary

afferentneuronsandtransmittedtothedorsalhornofthespinalcord.

• Nociceptive primary afferents are specialized sensory neurons: either small

myelinatedAδfibresorunmyelinatedCfibres.

• ThesesynapsemainlyinlaminaIandIIofthespinaldorsalhornwithspinal

second-order interneurons. This is also one of the principal sites of pain

amplification.

• Itispossiblethatduringinflammation,nociceptorsmaybecomeactivatedat

lowerthresholdsthanusual,thusgivingadegreeofperipheralsensitization.

Painneurophysiology:central

Thebrainandspinalcordareresponsibleforcentralpainprocessingofnoxious

stimulitransmittedfromtheperiphery.Numerousareas(upwardsof700centres)

withinthebraininfluencepainperception.

• Nociceptiveimpulsesascendbytwomainspinalpathways.

• Information from Aδ fibres encodes ‘fast pain’ through the anterolateral

neospinothalamic tract (ALNT), which transmits pain and temperature and

discriminativequalitiesofpain:location,quality,andintensityofpain.

• This ALNT projects to the lateral thalamus with further connections to the

sensorycortexallowingpainlocalization.

• InformationfromC fibresencodes‘slow pain’transmittedthroughthe more

primitive-origin spino-reticulo-diencephalic tract in the posterolateral cord.

This projects to the reticular system of the brainstem, thalamus, and

hypothalamus and onwards to the limbic system. These connections are

responsiblefortheaffective,emotionalaspectsofpain.

• Connectionstothesympatheticnervoussystemmediatearousal.

Theoriesofpainpathophysiology

Over the years, various theories have been proposed to try and explain the

complexnatureofpainsensationandhowthisismodulated.

• René Descartes first postulated the existence of pain nerves which directly

transmitperipheralpainfulstimulitothebrain.

• ThegatecontroltheoryofpainwasputforwardbyMelzackandWall.This

statesthatthereisagateinthespinalcordthatinfluencespaintransmission.

Non-noxious stimulation inhibits upward transmission of pain (closes the

gate),henceotherstimuliaffectingthesameperipheralnervedistribution(e.g.

rubbing)reducesacutepain.

• Dissociation between peripheral stimuli and activation of the pain

neuromatrix,aprocess knownas centralsensitization,is thoughtto underlie

chronicpainthatpersistsintheabsenceoftissuedamage.

Furtherreading

Wedirectthoseseriousintheirintentiontohelppatientswithchronicpaintoothertextsandto‘Explain

Pain’ delivered by the Neuro-orthopaedic Institute (  http://www.noigroup.com/en/Category/EP)or

similarcourses.

Generalizedpainsyndromes

Chronicwidespreadpain

Chronicwidespreadpain(CWP)isacommonfindingpresentin5–10%ofthe

general population. In the absence of diffuse degenerative or

inflammatory/autoimmune rheumatic MSK, fibromyalgia (FM) is the

commonestmanifestation.

• CWPaffectswomenmorethanmenwitharatioof1.5:1andisdefinedaspain

for>6monthsintwoormoresitesbothaboveandbelowthepelvis.

• CWPmaypresentalone,maybemisinterpretedasanothercondition,ormay

beassociatedorcomplicateanothercondition.

• Conditions that can be associated with CWP or give rise to CWP as a

secondaryeffectareshowninBox22.1.

• CWPisoftenassociatedwithdisturbedandunrefreshedsleep.

• PeoplewithCWPoftenhavefatigueandmanymayultimatelybediagnosed

withchronicfatiguesyndrome.

• Peripheral threat (/pain) signals will often be amplified by other threats

including anxiety, depression, and any other persistent or unresolved

psychological conflict. Assessment of these should be considered a normal

partofthe historyand should beconsidered sympatheticallyas contributory

butnotthesolecause.

Box22.1Some(ofthemostcommon)conditionsinadultsthatcaneither

causeCWPormaybeassociatedwithit

• SLE.

• PrimarySjögren’ssyndrome.

• SOXsyndromeandearlygeneralizedOA.

• UndifferentiatedAICTD.

• Chronicsarcoidosis.

• Antiphospholipidsyndrome.

• Psoriatic-relatedMSKdisease.

• SAPHOsyndrome.

• AxialorperipheralSpA.

• Thyroiddisease.

• Primaryhyperparathyroiddisease.

• Osteomalacia.

• Largevesselarteritis.

Fibromyalgiaand‘syndromic’fibromyalgia

Fibromyalgia (FM) is the term given to patients who have CWP that satisfies

classificationcriteria:eitherACR1990criteriaforFMorACR2010criteriafor

FMwhichexpandstheearliercriteriatoincludeawiderspectrumofsymptoms

andtheirseverity(‘syndromic’FMorFMsyndrome).

Historyofuseofthetermfibromyalgia

FM is a type of CWP that has the cardinal feature of sleep disturbance.

Historicallythiswaspreviouslylabelledasmuscularrheumatismorfibrositisto

describeaconditionwithpain,fatigue,andpsychologicalinvolvement.

• BothFMandCWPareoftenassociatedwithothersomaticsymptoms,suchas

chronicfatigue,IBS,multiplechemicalsensitivities,andheadachesyndromes.

Other causes of fatigue should always be excluded, e.g. hypothyroidism,

hypoadrenalism,primarySjögren’ssyndromeandanaemia(Box22.1).

• Both CWP and FM are associated with alterations in peripheral and central

pain processing. Painful stimuli are detected at lower levels in affected

patients. Allodynia (pain in response to non-painful stimuli) found in these

conditionsisthoughttobeduetocentralsensitizationandan‘amplification’

phenomenon.

DiagnosisofFM

TherearetwoclassificationcriteriaforFM(ACR1990andACR2010criteria).

The 1990 criteria require diffuse tenderness at discrete anatomical sites. The

2010criteriaarebasedonmood,pain,andsleepdisturbance.The2010criteria

are designed to provide an alternative method of classification to allow long-

termfollow-upofFMpatientsandamethodofevaluatingthesymptomseverity

ofFM.

• ManyFMtenderpoints(Box22.2)areoverentheseswhicharescoredforpain

in enthesitis indices when assessing SpA conditions. It is of exceptional

importancethatSpAisdistinguishedfromFM.Ofcourse,bothmaycoexist.

An enthesitis predominant form of psoriatic arthritis is not uncommon (see

CASPARcriteriafordiagnosisofPsAin Chapter8).

• FMisalsofoundinupto25%ofpatientswithRA(see Chapter5),andSLE

(see  Chapter 10). It is also commonly found in association with

hypermobilityspectrumdisordersandhypermobility-EDS( Chapter19).

• Care must be taken to avoid misdiagnosing CWP/FM as the only cause for

painwhenthereisanAICTD,axSpA,orPsApresent.

• FM cases tend to aggregate within families but no genetic contribution has

beendefinedasyet.Itisimplausiblethatgeneticinfluenceswillnoteventually

bedefined;thuscommonenvironmentaltriggersshouldbeconsidered.

• The2010criteriaforclassificationofFMareshowninBox22.3.

Box22.2ACR1990criteriafordiagnosisoffibromyalgia

1.Historyofwidespreadchronicpain

Painisconsideredwidespreadandchronicwhenallofthefollowingare

present:

• Painintheleftandrightsideofthebody

• Painaboveandbelowthewaist

• Axialskeletalpain

• Painpresentfor3months

and

2.Paininatleast11/18tenderpointsitesondigitalpalpationwith4kg

pressure*.Onepointisgivenforeachsideofthebodyatthefollowing

9sites:

1. Occiput:atthesuboccipitalmuscleinsertions

2. Lowcervical:attheanterioraspectsoftheinter-transversespacesat

C5–C7

3. Trapezius:atthemidpointoftheupperborder

4. Supraspinatus:atoriginsabovescapulaspinenearmedialborder

5. 2ndrib:at2ndcostochondraljunction

6. Lateralhumeralepicondyles:2cmdistalfromepicondyles

7. Gluteal:inupperouterquadrants

8. Greatertrochanter:posteriortotrochanter

9. Knees:atmedialfatpadproximaltojointline

*Positivetenderpointwhensubjectsayspalpationwaspainful,(‘tender’isnotconsideredpainful).

FMissaidtobepresentwhenbothcriteria(CWPandtenderpointcount)aresatisfied.FMisnot

excludedbythepresenceofanotherdisorder.

CriteriatakenfromWolfeFetal.TheAmericanCollegeofRheumatology1990Criteriaforthe

ClassificationofFibromyalgia.ArthritisandRheumatism1990;33(2):160–72.

Box22.3ACR(revised)2010fibromyalgiacriteria

ApatientsatisfiescriteriaforFMifthefollowingthreecriteriaaremet:

1.Widespreadpainindex(WPI)≥7andasymptomseverity(SS)scalescore

of≥5orWPI3–6andSSscalescore≥9.

2.Symptomshavebeenpresentatasimilarlevelfor≥3months.

3. The patient does not have a disorder that would otherwise explain the

symptoms.

WPI=thenumberofareasinthelastweekwheretherehasbeenpain(score

0–19): left and right—shoulder girdle, upper arm, lower arm, ‘hip’

(buttock/trochanter),upperleg,lowerleg,jaw.Also:upperback,lowerback,

chest,abdomen,neck.

SSscalescore(0–12)iscalculatedby:

Scoringeachofthese3symptoms:wakingunrefreshed,fatigue,andcognitive

symptoms,onascaleof0–3where:

0=noproblem

1=slightormildproblems,generallymildorintermittent

2=moderate,considerableproblems,oftenpresentand/oratamoderatelevel

3=severe:pervasive,continuous,life-disturbingproblems.

Andadding

ascorefortheextent(severity)ofsomaticsymptoms*where:

0=nosymptoms

1=fewsymptoms

2=amoderatenumberofsymptoms

3=agreatdealofsymptoms.

*Somaticsymptomsthatmightbeconsidered:musclepain,IBS,fatigue/tiredness,thinkingor

rememberingproblem,muscleweakness,headache,pain/crampsintheabdomen,numbness/tingling,

dizziness,insomnia,depression,constipation,painintheupperabdomen,nauseanervousness,chest

pain,blurredvision,fever,diarrhoea,drymouth,itching,wheezing,Raynaud’s,hives,welts,ringingin

ears,vomiting,heartburn,oralulcers,lossof/changeintaste,seizures,dryeyes,shortofbreath,lossof

appetite,rash,sunsensitivity,hearingdifficulties,easybruising,hairloss,frequenturination,painful

urination,bladderspasms.

NewcriteriasummarizedfromWolfeFetal.TheAmericanCollegeofRheumatologyPreliminary

DiagnosticCriteriaforFibromyalgiaandMeasurementofSymptomSeverity.ArthritisCare&Research

2010;62:600–10.

ManagementofCWPandfibromyalgia

Theultimategoalofpainrehabilitationistoimprovequalityoflifeandsenseof

well-being rather than focus on pain reduction. With improvement in factors

such as sleep or anxiety and improvements in physical activity and general

participation,distraction frompain isimprovedandtheoverall senseof threat

reduced.Thiswillinturnreducethevolumeofpainsignal.

Managementissue1:explanationandreassurance

It is of paramount importance to consider carefully the way in which an

explanationisgivenastothenatureofthecondition.Thismaytakesometime

and may be best approached in the context of a multidisciplinary team

(psychologists,physiotherapists,OTs,doctors).

• It is important to assess the effect of symptoms on the patient’s life, and

developagoodrapportsopsychosocialissuescanbediscussed.

• Theemphasisintheexplanationshouldbereassurancethatthereisnoserious

underlyinginflammatoryorsystemiccondition,thatnothinghasbeenmissed,

andthereisnodamagetothejointsandmuscles.Thisfearblocksengagement

withexplanationsandunderminesrehabilitationstrategies.

• Effectiveexplanationusesappropriatelanguageandstoriestohelpthepatient

understand:

• moreaboutthecomplexityofpainprocessingandwhyitgoeswrong.

• whythereisn’taquickswitchtoturnitoff.

• why a return to activities and routines including normalization of sleep

helps.

• whythereneedstobeachangeincopingstrategies.

• Explanations also challenge the value of ongoing litigation and it may be

necessarytowaitforthistoberesolvedbeforebeginningapainmanagement

programme

• Educationoffamilyandpartnersisinvariablyhelpfulandoftenessential.

• BothCWP/FMareconditionswithrelapsesandremissions.Mostpatientswill

have ongoing symptoms. Patients with appropriate coping strategies,

improvementsinpsychosocialstressors,andgoodsocialsupportnetworksare

morelikelytohaveabetteroutcome.

Managementissue2:symptommanagement

OftenpeoplewithCWPlimitactivityduetoafearofprovokingmorepain.In

addition to addressing physical symptoms such as pain and fatigue,

psychologicalinput(e.g.cognitivebehaviouraltherapy)ishelpfulinproviding

toolstomanagepainandactivitylevels.

• Althoughexercisemaycauseashort-termincreaseinpain,agradedexercise

programmehasbeenshowntobebeneficial.

• Low-impactexercise,suchasPilatesmaybehelpful.Pilatesishelpfulbecause

it:

• requirescontrolavoidingjarringandunpredictablemovements.

• worksallindividualmusclegroupsincludingthosethathavebecomeweak

frompreviousunhelpfulpatternsofmuscleuse.

• istiringandreleasesendorphins.

• encourageseffectivestretching.

• buildsconfidenceandresilience.

• A physiotherapist should help support and guide engagement with Pilates,

yoga, and gym classes and may indicate what specific activity might be

avoidedinthefirstinstance.

• Pacing ofactivities isimportant, avoiding‘boom andbust’ patternsofover-

activitywhenfeelingwell,followedbyperiodsofinactivityduetosubsequent

painandfatigue.

• Cognitive behavioural therapies (CBTs) provide a small incremental benefit

overcontrolinterventionsinreducingpain,negativemoodanddisabilityatthe

endoftreatmentandatlong-termfollow-upinFM.

• Lack of adequate forms of sleep reduces resilience and promotes pain

amplification.Poorsleepisoneofthemajorbarrierstoimprovementandis

tackledattheoutsetofmostpainprogrammes.

• Sleepdisturbanceneedstobeaddressedthroughsleephygienemeasures(e.g.

haveaquietbedroom,reducelightandnoisewherepossible,avoideatinglate,

reducingcaffeineintakeintheevening).

• Sleep health information is available at:

https://www.sleepassociation.org/patients-general-public/insomnia/sleep-

hygiene-tips/

Managementissue3:pharmacologicaltherapy

The role of medication is to help establish and reinforce good sleep routines,

reduceanxietyandfearofpain,andwherepossibleallowimprovementsinpain

severitytoallowengagementwithpainprogrammerecommendations.Manyof

thetechniqueslearntinpsychological-basedtreatmentstrategieshelpwiththis,

reducingtherelianceonoftenunhelpfulpainmedications.

• NSAIDs and GCs are not effective and may cause morbidity due to side

effects.

• Narcoticsshouldbeavoided.

• Many patients will have tried analgesics with little effect. This in itself can

fuel anxiety as to the cause and severity of their underlying condition, and

frustrationandlackofconfidenceintheirdoctor.

• Tricyclic antidepressants such as amitriptyline (10–50 mg 2 hours before

bedtime) are often helpful in embedding changes to sleep routines and

improvingqualityofsleep,decreasingmorningstiffness,andalleviatingpain.

• Patientsshouldbewarnedofsideeffectsoftricyclicssuchasdrymouth,self-

limiting morning somnolence and weariness, and that they may take 3–4

weekstotakeeffect.

• Patientsareoftenalsowaryofbeinggivenan‘antidepressant’.Anexplanation

thatatricyclicisbeingusedasamodifieroftheimpactofpainisimportantto

improveadherence.Amitriptylineisoneofagroupofdrugsthatincrease5-

hydroxytryptamine.

• Amitriptylinecanbeusedwithtramadolandthiscombinationmaybehelpful

inthosewithsevereexacerbationsorwavesofpain.

• The efficacy of selective serotonin reuptake inhibitors (SSRIs) is debated

given variable evidence of efficacy. The use of fluoxetine, duloxetine

sertraline,or citalopramimprovesmoodandanxiety, butSSRIsmaybeless

effectivethantricyclicsintreatingpain,fatigue,andsleepdisturbance.

• Venlafaxine(aserotoninandnoradrenalinereuptakeinhibitor)inhighdosesis

effective in treating multiple symptoms in FM. Low-dose treatment is

ineffective.

• Pregabalinhasshownefficacyonpaininsomestudiesandcanbecombined

effectivelywithduloxetine.

• Sedative hypnotics have been reported to improve sleep in severe

circumstances.

• A recent meta-analysis of RCTs

 showed that duloxetine 60 mg, pregabalin

300mg,milnacipran100mg,and200mgweremoreefficaciousthanplacebo.

However, there was no significant difference in the efficacy and tolerability

betweenthemedicationsattherecommendeddoses.

• Overall however, when treatments are judged against quite strict criteria for

improvementthereisnotstrongevidenceforefficacy.

• The conclusion from the meta-analysis report

 was: ‘The available data

regardingefficacy...(treatingpain,sleep,physicalfunction,fatigue,anxiety,

depression,andcognition)...wereinsufficienttodrawdefiniteconclusions..

. (regarding response of FM patients to reported treatment modalities). . . .

Indirect evidence indicates that efficacy may be expected with the use of

serotonin noradrenaline reuptake inhibitors (SNRIs), noradrenaline reuptake

inhibitors(NRIs),andmultidisciplinarytreatment....’

• A number of meta-analyses of drug therapies are available in the Cochrane

Library( http://onlinelibrary.wiley.com/cochranelibrary).

References

1. Okifuji A, Gao J, Bokat C, et al. Management of fibromyalgia syndrome in 2016. Pain Manag

2016;6:383–400.

2. Bernardy K, Klose P, Busch AJ, et al. Cognitive behavioural therapies for fibromyalgia. Cochrane

DatabaseSystRev2013;9:CD009796.

3. Gilron I, Chaparro LE, Tu D, et al. Combination of pregabalin with duloxetine for fibromyalgia: a

randomizedcontrolledtrial.Pain2016;157:1532.

4. Papadopoulou D, Fassoulaki A, Tsoulas C, et al. A meta-analysis to determine the effect of

pharmacological and non-pharmacological treatments on fibromyalgia symptoms comprising

OMERACT-10responsecriteria.ClinRheumatol2016;35:573–86.

Localizedpainsyndromes

Localized pain syndromes are chronic pain conditions in a defined area. The

diagnosis of a localized pain syndrome is a diagnosis of exclusion given

conditions that can present with similar features. Often there is underlying

neuropathicpainandabnormalneuralactivity.

Chronicregionalpainsyndrome(CRPS)

Generalconsiderations

CRPSischaracterizedbyvariabledysfunctionoftheMSK,skin,neurological,

andvascularsystems.CRPSmayoccurinavarietyofsituationswithanumber

ofclinicalmanifestationsvaryingaroundcentralcorefeatures.

• Severaltermshaveevolved,describingaspectsofthesamecondition:reflex

sympathetic dystrophy, Sudeck’s atrophy, shoulder–hand syndrome, and

transientosteoporosis.

• ThesetermshavebeensupersededbythetermCRPS,whichisrecognizedby

theInternationalAssociationfortheStudyofPain.

• TherearetwosubtypesofCRPS:type1describessymptomsintheabsenceof

peripheralnerveinjury,andtype2(‘causalgia’)inthepresenceofinjurytoa

specificperipheralnerve.

Epidemiologyandaetiology

CRPSisacommondisorder.Itaffectsbothsexesequally,andoccursatanyage

in allracesand geographical regions. Althoughtheexact aetiology is unclear,

thereislikelytobeacombinationofperipheralandcentralneurologicalfactors

involved.

• Trauma(e.g.fracture,burn,surgery,etc.)isthemostcommontriggeringevent.

Theeventmaybetrivial.Oftennocauseisidentified.

• CRPSisreportedinuptoathirdofseriesofdistalforearmfracture.

• Several neurological conditions may act as triggers, including, for example,

hemiplegiaandmeningitis.Peripheralnerverootinjurymayalsoleadtothe

syndrome.

• Pregnancy, tumours,and prolongedimmobilization havealso beenlinked as

possibletriggeringfactors.However,25%ofcaseshavenocleartrigger.

• Itisimportanttotryandidentifypsychosocialstressesasthesemayhavean

effectonthepersistenceofsymptoms.

Clinicalfeatures

Typically,thesyndromeinvolvesthedistalpartofalimb,e.g.forearmorfoot.

Early clinical features of the condition include pain, soft tissue swelling (e.g.

maybesynovitisifoverajoint),reticular/livedorash,warmthoveraffectedpart.

Occasionallytheremaybelocalized,sweatingandpiloerection.

• The pain has several particular characteristics and is often described as

‘burning’.Thefeaturesinclude:

• allodynia—anotherwiseinnocuousstimulusproducespain.

• hyperalgesia—increasedpainperceptiontoagivenstimulus.

• hyperpathia—delayed over-reaction, often after repetitive cutaneous

stimulus.

• Theaffectedlimbisoftenguardedtoavoidanycontactasallodyniaisusually

extreme.

• NovelclinicalsignsdescribedinrecentyearssupportinvolvementoftheCNS

andMRIstudiesshowevidenceofcorticalreorganization.Theseclinicalsigns

include digit misperception, astereognosis, altered hand laterality, and

abnormalbodyschema.

• Patientsbecome‘depersonalized’fromtheiraffectedlimbwithafeelingthatit

nolongerbelongstothemandadesiretoremovethatlimb.

Investigation,staging,anddiagnosis

Clinical suspicion and knowledge, and a good history and examination will

makethediagnosisofCRPSinallcases,butitisimportanttorecognizechanges

thatmayoccurinsomeradiologicalandfunctionalimaging.Thesetestsmaybe

misinterpretedinothersettingsandmayhelpwithexplanationswithpatients.

• Laboratory tests need to be interpreted cautiously. ESR, CRP, and FBC

abnormalities may be present if there is underlying inflammatory rheumatic

MSKdisease.

• However, there may be evidence of bone demineralization (osteopenia on

radiographs, CT or low bone density estimated using regional DXA) if the

lesionissevere.

• High bone resorption can be indicated biochemically by hypercalciuria

(hypercalcaemia would be very unlikely), and raised plasma/serum collagen

crosslinks(e.g.CTX).

• Thermographycandemonstratechangesincutaneoustemperature.

• Perhaps of most value, and high specificity, is the triple-phase bone

scintigraphy(

99m

Tc-MDPscintigraphy).

• An experienced nuclear medicine physician can specify CRPS based on

characteristicpatternsofbonescintigraphyabnormalityinthe earlyregional

bloodflowdistribution,bloodpoolappearances,andlateskeletalradionuclide

uptake.

• CRPS stage I is essentially regional pain and swelling. In most cases, the

symptomsfluctuate,thengraduallyresolve.

• StageIICRPSisaperiodofdystrophicchange(see Plate10).Thistendsto

occurseveralmonthsafteronsetofthedisorder.Theaffectedregionbecomes

cool, pale, and often cyanosed in colour with abnormal sensation

(dysesthesia).

• StageIIICRPSismanifestbyadecreaseinhairandnailgrowth,osteopenia,

and eventually atrophy of skin and subcutaneous tissue. Stage III CRPS is

difficulttotreatandreverse.

• MostcasesofCRPStendnottoprogressbeyondstageI,oratmostearlystage

II.

• TheBudapestcriteriafordiagnosisofCRPSareshowninTable22.1.

Table22.1.TheBudapestcriteriafordiagnosisofCRPS.ForadiagnosisofCRPS,allfourcriteria(A–

D)mustbemet

Criteria A:continuingpaindisproportionatetotheincitingeventand

B:≥1symptomin≥3categories(below)

and

C:≥1signin≥2categories(below)

and

D:nootherdiagnosisbetterexplainsthesymptomsandsigns

Categories Sensory:allodynia(tolighttouchand/ortemperaturesensation

and/ordeepsomaticpressureand/orjointmovement)and/or

hyperalgesia(topinprick)

Vasomotor:temperatureasymmetry(>1°C)and/orskincolour

asymmetrybetweenlimbs

Sudomotor/oedema:oedemaand/orsweatingchangesand/or

sweatingasymmetry

Motor/trophic:decreasedrangeofmotionand/ormotor

dysfunction(weakness,tremor,dystonia)and/ortrophictissue

changes(hair,nail,skin)

ManagementofCRPS

Success treating CRPS relies on an early and accurate diagnosis and early

treatmentinordertopreventchronicity.

• OnceCRPSpersistsbeyond6–8months,itisdifficulttoreverse.

• Early and ongoing treatment should focus on the whole individual and not

simplytheregionalsymptoms.

• Treatment is based around the broad categories of physical therapies

(physiotherapy and desensitization therapy), psychological therapies

(cognitivebehaviouraltechniques),andpharmacotherapy.

• Attention to anxiety, psychosocial stressors, pain behaviour, and sleep

disturbanceisimportant.

• Patientsoftenrequirerepeatedreassuranceandcounselling.

• The aim should be to resume premorbid levels of activity so early physical

therapy(/hydrotherapy)inputshouldbeconsidered.

• Desensitization therapy of the affected region can help to normalize the

sensationsofhyperalgesiaandallodynia.

• Desensitizationisachievedbyapplyingdifferenttexturestotheaffectedarea,

concentrating particularly on the interface between normal and abnormal

sensations.

• Mirror therapyto reflectthe unaffected limbwhile performingsynchronized

movements can also help in regainingfunctionandrangeofmovement and

relievingpain.

• In early acute disease, IV pamidronate may be helpful in relieving pain,

especially if there are bony changes on imaging. Short courses of

glucocrticoids(GCs)mayalsobehelpfulintheacutestages.

• Tricyclic antidepressants canhelpcorrect sleep disturbance and increase the

painthreshold.

• Gabapentinorpregabalinmayalsobeofvalue.

• Transcutaneouselectricalnervestimulation(TENS)mayhelppaincontroland

allowentryintoaphysicalactivityprogramme.

• In some severe cases, regional sympathetic or ganglion blocks have been

reported to control pain sufficiently to facilitate engagement with pain

managementprogrammes.

• Patients may request limb amputation as a result of their depersonalization

fromthatlimb.However,thisshouldbediscouragedasitdoesnotguarantee

improvement in pain and such patients may suffer with intractable phantom

limbpain.

Otheradultregionalpainsyndromes

Post-herpeticneuralgia

Thisneuropathicpainconditiondevelopsinadermatomaldistributionfollowing

an episode of herpes zoster. It is defined as pain that continues for 3 months

following an attack of herpes zoster. Typically, the neuralgia begins as the

vesiclesstarttohealandcrustover.

• Paincanbevariableinseverityandisneuropathicinnature.

• Antivirals such as aciclovir are often used at the beginning of an attack of

herpes zoster to limit the duration of the attack and reduce the chances of

developing post-herpetic neuralgia. However, these are not useful in

establisheddisease.

• Treatmentincludesanticonvulsantssuchascarbamazepineandgabapentinas

wellastricyclicantidepressantssuchasamitriptyline.

• Ganglionregionalnerveblockscanbeconsideredforseverecases.

• Analgesicssuchasparacetamol,anti-inflammatories,andopioidsmayallbe

helpfulinmanagingpain.

• ShortcoursesofGCsareoftenusedtoreducethedurationofpain.

• ConservativemeasuresthatmaybehelpfulareTENS,acupuncture,relaxation

techniques,andheat/coldtherapy.

Trigeminalneuralgia

This is a type of neuropathic pain affecting the trigeminal nerve and causing

intense facial pain along the trigeminal nerve divisions. There are two main

types:typicalandatypicaltrigeminalneuralgia.

• Thetypicalformcausesattacksofseveresuddenpainononesideoftheface

whichcanlastforsecondstominuteswhiletheatypicalformcausesconstant

burningpain.

• Theexactaetiologyisunknownbutisthoughttobeduetolossofthemyelin

nervesheath.

• Treatmentis withanticonvulsantssuch ascarbamazepineandtricyclicssuch

asamitriptyline.Opioidsareusuallynoteffective.

• Surgerymaybeanoptionifconservativemeasuresfail.

Temporomandibularjoint(TMJ)dysfunction

ThemostimportantfeatureofTMJdysfunctionispainandrestrictedmandibular

opening.

• Thereisoftenclickingassociatedwithmovementofthejoint.

• About 20–30% of the general population have some degree of TMJ

dysfunction.

• Thereisalinktothehabitofteethgrindingsooftenprostheticmouthguards

arefashionedtowearparticularlyatnight.

• TheTMJcanbeaffectedinallinflammatoryarthritidessuchasRAandPsA

andsuchcausesshouldalwaysbeconsideredasanunderlyingcauseofTMJ

pain.

Chronicpaininchildrenandadolescents

Introduction

In childhood and adolescence, pain is a ubiquitous experience affecting over

80%ofindividualsinanygivenpreceding3–6-monthperiod.Asinadults,this

threat, or danger, sensation is associated with neuroendocrine, MSK, and

inflammatory responses, and provokes threat appraisal and behavioural

adaptationthatmaybeattentiveoravoidant.

• Prevalence rates of chronic (recurrent or persistent) pain in children and

adolescentsarehigh(11–38%)with5%experiencingsignificantpain-related

dysfunction.

• Chronicpainaffectsmostbodysiteswithaprevalencethatincreaseswithage

(seeTable22.2)

Table22.2Prevalenceofchronicpaininchildrenandadolescents

Paintype Prevalencerangefromvariousstudies(%)

Headache 8–83

Abdominalpain 4–53

Backpain 14–24

MSKpain 4–40

Multiplepains 4–49

Other/generalpains 5–88

• Over 10% of all GP contacts with adolescents are attributable to MSK pain

and of thoseseekingmedicalintervention the direct cost to the USA is $19

billion.

• Although the international criteria for chronicity is 3 months’ duration

(constantorintermittent),takenfromthedefinitioninadults,adiagnosiscan

oftenbemadesooner.

• On careful enquiry the site, character, and severity of pain, and any loss of

function, are often incongruous with the mechanism of any injury or

backgrounddiseasestate(JIA,sickle,IBD,etc.)andthisfrequentlyoverrides

therelevanceofduration.

Associationsofchronicpaininchildrenandadolescents

Most chronic MSK pain might reasonably be attributed to biomechanical

imbalancesandstressesthattypicallyresultfromtissuetightnessandchangesin

patternsofmuscleusewithnormalgrowthanddevelopment.

• Inappropriate patterns of muscle use may also derive from previous injury,

repetitive sport or dance activities, or commonly from deconditioning when

sedentarybehaviourpredominates.

• Othercommonassociationswithchronicpainandpainamplificationinclude

obesity, poor sleep health, lower socioeconomic status, parental

catastrophizing, risk aversion, thought and attention problems, anxiety, low

mood, rule breaking, aggressive behaviour and hypermobile joints, but the

extenttowhichthesefactorsarecontributoryinchildhoodvary.

• Pain in multiple sites, including chest, abdomen, and head, is strongly

associated with obesity in girls and a high number of psychosocial and

mechanicalfactors.

• MultipleMSKpainsinadolescencehaveahightendencytopersist(>2years)

with both psychosocial factors and lifestyle factors contributing to this

vulnerability.

Chronicwidespreadpaininchildrenandadolescents

Thediagnosistermchronicwidespreadpain(CWP)ispreferredtojuvenileFM

orjointhypermobilitysyndrome/hypermobilityspectrumdisorderorotherlabels

which intimate poorly established aetiologies, have overlapping diagnostic

criteria,markedheterogeneity,andmayunnecessarilyinculcate(ortrap)patients

intoanexpectationoflifelongdisability.

• Duetovariationindiagnosticlabelsandcriteria,theepidemiologyofCWPis

poorlyunderstood.

• The prevalenceof juvenilefibromyalgia(JFM), definedby ACRcriteriafor

adults(chronicMSKpain,multiplediscretetenderpoints,fatigue,andsleep

disturbance),isupto6%.

• JFM accountsfor8% ofdiagnoses madebypaediatric rheumatologists.The

prevalenceofjointhypermobilitysyndromeinchildrendiagnosedwithJFMis

probablythesameasinthegeneralpaediatricpopulation.

• Enigmaticsymptomsofdizziness,fatigue,blurringofvision,‘blackouts’,and

tachycardia occur in 50% of children and adolescents with CWP and might

reasonably be attributable to variations in ‘threat signalling’ and may be

exacerbatedbyanxiety.

• Labels of ‘postural orthostatic tachycardia syndrome’ PoTS, ‘autonomic

dysfunction,’or‘chronicLymedisease’areusuallyunhelpfulandmostofthe

clinical symptoms resolve with effective explanation and engagement in a

rehabilitativeprogramme.

• CWP maybetriggered by or coexistin5–20% of cases withanunderlying

disorder such as sickle cell disease, heart disease, or cancer. CWP in the

presenceofaSpAconditionrequirescarefuldisentanglingasenthesitislinked

toSpAmaybepresent(see Chapter8).

ManagementofCWP:generalprinciples

• Irrespective of the medical setting there is always a potential to positively

intervene,beginningwithrecognitionofaprimarypaindisorderandmaking

time for the patient to explain their history, the impact, and their

understanding.

• Thetherapeuticconsultacknowledgesthepainandexplainstheroleofpainas

athreatsignal.

• Further explanations about pain processing, in appropriate language, should

assist an understanding to promote engagement in the treatment strategies

describedinthenextsubsectionandreduceasenseofhelplessness.

• Effective explanations of pain are therapeutic and can be enormously

motivational.

• In particular, there should be an understanding of disruptions to the ‘4Ss’

(sleep,sports/physicalactivity,sociallife,andschool).

• A focus on returning to normal 4S routines should improve resilience and

improve quality of life, with consequent reductions in the psychological

impactofpainandenhancedbiofeedbacktocounteractpainsignals.

ProgrammesofcareforCWP

• Effectiveprogrammesofcaretargetanappropriateamountofresourcetothe

levelofneed.

• Integrationacrossanetworkofservicesisoftenrequiredwithcommunityand

secondarycareservicesworkingwithatertiaryhub.

• Thefocusofcareistoreturntonormalfunctionwithanincidentdecreasein

pain.

• Corefeaturesofaprogrammeofcareinclude:

• adequateexplanationaboutpainandrehabilitation.

• an interdisciplinary and goal-orientated approach with a specific focus on

self-management.

• medication used to enhance engagement with advice and other self-

managementstrategies.

• Pain workshops inform and educate in an engaging way, dispel myths, and

create a narrative that helps to increase participation and improvements in

qualityoflifedespiteminimalchangeslevelsofpain.Workshopsalsoprovide

thebenefitofpeersupport.

• Physical therapiessuch asphysiotherapyand occupationaltherapytreatment

strategiesaremosteffectivewhengoaloriented.

• Physiotherapistshelptoreducethefearofmovementandguidethepatient

through a programme of exercise and increase participation in general

physicalactivity.

• Physiotherapypromotesresilience,aswellasreducingmuscletightnessand

buildingstrength,stamina,balance,andnormalpatternsofmuscleuse.

• Occupationaltherapistssupportupperlimbphysicalactivity,agradedreturn

toschool,sleep advice,management ofbullyingand areturnto anactive

sociallife.

• Physiotherapists often support such re-engagement with regaining normal

4Sfunctiontoo.

PsychologicaltherapiesforCWP

• Psychologicalinterventionnowdrawsfromanarrayoftreatmentstrategiesin

additiontoCBT.

• Effectivepsychologyprogrammesincludeafocusonresilienceandpromotion

ofpatientstrengthsinadditiontoreducingbarrierstoengagementandcoping

modification.

• ACochranereviewin2014showedpsychologicaltreatmentsareeffectivein

reducing pain intensity and disability in various forms of CWP and the

benefitsappeartobemaintained.

• Evidencefortheeffectsofpsychologicaltherapiesonmoodislimitedasitis

foreffectsondisabilityinchildrenwithheadache.

Activemind–bodytechniques

• Techniquesareusefulinpromotingself-management.

• Techniquesincludebreathingstrategies(squarebreathing,diaphragmaticand

slow exhale breathing), mindfulness, yoga, Pilates, and progressive muscle

relaxation.Thisisnotanexclusivelistandthebenefitvariesbetweenpatients.

Parentcoaching

• A child or adolescent in pain exerts a considerable emotional, and often

financial,tollonfamilylife.

• Pain-relateddisabilityismoreconsistentlyrelatedtopoorfamilyfunctioning

thanpainintensity.

• Parenting behaviours can act to maintain or even enhance their child’s pain

experience; e.g. if the child has to interpret ambiguous emotional parental

expressions.

• Thereisariskofincreasedanxietyanddepressionforachildofaparentwith

CWP.Familialdysfunctioncanfollow.

• Normalizing parental protectiveness reduces guilt and defensiveness and

refocusesparents’attentiononhealthyandadaptivebehaviours.

• Parentsaretaughthowtocalmthemselvesanduseskillstodistractandavoid

emotionalescalation.Afocusshouldbemaintainedontheirchild’s function

andparticipation.

• Parents’painexperiencesshouldbeaddressedanddiscussedopenlywiththe

childpresent.Itshouldbeclearlypointedoutthatthechild’spainisdifferent

from the parent’s disability and pain, with an expectation that the child can

becomepainfree.

• Parents are taught how to optimize the independence of teenagers and

encourageself-managementskills.

PharmacotherapyinCWP

• Thereislittleevidencetosupportthesoleuseofmedicationbutitmayhavea

roleintheintegratedmanagementplandescribedhere.

• There are no RCTs which confirm the benefit of paracetamol in treating

paediatricCWPbutthereissomelimitedevidenceforibuprofenalthoughboth

are associated with potential long-term side effects including overuse

headaches.

• Opiates should be avoided inprimarypain disorders due to poor safetyand

sideeffectprofilesassociatedwithworseoutcomes.

• Care should be taken with opiate use when IBD or sickle cell disease is

associatedwithaprimarypaindisorder.

• CodeinehasbeenwithdrawnfromtheWHOpainladderforchildren.

• Adjuvant therapies including low-dose tricyclic antidepressants,

gabapentinoids,SSRIs,andmelatoninmaybehelpful.

• TherearenoRCTswhichsupporttheuseofgabapentinintreatingpaediatric

CWP,anditsusemayresultincognitiveimpairmentandreducedresilience.

• The anxiolytic effects of tricyclics and SSRIs may help to improve

engagementwithmanagementstrategiesandresiliencefromimprovingsleep.

• MedicationisassociatedwithastrongplaceboeffectinCWP.Forexample,in

variousRCTsformigrainetherapies,aplaceboresponse istypically seenin

50–60%ofstudyparticipantsandcandecreaseheadachefrequencyfromsixto

threeheadaches/month.

Complexregionalpainsyndromeinchildrenand

adolescents

CRPS is clinically distinct from adult CRPS in that the lower limb is more

commonly involved than the upper limb, there is a marked female

predominance, dystrophic changes and long-term disability are less common,

andmultiplelimbscantypicallybecomeinvolved.

• Thepeakincidenceisinearlyadolescence(median13years).

• MRIshowsincreasedbonesignal(‘oedema’)earlyinthecondition.

• Thermographyhighlightsabnormalregionalbloodflowchanges,whichcanbe

comparedtotheotherlimbs.

• Laterinthediseaseradiographsshowosteopenia.

• Ultimately,limbdeformityoccursinthemostseverecases.

ManagementofCRPS

• EffectivemanagementofCRPSrequiresacarefulexplanationofthecondition

to the child or adolescent and their family, a graded exercise programme

supervised by a therapist experienced in chronic pain management, and

frequentdesensitization.

• Workonrestoringnormal4Sfunctionimprovesresilienceandmostpatients

respondwithin4–6therapysessions.Patientscanexpecttobecomepainfree

andreturntoallactivities.

• 25–35% of children and adolescents with CRPS are resistant to routine

management techniques and will benefit from more intense programmes of

careasdescribedforCWP(see ,‘Chronicwidespreadpain’,pp.639–641).

PartIII

Medicinemanagementand

emergencies

Chapter23
Drugsusedinrheumatologypractice
Introduction
Painrelief
Glucocorticoids
Disease-modifyingantirheumaticdrugs
Othermedications
Introduction
A variety of pharmacological agents are used across the breadth of rheumatic
diseases. Therapeutic options are discussed in each of the disease-specific
chaptersinPartIIofthisbook.
Thischapterhighlightscommonthemespertinenttoprescribingforpainrelief
and control of autoimmune rheumatic disease. It is not the intention of this
chaptertodescribealloftheseindetail,althoughspecificissuesarediscussed.
Protocolsfortheuseofcertainagentssuchaspooled-immunoglobulinwillalso
bedescribed.
Foradetaileddescriptionofaspecificdrugitisrecommendedthereaderuse
a National Formulary and in the UK all medicine summary of product
characteristics(SPCs)areavailableat http://www.medicines.org.uk
Table23.1liststhecommonclassesofdrugusedinrheumatologyandisthe
frameworkforthecontentofthischapter.
Table23.1Pharmacotherapyofrheumatologicaldiseases
Drugtype Examples
Painrelief Paracetamolandcompound
analgesics
Opioidanalgesics

NSAIDs

Antidepressants

Gabapentinandpregabalin

Hypnoticsandmusclerelaxants

Topicalagents

Glucocorticoids(GCs) Prednisolone,triamcinolone,

methylprednisolone

Conventionalsyntheticdisease-

modifyingantirheumaticdrugs

(sDMARDs)

Azathioprine

Ciclosporin

Cyclophosphamide

Gold(Myocrisin

IMorauranofin

oral)

Hydroxychloroquine(HCQ)

Leflunomide

Methotrexate(MTX)

Mycophenolatemofetil(MMF)

Penicillamine

Sulfasalazine

TargetedsDMARDs Tofacitinib

Apremilast

BiologicalDMARDs Anti-TNFα:etanercept,infliximab,

adalimumab,certolizumab,

golimumab

AntiB-cell(CD20):rituximab(RTX)

AntiBLyS/BAFF:belimumab

IL-1receptorantagonists:anakinra

IL-6receptorantagonists:tocilizumab

IL-12/23antagonists:ustekinumab

IL-17Aantagonists:secukinumab

CTLA4-Ig:abatacept

Other Hyperuricaemia/gout:allopurinol,

febuxostat

Osteoporosis:bisphosphonates,

denosumab,strontium,teriparatide

Pulmonaryhypertensionand

Raynaud’sdisease:iloprost,

sildenafil,bosentan

Intravenousimmunoglobulin

Painrelief

Generalconsiderations

Thedescriptorsandassessmentoftheimpactofpainarediscussedin Chapters

1 and 22. Good pain management is associated with improvement in various

physiologicalandpsychologicaloutcomemeasures.

• In general, pain management may be broadly divided into pharmacological

and non-pharmacological methods. The individual description of each non-

pharmacologicalmethodisbeyondthescopeofthischapterbutmayinclude

thefollowing:

• Hot/cold/pressurecompress.

• Physicaltherapies—landbasedandhydrotherapy.

• Transcutaneouselectricalnervestimulation(TENS).

• Acupuncture.

• Hypnosis.

• Cognitiveandbehaviouraltherapy(CBT).

• Pulsedradiofrequencyandnerveablationtherapies.

• Low-levellasertherapy(LLLT).

• Massage,relaxationtherapy,andmeditation.

• Othercomplementarymedicinemethods.

• Effective pain management must begin with a thorough assessment of the

patient’spain,treatmentexpectations,andconcerns.

• Unrealistic expectations or misunderstanding of pain could mean that the

managementstrategymayfailfromthebeginning.

• In chronic painful conditions please refer to Chapter 22. Patients should be

aware that there might be a period of trial and error before the optimal

combination of pain relief is found although in many circumstances

medicationmaybeunhelpful.

• Inassessingefficacyofanoralanalgesic,itisimportanttoconsider:

• theanalgesiceffect.

• thefrequencyandmaximumdosetried.

• anyunwantedsideeffects.

• Iftherewastemporaryreliefthatthenworeoff,thismaybeduetoeitheran

insufficientdose,ortheintervalbetweendosesistoolong.

• Unpleasantsideeffectsmayalsoputpatientsoffsomemedications.

• Patientsmayusetheterm‘addiction’toexpressconcernsoverthelong-term

useofanalgesics,inparticular,opioid-basedpainrelief.Ifsuchconcernsare

notaddressed,patientsmaybereluctanttotakeopioidsregularlywhichinturn

leadstopoorpaincontrol.

• Rather than ‘substance abuse’, the patient is most likely reflecting on the

possibilityof‘tolerance,’whenciting‘addiction’,i.e.‘becomingusedto’the

analgesicsothatahigherdoseisrequiredtosustaintheeffectovertime.This

oftenneedsclarificationduringconsultation.

• Abuse of opioids—addiction or recreational use and deliberate self-harm by

overdosing—isalegitimatecauseforconcern.

• The safety and suitability of these agents are very much dependent on

assessmentoftheindividualpatient.

• Follow-up appointments are important to allow both the patient and the

cliniciantoevaluatetheefficacyofatreatmentregimenandtothenmakethe

necessaryadjustments.

• Thereisverylittlehigh-qualityevidencefortheuseofanalgaesiainpaediatric

pain.

Analgesicescalation:the‘analgesicladder’

TheWHOanalgesicladder(Fig.23.1)isausefulframeworktoconsiderwhen

commencing patients on pharmacological pain treatment. But see also more

specificguidesformanagingandprescribingstronganalgesicsinchronicpain

(e.g. SIGN-136: www.sign.ac.uk; and at CDC:

www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm).

• Escalationofpainreliefmodalityfollowsastepwiseapproachdependingon

theassessmentoftheseverityofpain.

• Movement up the analgesic ladder is a balancing act between increasing

analgesicpotencyversusincreasingriskofsideeffects.

Fig.23.1WHOanalgesicladder.ReprintedfromWHO’scancerpainladderforadults,Copyright(2014)

http://www.who.int/cancer/palliative/painladder/en/.AccessedMay2017.

• Atthebottomoftheladder(Step1)arenon-opioidcompoundswithrelatively

good safetyprofilesuch as paracetamol andnon-steroidalanti-inflammatory

drugs(NSAIDs).Theseareeffectiveformildtomoderatepainseverity.

• Step2involvesaddinginweakopioidssuchastramadolorcodeinephosphate

for painof moderate severity, although codeineisno longer includedinthe

WHOladderforpainreliefinchildren.Thisisbecausechildrenarevariable

metabolisersofcodeine,leadingtoanunpredictableeffect.Codeineshouldnot

beusedinchronicpaininlongtermpaediatricconditions.

• Iflongtermopioiduseistobemaintainedconsiderconvertingtosustained-

release form as a basal analgesia. This is supplemented with instant-release

opioidforbreakthroughpain.Cautionshouldbetakenwhenusingopioidsin

longtermpaediatricconditionsandalternativestrategiestopainmanagement

shouldbesought.

• Opioids used for an extended period lead to tolerance, create physical

dependency,andshouldnotbewithdrawnabruptly.

• If an episode of acute pain is superimposed upon chronic pain requiring

regularstrongopioids,anyanalgesiaprescribedshould bein additionto the

regularopioidregimen.

• Someanalgesics,whentakentogether,haveasynergisticeffectthatisgreater

than the sum of its individual effects. It makes sense therefore to have a

compoundform(e.g.co-codamolwhichcontainscodeineandparacetamol).

• Acompoundagent maybe easierforthepatientto manageby reducingthe

numberofseparatepillstoingest.However,theabilitytoalterthedoseofone

of the componentagentswithoutaltering the other is lost. There is alsothe

additional risk of patients double dosing on a medication from failure to

recognize the active components of the drug (e.g. taking co-codamol and

paracetamoltogether).

• Clearadviceonthe optionsfor increasingdoseaccordingtotolerabilityand

efficacyshouldbegiven,includingtheprincipleofstartingatthelowestdose

wheneverpossible(particularlyintheelderly).Clearguidanceputsthepatient

incontroloftheirpainrelief.

Simpleandcompoundanalgesics

Paracetamol(acetaminophen)

Paracetamol is thought to reduce pain by inhibiting prostaglandin synthesis

withinthecentralnervoussystem. Ithasboth analgesicandantipyreticactivity

withoutanti-inflammatoryactivity.

• Itisavailableoverthecounterinmanycountriesandiseffectiveinmanaging

softtissueinjury,jointpain,dentalpain,andheadache.

• Itisusuallygivenorallyat4g/day(children30–60mg/kg/day;max4g)given

in4divideddoses.ItisalsoavailableinsuppositoryandIVformulations.

• Itisreasonabletotryparacetamolfirst.MostGPswillanditisimportantto

assurethepatientofitsefficacy.Thespecialistmayhearpatientssay‘myGP

justgavemeparacetamol’.

• CommonconcernsandinteractionsareshowninTable23.2.

Table23.2Cautionsandsideeffectswithparacetamol

Caution Comment

Hepatictoxicity Avoidinknownsignificantliverdiseaseandalcoholabuse

Renaltoxicity Notethattheeffervescentformulationscontainsodium—

avoidinmoderate–severerenalimpairment

Blooddyscrasia E.g.thrombocytopeniaandleucopeniacanbeinducedor

worsened

Pregnancyand

breastfeeding

Notknowntobeharmful

Commoninteractions

Coumarin

(warfarin)

Paracetamolmayenhancetheanticoagulanteffect

Absorptionand

metabolism

Metoclopramideincreasesabsorption;carbamazepine

acceleratesmetabolismofparacetamol

Paracetamolcompounds

• Paracetamol 500 mg is also available in compound analgesics, such as co-

codamol (paracetamol and codeine), co-dydramol (paracetamol and

dihydrocodeine),andparacetamolandtramadol.Thesearenotrecommended

inchronicpaediatricconditions.

• Careshouldalwaysbetaken,aswith‘over-the-counter’aspirinproductsand

otherNSAIDs,thatpatientsensuretheydonottakemorethanthemaximum

daily dose of paracetamol, irrespective of the combination of single and

compoundmedicationsusedtogether.

• Thecodeinecontentvariesintheseformulationsbetween10,15,and30mg

pertablettoamaximumtotaldailydoseof240mgdividedinto8tabletsand

takenas2tabletsfourtimesaday.

• Codeineisdiscussedlaterunderopioidanalgesics.

• Because of safety concerns (related to toxicity in overdose) co-proxamol

(paracetamolanddextropropoxyphene)isonlyavailableintheUKbyspecial

arrangementonanamed-patientbasis.

Opioidanalgesics

Opioiddrugsactasagonistsatopioidreceptorswhicharefoundmainlyinthe

brainandspinalcordandalsoperipherally.

• Forallopioiddrugs,therearenumerouscautions(See Table23.3)andcare

shouldbetakeninallchronicconditions,especiallyinchildren.

Table23.3Cautionsandsideeffectsofopioidanalgesics

Caution Comment

Hypotension Particularcarewhenalsotakingantihypertensives,

antipsychotics,orantidepressants

Sedationand

respiratory

suppression

Avoidinchronicobstructivepulmonarydisease,head

injury,anysituationofreducedlevelofconsciousness;

takeparticularcarewhenalsotakingantipsychotics,

antidepressants,orantihistamines.Counselcautionover

drivinganduseofmachinery

Hepatictoxicity Avoidinknownsignificantliverdisease,reducedosein

milddisease

Renaltoxicity Avoidinknownsignificantrenaldisease,reducedosein

milddisease

Blooddyscrasia E.g.thrombocytopenia;leucopeniacanbeinducedor

worsened

Porphyria Avoid

Pregnancy Avoid

Breastfeeding Preferablyavoid.Notecodeineisnotknowntobeharmful

asconcentrationareverysmall;however,individualsvary

inrateofmetabolismandcloseobservationshouldbe

madeforsignsofinfantmorphineoverdose

Gastrointestinal Opioidsinducenausea,vomiting,constipation,

pancreatitis,obstruction

Neuropsychiatric Opioidsinduceheadache,confusion,dys/euphoria,

hallucinations,moodchange,seizures

Genitourinary Sexualdysfunction,urinaryretention,avoidinsignificant

obstructiveprostatichypertrophy

Age Reducedosageintheelderly,avoidinchildhood

Commonlyusedweakopioids:codeineanddihydrocodeine

• Codeineanddihydrocodeine(alsoavailableasmodifiedrelease)canbeused

asasingleagenttomaximumdailyadultdosageof240mg(usually2×30mg

tabletsfourtimesaday).Itisavailablein15mgor30mgtablets.

• Itisalsoavailableincompoundagentswithparacetamolasdescribedearlier

andwithibuprofenoraspirin.

• Codeine is marketed in various salt compounds including phosphate and

sulfate (typical in the USA, Canada, and UK), hydrochloride (continental

Europe),hydro-iodide,andcitrate.

• Low-dosecodeineisavailable‘overthecounter’insomecountriesandisalso

foundincoughsuppressants.Inthemajorityofcountrieshowever,itremains

prescriptiononlyduetoconcernsoverdependencyandmisuse.Itsuseisstill

classedasillegalinafewplaces.Travellerswithlegitimateprescriptionsare

advisedtocarrydocumentationoftheirconditionfromtheirphysician.

• Cimetidine,actingasaP450enzymeinhibitor,increasesplasmaconcentration

ofcodeineanddihydrocodeine.

• Metoclopramide and domperidone are antagonized by codeine and

dihydrocodeine.

Tramadolandmeptazinol

Tramadolisaweakopioidagonist.Itinhibitsthereuptakeofbothserotoninand

norepinephrine(noradrenaline)atthedorsalhorn.

• Themaximumrecommendedadultdoseis400mg/dayindivideddoses.Itis

availableinmodified-release12-hourlypreparations(200mgtwicedaily)and

incombinationwithparacetamol.

• Meptazinolisapartialopioidreceptorantagonistandisgivenat800mg/day

individeddoses.Itsmixedeffectreducestheriskofdependenceandisless

likelytobeusedasasubstanceofabuse.

• Theseagentsareoftentriedafterorinsteadofcodeinecompoundsgiventhe

differenceinmechanismsofaction.

• They have a more favourable gastrointestinal (GI) side effect profile than

codeineandmaybeoneofthereasonsfortryingthembeforecodeineinthose

pronetoconstipation.However,thisisoffsetbyagreaterriskofintolerance

fromneuropsychiatriceffects.

Commonlyusedstrongopioids

Theseincludemorphinesulfateandoxycodonehydrochloride5–10mg,both4–

6-hourly(canbetitratedupto400mgperdayinseverecases);thelatteralsohas

a compound of oxycodone/naloxone, which may be beneficial in those with

severe constipation from opioids despite trials of different classes of laxative.

Thereafter,escalationmightmovetomorphinesalts,butbeforeanyoftheseare

utilizeditiscommontotrypatchformulations.

Opioidsdeliveredthroughtransdermalpatches

Theseareappliedtotheskinand,therefore,inadditiontotheabove-mentioned

cautions,beawareofallergicreactionwithlocalizedsensitivity.

• Buprenorphine (also available in the UK as Temgesic

 200 micrograms

sublingual)isproducedasBuTrans

andTranstec

.Both haveformulations

that allow a wide variety of dosing, e.g. BuTrans 5 micrograms/hour 7-day

patch,graduallybuildingdose,perhapsevery2weeksdependingontolerance

andresponseofsymptoms.

Non-steroidalanti-inflammatorydrugs

NSAIDs are commonly used. Most have a licensed indication for OA (see

Chapter 6) and RA (see  Chapter 5); some have a licence for ankylosing

spondylitis(see Chapter8).

• Inreality,mostNSAIDsareprescribedineffect‘offlicence’foranumberof

rheumatic conditions outside these diagnoses, but based on being effective

analgesics with the capacity to reduce inflammation such as occurs in soft

tissues,tendonitis,andsynovitis.

• NSAIDsareclassifiedbytheirinhibitoryactiononcyclooxygenase1(COX-

1), e.g. ibuprofen, naproxen, and diclofenac, or COX-2, e.g. celecoxib and

etoricoxib.Some agents(e.g.oxicams)demonstrateinhibitory actionagainst

bothenzymepathways.

• ItisreasonabletotryaNSAIDfromadifferentclasswhenanotherhasfailed.

• Ibuprofen and aspirin compounds are available over the counter in many

countries.Naproxen(250–500mgtwicedaily)anddiclofenac(150mgdaily

in divided doses) probably represent the two most commonly prescribed

NSAIDsworldwide.

• COX-2inhibitorsarediscussedlaterinthissection.

• Oral preparations are most often used. Some are available as slow-release

formulations,e.g.diclofenac.

• Althoughperrectumagentsarealsoavailableinsome,thesedonotappearto

reducesideeffect(specificallygastric)enoughtowarranttheirpreferenceover

oralagentsinthemajorityofcases.

• Topicalagentshavevariableefficacy,oftenwithlimitedevidenceofbenefit.

Thatsaid,theyarepopularwithpatientsaspartoftheirmanagement.

• Paediatricdosingincludes:Ibuprofen10mg/kg4-6timesdaily;naproxen10–

20mg/kg/dayin 2–3divideddoses;diclofenac3–5mg/kg/dayin2–3 divided

doses.

AdverseeffectsofNSAIDs

Anumberofadversereactionsarerecognized.CautionappliestoallNSAIDs,

particularlyavoidingtheiruseinhepaticandrenalimpairment,pregnancy,and

GIulceration(Table23.4).

• Using the lowest possible dose for the shortest period of time lessens the

adverseeffectsriskofNSAIDs.Itisinevitable,however,thatthosewithlong-

termconditionsforwhichremissionislessthanoptimalwillrequirelong-term

therapy.

• Whilecardiovascularcomplicationsoccur,manypatientswithcardiovascular

diseaseandriskfactorsuseNSAIDs,particularlyifthebenefitisconsideredto

outweigh the risk (e.g. improved function/exercise tolerance encourages a

healthierlifestyle).

• Itisimperativethatbloodpressureandrenalfunctionaremonitoredregularly

(preferablyevery3months).

• The highest risk of cardiovascular complications is with diclofenac, COX-2

NSAIDs, and high-dose ibuprofen (2.4 g daily). The lowest risk is with

naproxen(1gdaily)andibuprofen(1.2gorlessdaily).

• It is not uncommon for individuals to also be on aspirin for its platelet

inhibitoryfunction.

• AllNSAIDsarecontraindicatedinsevereheartfailure.

• GIrisksaredocumentedinTable23.4.

• ThehighestGIriskisseenwithpiroxicamandketoprofen; intermediaterisk

withdiclofenac,etodolac,indometacin,naproxen,andoxicams;andthelowest

riskwithibuprofen.

• Inrenaldisease,NSAIDsshouldbeusedwithcautionandavoidedifpossible.

• NSAIDs can induce acute kidney injury, as well as exacerbate chronic

impairment.The‘ruleofthumb’oflowestpossibledoseforshortestpossible

periodoftimeapplies.

• NSAIDs can exacerbate asthma; however, it should not be an absolute

contraindicationtoprescribing.

• Manypatientsmaywellhaveinadvertentlytriedaspirinandibuprofenover-

the-counter compounds without complication. The clinician may therefore

gain some sense of tolerability. The decision to prescribe should always be

based on the severity and responsiveness/stability of asthma in each

individual.

NSAIDcautions:sDMARDco-prescribing

• Concern is often expressed over the co-administration of sDMARDs and

NSAIDs.Toxicitymonitoringisafundamentalresponsibilitywhenmanaging

sDMARDs.

• sDMARDmonitoringappliesirrespectiveofNSAIDuse.

• Inprinciple,asdiseasecomesundercontrolonsDMARDsitisappropriateto

reducethefrequencyofNSAIDuseifpossible.

NSAIDcautions:pregnancyandbreastfeeding

ItisgenerallyadvisedthatNSAIDsshouldbeavoidedinpregnancyunlessthe

benefitstowell-beingsignificantlyoutweightherisk.

• NSAIDscanbeusedwithcautioninthefirstandsecondtrimesterbutshould

beavoidedinthethirdtrimesterduetotheaddedriskincludingclosureofthe

fetalductusarteriosusinutero,delayinonset,andanincreaseintheduration

oflabour.Inaddition,pulmonaryhypertensionmayaffectthenewborninfant.

• Insomecases,studiesshowconcentrationsofcertainNSAIDstobetoolowin

breast milk to warrant concern. In general, manufacturers advise avoiding

NSAIDsforthedurationofbreastfeeding.

• Low-dose aspirin may be continued throughout pregnancy but high-dose

aspirinshouldbeavoided.

• There are limited data for COX-2 inhibitors, which have been shown to be

teratogenicinanimalstudiesandhencetheseshouldbeavoidedinpregnancy

andbreastfeeding.

Table23.4AdverseeffectsofNSAIDs

Organ/complication Occurrence Comments

GItract Common Gastritis,bleeding,and

perforation.Highriskinthe

elderlyandthosewithahistoryof

ulcers

Renal Common Fluidretention,papillarynecrosis

Hypertension Common Interferencewithdrugssuchas

thiazidediuretics

Cardiac/myocardial

infarction

Increasedriskin

thosewith

cardiovascularrisk

factors

COX-1andCOX-2drugs

Lung Notuncommon Exacerbationofasthma,

pneumonitis(naproxen)

Skin Notuncommon Hypersensitivity,erythema

multiforme

Centralnervous

system(CNS)

Notuncommon Tinnitus,fatigue,cognitive

disturbance

Rare Asepticmeningitis

Liver Uncommon Drug-inducedhepatitis

Haematological Rare Bonemarrowdyscrasias

Aspirin

• As the prototype NSAID, aspirin is available in single and compound

formulationsoverthecounter.WhileitisrarelyprescribedasanNSAID,itis

importanttoacknowledgeitsavailability,aswellasitscommonuseinlower

dosage(75–150mgdaily)asacardio-protectiveagent,whenprescribingother

NSAIDs,andadvisingonsideeffectsanddruginteractions.

• For analgesic effect, aspirin is dosed at 300–900 mg four times a day

(maximum adult dose 4 g/day). It is available in oral and suppository

formulations.

• Low-dose aspirin may be continued throughout pregnancy but high-dose

aspirinshouldbeavoided.

• Aspirin isavoidedin childrenunderthe ageof16 years (exceptfor cardiac

conditionssuchasKawasakiDisease)duetotheriskofReyesyndrome.

Oxicams

• ThisgroupofNSAIDswasdevelopedfortheirlongerhalf-life.

• Meloxicam(7.5–15mgdaily)andpiroxicam(20mgdaily)arethetwomost

commonlyusedagents.

• Piroxicamhasarelativelyhighrelativetoxicity:efficacyratioforGIadverse

effectscomparedwithotherNSAIDs.

Coxibs/COX-2inhibitors

• TheseagentswereintroducedbecauseoftheirefficacyandselectiveCOX-2

inhibition, recognizing the value of preserving COX-1 ‘protective’ enzyme

activity,particularlyinrelationtoGItolerability.

• However, large-scale phase III control trials, an integral part of modern

pharmacological practice and essential in seeking approval for a licence,

demonstrated an appreciable cardiovascular risk. As a consequence, several

COX-2drugs(e.g.rofecoxib)havebeenwithdrawn.

• Celecoxib(100–200mgtwicedaily)andetoricoxib (30–120mgonce daily)

areavailableinEurope.CelecoxibisavailableintheUSA.In2007,theFood

andDrugAdministration(FDA)votednottoapproveetoricoxib.

• Regularbloodpressuremonitoringisrequired.

Antidepressants

Severalantidepressantsareusedinthemanagementofpain,usuallyasasingle

agent given at bedtime, sometimes in combination with other drugs using

differentmechanismsofaction,andoftenatlowerdosesthantypicallyusedfor

controllingdepression.Thereisnocompellingevidencefortheiruseinchronic

paediatricpain.

• Thereisoftenaneedtoexplaintopatientsthatthesedrugsarebeingusedfor

pain control and not for depression, even if there is a degree of reactive-

depressionpresentasaconsequenceofchronicpain.

• Educatingthepatientandexplainingthemechanismsofaction(blockingpain

messages from travelling up the spinal cord and modifying the response to

pain in the midbrain), one can gain greater compliance and enhance the

clinician–patientrelationship.

• Adetailedexplorationofthemechanismsisbeyondthescopeofthisbook,but

mostagentsarethoughttohaveadualeffectbymodifyingresponsivenessof

spinalopioidreceptors,andchangingmoodandperceptioncentrally.

• Theseagentsareperhapsmostlogicallyusedwhenpaindisturbssleep.Amild

sedativeandrelaxanteffectmayalsobebeneficial.

Serotoninandnorepinephrinereuptakeinhibitors

Tricyclics

Tricyclics are predominantly serotonin and/or norepinephrine re-uptake

inhibitors.The‘typical’agentsinthisgroupincludeamitriptyline,clomipramine,

imipramine,anddosulepin.

• Amitriptyline is the agent most frequently used (although sometimes

nortriptylineisbettertolerated).Givenatdosesupto75mg/daytakenbefore

bedtime, it is often titrated from a baseline of 10–25 mg in 10 mg steps

gradually until a balance between maximum efficacy and tolerability is

reached.

• CommonsideeffectsandinteractionsareshowninTable23.5.

Selectiveserotoninreuptakeinhibitors(SSRIs)

• Thisgroupincludesfluoxetine(20–40mgoncedaily),sertraline(50mgonce

daily),andparoxetine(20mgoncedaily).

• Randomized control trials in fibromyalgia (FM; see  Chapter 22)

demonstrate SSRI efficacy similar to 25 mg amitriptyline; however, the

averageimpactonpainreductionandqualityoflifeisonlyabout15–20%and,

assuch,theseagentsareprobablynotsuitablecandidatesasanalgesicswhen

usedinisolation.ThesideeffectprofileinTable23.5applies.

Mixedserotonin-norepinephrinereuptakeinhibitors(SNRIs)

• Increasinginterestinthecomplexitiesofcentralpainpathwaysandtheaction

ofSNRIshasledtoseveralstudiesdemonstratingSNRIefficacyinFM(see

Chapter22).

Table23.5Cautionsandsideeffectsofserotonin/norepinephrinereuptakeinhibitors

Caution Comment

Sedative Careneededwhenusedwithotherpotentiallysedating

agent.Note:CNStoxiceffectsoftramadolcanbe

enhanced(serotoninsyndrome).Alsonotecautionwith

drivingorusingmachinery

Antimuscarinic

action

Cautioninthosewithocular(closed-angleglaucoma),

genitourinary(retention,prostatichypertrophy),dry

eyes/mouth,constipation

Cardiovascular Riskofdysrhythmiasespeciallyventricular(e.g.increased

withconcomitantuseofsotalolandamiodarone)

Hypotension Increasedriskinpatientsondiuretics

Thyroiddisease Amitriptylineenhanceseffectsofthyroiddrugs

Epilepsy Amitriptylineantagonizesantiepilepticsreducingthe

thresholdforseizures

Sexual

dysfunction

Sexualdysfunctionmayoccur.

Hyponatraemia Usuallyintheelderlyandpossiblyduetoinappropriate

secretionofantidiuretichormones.

Hepatic

impairment

Trytoavoidinsevereliverdisease—riskofsedation

Pregnancyand

breastfeeding

Avoidunlessbeingusedforpsychiatricreasonsandinthe

bestinterestsofwell-being

Neuropsychiatric Inductionofhallucinations,delusions,(hypo)mania,

neurolepticmalignantsyndrome,andsuicidalbehaviour

Motorfunction Tremor/extrapyramidalsigns

Endocrine Breastenlargement,galactorrhoea

• The FDA (USA) approved duloxetine (2008) and milnacipran (2009) for

treatmentofFMinadults.Neitherisapprovedforuseinchildren.

• Duloxetine is given as 60–120 mg daily and milnacipran at 100 mg twice

daily.Sideeffectsincludenausea,headache,insomnia,dizziness,constipation,

hepaticdysfunction,hyponatraemia,andorthostatichypotension(duloxetine)

andhypertension(milnacipran).

• Likeallantidepressantsduloxetinecarriesawarninghighlightinganincreased

riskofsuicide,especiallyinchildrenandyoungadults.

• Tramadol should not be co-administered with duloxetine; there is a risk of

developing serotonin syndrome. Through cytochrome P450 enzyme system

interactions,duloxetinemayprolongopioideffects.

Otheradjuvantanalgesics

Gabapentin and its analogue pregabalin (both structural analogues of γ-

aminobutyric acid (GABA)), has been shown to have efficacy, particularly in

studiesofFM (see Chapter22), although the NNT is 9 and there is a high

incidence of side effects. There is no compelling evidence for their use in

chronicpaininchildrenandadolescents.

Gabapentin

• Dose:oral,titratedfrom300mgdailytomaximum3600mgdailyindivided

doses,e.g.300mgoncedailyonday1,then300mgtwicedailyonday2,then

300 mg 3 times daily on day 3, then increased according to response and

tolerabilityinincrementof300mgdailyevery2–3daystomaximumdoseof

3600mgdaily.

• DoseneedstobereducedinrenalimpairmentaccordingtoGFR.

• Side effects: dizziness/light-headedness, oedema, weight gain, and

sedation/mental impairment. Other concerns include leucopenia, ataxia,

Stevens–Johnsonsyndrome,hepatitis,andpancreatitis.

• Avoidduringpregnancyandbreastfeeding.

• Discontinuationhastobedonegraduallyoverminimumof1week.

Pregabalin

• Dose:oral,titratedafter3–7daysfrom150mgtomaximum600mgdailyin

2–3divideddoses.

• DoseneedstobereducedinrenalimpairmentaccordingtoGFR.

• Side effects: dizziness/light-headedness, oedema, weight gain, and

sedation/mental impairment. Other concerns include visual disturbance,

neutropenia,ataxia,arrhythmia,Stevens–Johnsonsyndrome,andpancreatitis.

• Avoidduringpregnancyandbreastfeeding.

• Discontinuationhastobedonegraduallyoverminimumof1week.

Musclerelaxants

Themostlikelyagenttoconsiderisdiazepam,abenzodiazepine.

• Givenatdosesof2–5mgthreetimesadayforupto14daysdiazepamcanbe

helpful in alleviating acute severe pain associated with spasm, particularly

acrosstheneckandshouldergirdle,andthelumbarspine.

• Diazepamshouldbeavoidedinhepaticandrenalimpairment,pregnancy,and

breastfeeding.

• As with opioids, care should be taken to counsel the patient over perceived

riskofdependencyofbenzodiazepines,andprescriptionshouldbeavoidedif

thereareanyconcernsoverpotentialabuse.

• Drugssuchasbaclofen,dantrolene,methocarbamol,andtizanidineusuallysit

withintherealmoftheneurologistandmaybevaluableincontrollingmuscle

spasm and pain in conditions such as stroke and multiple sclerosis. Where

indicated,therheumatologistshouldseekadvicefromaneurologistifspasm

painisconsideredtobetheconsequenceofaneurologicalcondition.

• Quinine sulfate is often used in doses of 200–300 mg to control cramps. It

shouldbeprescribedwithcautioninpatientswitharrhythmiaandavoidedor

dosehalvedinhepaticandrenalimpairment.

• Quinine sulfate is contraindicated in haemoglobinuria, myasthenia gravis,

optic neuritis, and tinnitus; and it may be teratogenic (certainly in higher

dosage)inthefirsttrimesterofpregnancy,butsafeduringbreastfeeding.

Topicalagents

• The most common classes to be used (excluding opioid transcutaneous

delivery by patch) include a variety of ‘over-the-counter’ preparations

(rubefacients),NSAIDs,andcapsaicin.

• Capsaicinisanactivecomponentofchilipeppers.Itislicensedtotreatpost-

herpeticneuralgiaanddiabeticneuropathy.Itcanbeconsideredanadjunctto

treatingOA.Oneriskisasevereburningandirritationifcontactismadewith

mucous membranes, including the lips and conjunctiva. Hand-washing after

useshouldbemeticulous.

• Capsaicinisprescribedasa45gtubeof0.025%or0.075%concentration,to

be applied twice daily in the smallest of volume; literally a tiny amount

squeezed ontothetip of thelittlefinger and thenrubbedin over thesiteof

pain.

Glucocorticoids

Glucocorticoids(GCs;‘steroids’)arepowerfulanti-inflammatoriesandrangein

usefrom shortdurationoflowand highdosagetogaincontrol ofacondition

(including intra-articular; see  Chapter 24), through to prolonged and even

lifelongtherapy.

Commonly used GCs are prednisolone, methylprednisolone, and

triamcinolone. Disease-specific indications and dosing regimens are stated in

eachrelevantchapterofthisbook.

Table 23.6 highlights the major and common cautions and concerns that

shouldbemonitoredanddiscussedwiththepatient.Patientson long-termGC

treatmentshouldbeencouragedtoholdasteroidtreatmentcardorsomeformof

alertbracelet,etc.

Table23.6Cautionsandcomplicationsofglucocorticoiduse

Caution Comment

Adrenal

insufficiency

Long-termusecanleadtoadrenalatrophy

Abruptwithdrawalshouldbeavoided

Replacement(evenhigherdosing)shouldbegivenduring

surgery, inter-current illness (especially associated

vomiting)

Diabetes Inductionandexacerbationofhyperglycaemia

Hypokalaemia Cancausehypokalaemia

Infection GCs are immunosuppressive—there is an increased

susceptibility to infections and severity of infections

especiallyafterprolongeduse

Liveviralimmunizationshouldbeavoided

Exposure to chickenpox or measles leading to concern

over significant infection should be managed with

passiveimmunoglobulin

MayexposelatentTB

Neuropsychiatric Caninducemania,confusion,delirium,andsuicidal

thoughts—canoccurearlyafterstartingcorticosteroid(3–

5daysonaverage)andtakeseveralweekstoresolve

havingdiscontinuedtherapy

Weightgain Thismaybeeitherasaconsequenceofperipheraloedema

orincreasedappetite—patientsshouldbewarnedtobe

carefulofthisandtousetrickslikedrinksofwaterto

reducesenseofhunger

Skin Long-termuseleadstoatrophyandbruising

Eyes Increasedriskofcataractsandglaucoma

Cardiovascular Inductionandexacerbationofhypertensionand

congestivecardiacfailure

Pepticulceration

Boneandmuscle Inductionandexacerbationofosteoporosis

Growthretardation

Myopathy

Osteonecrosis

Pregnancy GCscanbeusedorcontinuedifindicated—preferably

lowestdosepossible.Noevidenceofteratogeniceffects;

occasionalneonataladrenalsuppressionwhichusually

resolvesspontaneously

Breastfeeding Dosesofprednisoloneupto40mgdailyareunlikelyto

resultinsystemiceffectininfants

Glucocorticoidinteractions

• Because of the tendency for GCs to increase blood pressure, the effect of

antihypertensivesmaybeblunted.Monitoringiskey.

• BarbituratesandantiepilepticsincreasethemetabolismofGCs.

• DiureticsmaybeantagonizedbyGCs.

• ErythromycinandazolesmayinhibitthemetabolismofGCsthusincreasing

theireffect.

• GCsmayamplifytheseverityofNSAIDspepticulcerationrisk.

• GCs may increase the risk of bone marrow suppression with methotrexate

(MTX).

• GCsincombinationwiththeophyllineincreaseshypokalaemiarisk.

• GCsmayincreaseordecreasetheanticoagulanteffectofwarfarin.

Disease-modifyingantirheumaticdrugs

Disease-modifying antirheumatic drugs (DMARDS) are the cornerstone of

disease management aimed at the slowing or arrest and remission of chronic

inflammatoryrheumaticdisease.Foradditionaldetailseealso Chapter5(RA)

and Chapter8(SpAs).Terminologycanbeconfusingsincetheintroductionof

‘biologics’, which are also ‘disease-modifying’. A new nomenclature of

DMARDterminologyhasbeenproposedbySmolenetal.

• Firstly: ‘synthetic DMARDs’, which are subdivided into conventional

synthetic DMARDs (csDMARDs), i.e. traditional DMARDs, and targeted

syntheticDMARDs(tsDMARDs),whichareoralsyntheticdrugsdesignedto

targetaparticularmolecularstructure.

• Secondly: ‘biologic DMARDs’ (bDMARDs), which are subdivided into

biologic original DMARDs (boDMARDs) and biosimilar DMARDs

(bsDMARDs).

• Atthetimeofwritingitisunknownwhetherthisproposednomenclaturewill

be generally accepted. In this book we have mainly used the terminology

sDMARDs and bDMARDs, and have avoided introducing the other terms

extensively, with the exception being this chapter with the distinction being

madeclearinthefollowingsubsections.

ConventionalsyntheticDMARDs

Generalconsiderations

ConventionalsyntheticDMARDs(csDMARDs)areslow-actingdrugsthattake

8–12weekstobegintodemonstratebenefit,andeventhen,possiblylongerto

achievemaximumbenefitasthedoseisescalated(typically>6months).Patients

should always be informed of this, clarifying expectations and improving

compliance.

• It is not uncommon for combinations of csDMARDs to be used either by

sequential ‘step up’ (adding one after the other over time) or ‘step down’

(startingwithtwoorthree,andreducingtooneovertime).

• IntheUK,itisunlikelythatmorethanthreecsDMARDswouldbeusedsince

theintroductionofbDMARDs:UKguidanceallowsuseofbDMARDsafter

failureofatleasttwocsDMARDs(seelater).

• The most common drugs used are: hydroxychloroquine (HCQ), leflunomide

(LEF),MTX,andsulfasalazine(SSZ).

• Ofthesedrugs,MTXisprobablythedrugoffirstchoiceformostconditions

(e.g.RA,PsA,JIA)atdosesof7.5–30mgweekly.

• csDMARDsarenotwithouttheirtoxicityandtheproteancomplicationsand

monitoringrequirementscanseemdaunting.

• Tables23.7–23.10describeprinciplesapplicabletoallcsDMARDs.

• Advice on immunization and risk assessment of viral infection is shown in

Box23.1.

• GeneralmonitoringofcsDMARDs—seeTable23.7(pleaserefertoBox23.2

forcommon sideeffectstoassessfor, atevery bloodtestcheckandclinical

review).

• CommoncsDMARDsideeffectsandadviceoninitialactiontobetaken—see

Box23.2.

• Useinpregnancyandbreastfeeding—seeTable23.10.

• AllcsDMARDsshouldbeusedwithcautioninhepaticandrenalimpairment,

blood dyscrasias (including suspected or known G6PD deficiency and

porphyria),recurrentinfection,andintheelderly.

Box23.1Immunizationandassessmentofinfectionriskbefore

commencingcsDMARDs

Disclaimer: all readers should refer to their own local practice guidelines.

Informationhereisincompleteandbriefandaskeletonguideonly.

• In some circumstances it may be appropriate to give live vaccines to

patients on DMARDs. Refer to local guidelines. (e.g. oral polio, BCG,

MMR,yellowfever).

• Patientsshouldreceivethepneumococcalvaccine.

• Annualfluvaccinationisrecommended.

• Patientsexposedtochickenpox(whohavenoclearhistoryofchickenpox

in the past) or to shingles, should receive passive immunization using

varicellazosterimmunoglobulin.

• Patients should be screened for hepatitis B and C risk by history, and, if

required,serumantibodies.

• PatientsshouldbeassessedforriskofHIVandtestedifapplicable.

• Patientsshouldbeassessedforriskofactive/latentTB.

csDMARDmanagementforsurgeryandduringinfectiveillness

• csDMARDs do not need to be discontinued before surgery though some

surgeons/surgicalspecialtiesrequestcsDMARDsarediscontinued.Thereisa

lackoverallofrobustdataasfewrandomizedtrialshavebeenundertaken.

• IfthesurgeonwishescsDMARDstobestoppedthen,asa‘ruleofthumb’,itis

reasonabletodiscontinuefor2weeksbeforeandupto2weeksaftersurgery.

• It is not possible to predict the risk of a flare of inflammation during this

period,althoughmanypatientsreportaleveloftoleranceforupto4weeks.

• csDMARDsarediscontinuedduringsevereinfectiveillnessifthereisconcern

theirimmunosuppressanteffectoutweighstheriskofadiseaseflare.

Table23.7PrinciplesofmonitoringofcsDMARDs.

Disclaimer: all readers should refer to their own local practice guidelines. Information here is

incompleteandbriefandaskeletonguideonly.

Timeline Action

Pre-

treatment

assessment

FBC,creatinine,U&E,LFTs,CRPandESR,urinalysis

(protein),CXR(pre-MTX),bloodpressure,excludecurrent

infection,excludeunexplainedrash/skinlesion,complete

applicablediseaseactivityassessmenttools,requestvisual

acuitymeasurementbeforestartingHCQ

Monitoring

forthefirst

6–8weeks

FBCandLFTevery2weeks(4weeklyinchildrenforMTX

andAzaand2weeklyMMFandLFD)for6–8weeks(except

forAZAandMMF(weekly),HCQ(notrequired),gold(FBC

andurinalysisbeforeeverydose),SSZ(every4weeks)).Also,

creatinine,U&Eforciclosporin

6–8-week

clinical

assessment

FBC,creatinine,U&E,LFTs,CRP,ESR,urinalysis,blood

pressure,excludeinfectionandskinlesions,complete

applicablediseaseactivityassessmenttools

Monitoring

between2

and6

monthsif

drugdose

stable

FBCandLFTevery4weeks(exceptforHCQ(notrequired),

gold(beforeeverydose),SSZ(3-monthlyifstableinfirst3

months)).Somedrugsrequireclosemonitoringofcreatinine

andurinalysis—seeciclosporin

6-month

clinical

assessment

FBC,creatinine,U&E,LFTs,CRPand/orESR(aspartof

assessmentcriteria),urinalysis(proteinandblood),blood

pressure,excludecurrentinfectionandrash/skinlesions,

completeapplicablediseaseactivityassessmenttools

Monitoring

after6

monthsif

stabledrug

dose

FBCandLFTevery8–12weeks.Somedrugsrequireclose

monitoringofcreatinine,U&E,andurinalysis—seeciclosporin

Yearly

clinical

assessment

FBC,creatinine,U&E,LFTs,CRP,andESR

Assessment

every6

monthsif

dosestable

Urinalysis(protein),bloodpressure,excludecurrentinfection,

excludeunexplainedrash/skinlesion,completeapplicable

diseaseactivityassessmenttools

Generalprinciples

Returntotheearlymonitoringprotocolwheneverincreasingdrugdoseaftera

periodofstabledosage,orwhenintroducinganothercsDMARDoran

NSAIDorotherpotentiallytoxicdrug(byinteraction)forthefirsttime.

Seepublishedguidelines,e.g.atBritishSocietyofRheumatology:

http://www.rheumatology.org.uk/resources/guidelines/default.aspx

Familyplanning,pregnancyandbreastfeeding,whiletakingcsDMARDs

• Some csDMARDs can be taken reasonably safely while pregnant and

breastfeeding;seeguidelines(e.g.BSRguidelineonprescribingforpregnancy

and breastfeeding can be found at:

http://www.rheumatology.org.uk/resources/guidelines/default.aspx).

•  Table 23.8 shows specific regimens advised before trying to conceive, and

whichdrugstoavoidduringpregnancyandbreastfeeding.

• LEFshouldbestopped2yearsbeforetryingtoconceive,or‘washed’outas

describedlaterinthissection(see ‘Leflunomide’,p.670).

• AdviceonuseofanalgesicsandGCsinpregnancyandbreastfeedingisgiven

intheprevioussections.

MalignancyriskwithcsDMARDs

• EstablishingtheriskofmalignancyfromcsDMARDsischallengingowingto

theexcessincidenceofmalignancyinsomeoftheconditionsbeingtreatedand

alackof‘real-world’dataofcsDMARDuse.

• MMF,CYC,andAZAareassociatedwithincreasedincidenceofmalignancy

butSSZ,HCQ,MTX,andLEFareprobablynot.

SharedcareinformationoncsDMARDsandtheiruse

• ItisessentialthatthepatientreceivesinformationandadviceoncsDMARDs

and their primary care physician has access to correspondence from the

prescribingclinicianandresultsofmonitoring.

• It is essential that there is clarity over the roles and responsibilities of the

prescribingandprimary/communitycliniciansandthepatient.

• Various guidelines on csDMARD monitoring exist (e.g. see UK BSR

guidelines 2017 at:

http://www.rheumatology.org.uk/resources/guidelines/default.aspx).

• Box23.2broadlyoutlinesmanagementofcsDMARDsideeffects.

Box23.2csDMARDmonitoringandsideeffectsmanagement

Disclaimer: all readers should refer to their own local practice guidelines.

Informationhereisincompleteandbriefandaskeletonguideonly.

• AbnormalASTorALT.StopcsDMARDifenzymelevel>twiceupperlimit

of normal. As with all blood indices listed below, repeat weekly until

normalized.

• Abnormalleucocytecount.StopcsDMARDifneutrophils<1.5×10

/L,or

ifsteepdownwardtrendincount,andassessforinfection.Witheosinophilia

>0.5×10

/L,increasedvigilancerequiredbutmaybeunassociatedatopy.

• Low platelets. Stop csDMARD if platelet count <100 × 10

/L or serial

resultsshowsignificanttrenddownwards.

• Abnormal bruising. Check clotting screen and platelets urgently. If

abnormal withhold csDMARD immediately. Bruises are common in

children.

• AbnormalMCV.IfMCV>110fL,checkfolate,vitaminB12,TSH,andfor

excess alcohol intake. MCV+ may be an effect of AZA, MTX, SSZ, or

allopurinol

• Proteinuria. Send urine for microscopy/culture + treat infection. Quantify

proteinuria,checkcreatinine,U&E,excludehaematuria+urinarycastsand

obtaining‘KUB’ultrasound.ConsiderwithdrawingcsDMARD.

• Note: proteinuria may indicate worsening disease so stopping the

csDMARDmaybeinappropriate.

• Rash.Ifmildinadults,dropcsDMARDdose.Ifmoderate/severe,thenstop

csDMARD.Rashesarecommoninchildrenbutadvicemaybesought.

• Mucosalulceration.Considercauseofulcerationandaddfolate(forMTX)

andadjustdoseifpersistent.IfsevereconsidertrialoffcsDMARD.

• Hairloss.Considercauseofalopeciaandadjustdoseifpersistent.Atrial

off treatment may be appropriatebuthairgrowth may not recover for ≥1

haircycle,i.e.severalmonths.

• Hypertension.Ifmildrise,mayrespondtosmalldropincsDMARDdoseor

leavealoneandmonitor.Ifmoderatetosevere,treathypertensionfirst(see

adviceforciclosporinondosereduction).

• Weightloss.Considerthecauseofweightlossandreducethedoseorstop

foratrialperioddependingontheseverity.

• Dyspnoea. Chest exam + CXR. Treat infection and cardiac failure. If

pulmonary fibrosis suspected stop csDMARD and arrange further

investigation.

• Advisable actions if stopping a csDMARD. Repeat bloodtestafter1or 2

weeks. Assess foranyrecent change in medication, alcoholconsumption,

illness, csDMARD dosing error. Treat disease ‘flare’ with GCs. If trend

downwards in laboratory indices, then csDMARD should be reviewed

irrespectiveoflaboratoryvalue.Onceabnormalitiesreturntonormal,start

csDMARD at a lower dose, or switch to a new csDMARD, and in both

casesreturntotheearlymonitoringphase.

Azathioprine

Azathioprine (AZA) is prescribed for a number of autoinflammatory and

autoimmune conditions. AZA inhibits purine synthesis by generating

thioguaninenucleotidesfromitsmetabolite:6-mercaptopurine(6-MP).

• The typical dose of AZA is 0.5–1 mg/kg/day orally in twice-daily divided

doses, increasing after 4–6 weeks to 2–3 mg/kg/day with an anticipated

responsewithin6–12weeks.

• Thiopurinemethyltransferase (TPMT)activitystatus canbecheckedbefore

AZAisstarted:

• 99%ofpeoplewillhavehighorintermediateTPMTlevelsandbe atlow

riskofAZAtoxicity(fromslowAZAclearance).

• In a TPMT deficiency homozygous state (0.3% of population (1:300)) it

maybefatal—toxicityoccurringinthefirst6weeks.

• Intheheterozygousstate(10%ofpopulation),theremaybedelayed(upto6

months),butusuallyreversible,bonemarrowtoxicity.

• Although measurement of TPMT is advised in guidelines, it may be

impracticalsocloseFBCmonitoringinthefirst6–12weeksoftreatmentis

imperative.

• AZAcancauseaphotosensitivityreaction—patientsshouldbeadvisedtowear

sunscreensandprotectivecovering.

• AZAhassomespecificdruginteractions:

• Allopurinol:AZAdoseshouldbereducedto0.25–0.5mg/kg/day.

• Angiotensin-converting enzyme (ACE) inhibitors: co-prescription may

exacerbateanaemia.

• Anticonvulsants:AZAmayreduceabsorption.

• Aminosalicylates: (mesalazine (ME)/SSZ): increase risk of bone marrow

toxicity.

• Ciclosporin:AZAcandecreaseciclosporinlevels.

• Co-trimoxazole/trimethoprim:bonemarrowtoxicity.

• Warfarin:AZAinhibitsanticoagulanteffects.

Ciclosporin

Ciclosporin is considered in PsA, RA, AICTDs, uveitis, and MAS. It is a

calcineurininhibitorandhasafairlyselectiveactiononlymphocytes:blocking

mitosisandinhibitinglymphokinerelease.

• Ciclosporindoseistypically2.5mg/kg/dayorallyintwice-dailydosesfor6

weeks,thenmaybeincreasedat4-weeklyintervalsin25mgincrementsupto

amaximumof4mg/kg/day.Responsein<12weeks.

• Pre-monitoring(Table23.8)shouldincludefastinglipids,repeated6-monthly

andthedrugdiscontinuedifanuncontrollablesignificantriseinlipidsoccurs.

• Monitoring includes checking creatinine clearance/GFR. A rise in creatinine

>30% above baseline on two consecutive readings 7 days apart warrants

stoppingthedrugandreassessing.

• It is essential that blood pressure monitoring be commenced at baseline. If

uncontrollablehypertensionoccurs,thedrugshouldbestopped.

• Electrolyte balance should be checked every 2 weeks until stable dose

achievedandthenevery3monthswithotherroutinemonitoring(Table23.8).

If the potassium rises above the laboratory threshold the drug should be

stoppedandre-assessed(havingensureditisnotaresultofothermedication

changes).

• Grapefruit (including juice) increases the bioavailability of ciclosporin.

Grapefruitshouldbeavoidedforanhourbeforeandaftertakingthedrug.

• Ciclosporinhassomespecificdruginteractions.Ciclosporinisaninhibitorof

CYP3A4,whichmetabolizessomedrugs:

• Calciumchannelblockers:reducedoseofciclosporinto50%.

• Statins:useinlowdoseasciclosporincanelevateconcentrationofallthese

drugs.

• Colchicine:shouldbeavoided.

• Diclofenac:reducethemaximumdoseofdiclofenacto75mgdaily.

• Digoxin: measure levels and reduce dose accordingly as ciclosporin can

increaseserumlevels.

• Diuretics:cautionwithelectrolyteimbalance.

• Hydroxychloroquine (HCQ): may increase plasma concentrations of

ciclosporin.

• PUVA: avoid ciclosporin given significant increase risk of invasive

squamouscellcarcinoma.

• Concomitantuse of potentially nephrotoxicdrugs requiresspecialconcern

andmonitoring.

• Simvastatin:avoiddosingabove10mg/day.

• St.John’swort:decreasesciclosporinactivity.

Table23.8Disease-modifyingantirheumaticdrugsinpregnancyandbreastfeeding

Drug Effects

Azathioprine Pregnancy:compatiblethroughoutpregnancywithdose≤2

mg/kg/day

Breastfeeding:compatiblewithbreastfeeding

Ciclosporin Pregnancy: compatible throughout pregnancy with lowest

possible dose. Suggested monitoring of blood pressure,

renalfunction,bloodglucoseanddruglevels

Breastfeeding:compatible—thoughfromlimiteddata

HCQ Pregnancy:compatiblethroughoutpregnancy

Breastfeeding:compatiblewithbreastfeeding

Leflunomide

(LEF)

Pregnancy:potentialteratogenic—avoid

Note:LEFhasalonghalf-life.Rapidremovaloftheactive

metabolite can be achieved using washout with

colestyramine8gthreetimesadayoractivatedcharcoal

50gfourtimesadayfor11days.Bloodconcentrations

should be checked twice, 14 days apart prior to

conceiving(levelsshouldbe<0.02mg/L)

Breastfeeding:avoidLEF

Methotrexate

(MTX)

Pregnancy: teratogenic and abortifacient. Termination not

mandatory.StopMTX3monthsbeforestartingtotryto

conceive

Breastfeeding:avoiddrug

Mycophenolate

mofetil(MMF)

Pregnancy:teratogenicandabortifacientavoidMMF.Stop

MMF >6 weeks before starting to try to conceive.

Recommenduseoftwoformsofcontraceptionotherwise.

Breastfeeding:avoidMMF

Sulfasalazine Pregnancy: compatible throughout pregnancy with folate

supplementof5mg/day

Breastfeeding:compatiblewithfull-term,healthyinfants

CYC,gold,

penicillamine

Avoidinpregnancyandbreastfeeding

Cyclophosphamide

Themainuse ofthe cytotoxicdrugcyclophosphamide (CYC)is for organ- or

life-threatening manifestations of autoimmune connective tissue diseases

(AICTDs)andforremissioninductionofvasculitis.

• CYC can be administered either orally at a dose of 1.5–2 mg/kg/day or IV

givenasapulsedregimen.

• IVCYCdoseistypicallycalculatedbasedonweightorbodysurfaceareaand

adjustedforrenalfunctionandage;givenonceevery2–4weeksforupto3–6

months.

• For ANCA-associatedvasculitis(AAV), the CYCLOPSregimen is used:IV

CYCatdoseof15mg/kg(reducedforageandrenalfunction)each2weeks

for6weekstheneach3weeksfor3months.

• Pulsed IV CYC regimens are associated with lower total lifetime doses and

reducedtoxicity.

• CYC-inducedsuppressionofgametogenesisisoftenirreversible.Priortothe

decision to use CYC, patients should be counselled about infertility and

offered the use of GNRH analogue and/or harvesting and storage of

sperm/ova.

• Urothelial toxicity from the active CYC metabolite acrolein can cause

haemorrhagiccystitis.PatientsshouldbewellhydratedbeforereceivingCYC

andfor24–48hoursafterIVadministration.

• MesnaisgiventoreduceriskofCYC-inducedurothelialtoxicity. Theusual

doseis2gbeforeandrepeated2and6hoursafterIVtherapy.

• Commonsideeffectsincludenausea,vomiting,diarrhoea,arthralgia,fatigue,

headache,tachycardia,andhypotension.

• Prophylactic antiemesis treatment should be offered to patients who are

receivingIVCYC.

• Co-trimoxazole 960 mg three times a week should be prescribed for

prophylaxisagainstPneumocystisduringtreatmentwithCYC.

• Leucopenia/neutropeniaisasignificantriskandCYCdoseshouldbereduced

ifthishappens.FBCmaybecheckedondays0,7,10,and14afterthefirst

infusion and with any subsequent infusions where the dose is changed. An

FBC is often checked on day 12 (the usual nadir in neutrophil count) in

anticipationofthenextinfusion.

• Afterinductionofdiseaseremission,theusualpracticeistoswitchfromCYC

to alternative maintenance therapy such as AZA or MTX) to maintain

remission.

• ThereareafewCYCdruginteractions:

• Avoidclozapine:increasedriskofagranulocytosis.

• Digoxin:CYCreducesabsorption.

• Phenytoin:CYCreducesabsorption.

Gold(auranofinandsodiumaurothiomalate)

Gold was used extensively in the management of RA and JIA but its use has

becomeinfrequentsincethewidespreadadoptionofrelativelyhigh-doseMTX

andtheavailabilityofbDMARDs.

• The precise mode of action of gold is unknown though numerous in vitro

actionswhichmayberelevanthavebeenobserved.

• Gold is given as 3 mg 2–3 times daily (oral; auranofin) or as a 50 mg IM

injection(sodiumaurothiomalate),usuallymonthly.

• Atestdoseof10mgIMsodiumaurothiomalateshouldbegivenonthefirst

treatment;thereafter 50mg isgivenweeklyuntildiseaseresponseachieved.

Thereafter,theinjectionisgivenevery4weeks.

• Inchildren,IMgoldisgivenat1mg/kguptoamaximumof50mg.

• Ifnoresponseisseenafteracumulativedoseof1g(about20weeklydoses)

ofsodiumaurothiomalate,itshouldbediscontinued.

• Both formulations of gold are contraindicated in severe renal or hepatic

disease,ulcerativecolitis,historyofmarrowdysplasia,porphyria,exfoliative

dermatitis,SLE,pulmonaryfibrosis,andbronchiolitis.

Hydroxychloroquine(HCQ)andchloroquinephosphate

HCQandchloroquinephosphateare(old)antimalarials.Theiruseiscommonin

themanagementofRA,andinalltheAICTDs.HCQisespeciallypopularforits

useasmaintenancetreatmentinSLE(see Chapter10).

• Antimalarial drugs have a number of anti-inflammatory and

immunomodulatoryactions.

• HCQ is produced as a sulphate. Some side effects to HCQ may be a

consequence of the sulphate component of the drug (e.g. rash) thus a

phosphateformofHCQcanbeusedinstead.

• The therapeutic dose of HCQ is 200 mg once or twice daily. The dose of

chloroquinephosphateis250mgoncedaily.

• The dailydoseof chloroquineshouldnot exceed 6.5mg/kg. Alternate daily

regimesmaybeusedinsmallchildren.

• Enquire about visual impairment and measure acuity. Near-vision testing

should demonstrate the capacity to read small print N8 or N6 on an acuity

chart.

• Athoroughbaselinevisualassessment,includingaviewoftheretina,maybe

requestedofanoptometrist,opticianorophthalmologistpriortodrugonset.

• Once on an antimalarial, patients should report any changes in visual

acuity/blurring; this would trigger re-assessment at any time and immediate

withdrawal of the drug until the nature of the problem is found. Otherwise,

accuratevisualacuityassessmentshouldtakeplaceannually.

• Antimalarialscanexacerbatepsoriasis.

• Antimalarials can cause skin rash, nausea, diarrhoea and can in rare cases

causecardiacconductionabnormalities.

• Thereareafewdruginteractions:

• Antimalarialscanincreasetheplasmaconcentrationofdigoxin,MTX,and

ciclosporin.

• Avoid antimalarial use with amiodarone, quinine, mefloquine, and

quinolonesforriskofhypersensitivityreaction.

Leflunomide

LEFisusedin RA,PsA,andJIAandcanbeusedincsDMARDcombination

regimens. LEF is an ‘antiproliferative’ drug inhibiting the enzyme dihydro-

orodatedehydrogenase.

• Aloadingdoseof100mgdailyfor3daysissuggested(seeSPC)butoften

thiscausesGI upset andmostrheumatologists avoid it,startingat the long-

termmaintenancedoseof20mgdaily.

• Adoseof10mgdailymaybesufficientiftherearesideeffectson20mg.

• Thedoseinchildrenover3yearsofageis5mgdailyif<10kg;10mgdailyis

10-40kg;20mgdailyif>40kg.

• LEF has a long half-life and requires a washout when severe toxicity is

suspected.Awashoutisachievedusingcolestyramine8gthreetimesadayor

activated charcoal 50 g four times a day for 11 days. Blood concentrations

shouldbecheckedtwice,14daysapartpriortoconceiving(levelsshouldbe

<0.02mg/L).

• CautionisrecommendedwhenusingLEFwithMTX,sincethiscombination

hasbeenassociatedwithliverdysfunctionandfailure.Cytopeniahasalsobeen

observed.

• BloodpressureismonitoredwithbloodmonitoringsinceLEFmaycausean

increaseinBPanddestabilizecontrolledhypertension.

• Rarely,LEFcancausepneumonitis,acuteallergicreactionandneuropathies.

• WomenplanningafamilyshouldhavestoppedLEFfor2years(teratogenic)

(andmen3months)beforetryingtoconceive.

• ThereareafewdruginteractionswithLEF:

• LEFcanincreasetheanticoagulanteffectofwarfarin.

• LEFenhancesthehypoglycaemiceffectsoftolbutamide.

• LEFmayleadtoincreasedconcentrationsofanticonvulsants.

Methotrexate

MTX is the most commonly used csDMARD. It is used as a first-line

csDMARD in RA, JIA and PsA, and in managing some AICTDs and

vasculitides.

• TheactionofMTXasanimmunomodulatorisnotclear,althoughitisknown

tobeaninhibitorofdihydrofolatereductaseinhighdoses.Thisisassociated

with aninhibitionofDNA, RNA, and protein synthesis andmayeffect cell

division.

• ThetypicalmaintenancedoseofMTXis15–25mgonceaweek.

• TheuseofMTXvariesacrosscentres,buttypicallybeginsat10–15mgper

weekandincreaseby2.5–5mgevery2weeksforaperiodof6–8weeks.

• In children and adolescents the subcutaneous route is commonly used at

initiationatadoseof10–15mg/m

.Higherdosesofupto20–25mg/m

maybe

usedbutareassociatedwithmoresideeffectsandalowerrateofadditional

benefit.

• A lowerdoseand slower escalationisrecommended in theelderly and frail

andwherethereisreducedrenalclearance.

• ThesubcutaneousrouteisassociatedwithreducedriskofGIsideeffectsand

higherbioavailability,comparedtooral.

• MTXtabletsshouldbetakenwhole,notcrushedorchewed.

• MTXtabletscomein2.5mgand10mgformulations.Itisrecommendedthat

only2.5mgtabletsareprescribedanddispensedtoavoidconfusionandrisk

ofoverdose.

• Folic acid (5mg once per week) is often given to reduce the risk of side

effects.Itmaybeincreasedupto6daysoftheweekavoidingthesamedayas

MTX.

• Folic acid may be increased when there is: raised MCV, mildly deranged

LFTs,anaemia,mucositissymptoms,nausea,mucosalulceration;hairloss.

• Emergencyfolinicacid‘rescue’(15–25mgfourtimesadayIVororal)should

be given if any concern over severe toxicity (primarily pneumonitis and

marrowsuppression)andinoverdoseusuallyaboveacumulativeof100mg

MTX.IfserumMTXlevelscanbemeasureditisadvisabletocontinuerescue

until MTX levels fall below <0.1 µmol/L. In most cases, the response is

judgedbythedailyimprovementinhaematologicalindices.

• Theroleofliverbiopsyandserumpro-collagenIII(PIIINP)testingremains

unclear.Somecentresconsiderobtainingaliverbiopsywhentherehasbeen

threeconsecutiveelevationsinPIIINPovera12monthperiod.Thedecisionto

stoptherapywouldbebasedonarisk/benefitassessmentineachindividual.

• History should be taken at each monitoring visit for new dyspnoea as a

screening assessment for pneumonitis or pulmonary fibrosis. Further

investigationmayrequirehigh-resolutionCTandlungfunctiontestsdetailing

lungvolumeandgastransfercoefficients.

• The antifolate effect of some drugs, particularly co-trimoxazole and

trimethoprim,mayincreasethetoxicityofMTX.

• MTXconcentrationcanbeincreasedslightlybyregularNSAIDs.

Mycophenolatemofetil

MMFhasbeenroutinelyusedinorgantransplantation.MMFhasalsobeenused

in the control of lupus nephritis, myositis, and vasculitis, often in ‘remission

maintaining’orin‘steroid-sparing’roles.

• MMFisthe2-morpholinoethylesterofmycophenolicacid(MPA).MPAisa

potent, selective, uncompetitive and reversible inhibitor of inosine

monophosphatedehydrogenase,andthereforeinhibitsthedenovopathwayof

guanosinenucleotidesynthesiswithoutincorporationintoDNA.

• BecauseTandBlymphocytesarecriticallydependentfortheirproliferation

onde novo synthesis of purines whereas other celltypescanutilize salvage

pathways, MPA has more potent cytostatic effects on lymphocytes than on

othercells.

• MMFdoseis1–3g/day(300–600mg/m

inchildrenandadolescents)orallyin

divideddoses,startingat500mgdailyforthe7days,then500mgtwicedaily

for7days,buildingsequentiallybyanadditional500mgdailyevery7days

overtheensuingweekstoanoptimal/tolerabledose.

• MMF is monitored using FBC, LFTs, and urinalysis (screening for

nephrotoxicity).

• MaindruginteractionsofMMF:

• Decreased absorption of MMF can occur with antacids (magnesium and

aluminiumhydroxide)andcolestyramine.

• Increasedconcentrationmayarisewiththeuseofaciclovir.

• ConcomitantNSAIDsmayaddtonephrotoxicrisk.

Sulfasalazine

Sulfasalazine (SSZ) is a useful csDMARD in treating peripheral and

enteropathicSpA andRA. Thereis weakto moderateevidenceforefficacyin

PsA.

• A SSZ is an active substance although most is converted by bacteria in the

colon into the active metabolites colon where bacteria split the drug into

sulfapyridine(SP)andmesalazine(ME).MostSPisabsorbed,hydroxylated,

orglucuronidatedandamixofunchangedandmetabolizedSPappearsinthe

urine. Some ME is taken up and acetylated in the colon wall. SSZ is also

excretedunchangedinthebileandurine.

• OverallSSZanditsmetabolitesexertimmunomodulatoryeffects,antibacterial

effects, effects on the arachidonic acid cascade, and alteration of activity of

certainenzymes.

• SSZtherapeuticdoserangeisfrom1.5gto3gdailyindivideddoses.The

dose in children and adolescents is 30-50mg/kg/day (maximum 3g daily) in

twodivideddoses.

• A dose increment regimen is typically advised starting at 500 mg/day

(approximately 10mg/kg in children) for 7 days and increasing by an

additional500mgdailyevery7daysovertheensuingweekstotheplanned

therapeuticdose.

• Patientsshouldbewarnedthatbodilyfluidsmayturnadarkeryellow/orange

andnottobealarmed.

• SSZmayleadtostainingofcontactlenses.

• Theenteric-coatedformulationiswelltolerated.SSZalsocanbeprescribedin

liquidform.

• SlowacetylatorsofSSZmaydevelopadrug-inducedlupus-likesyndrome.It

isnotnecessarytocheckacetylatorphenotypesincethedrugwillhavebeen

stoppedwhensuspicionoccurs.

• The majority of patients who develop SSZ side effects do so in the first 3

monthsoftakingthedrug.Correspondingly,laboratorytestmonitoringcanbe

relaxedandinmostguidelines,inlong-termuse,isonlyadvisedonceevery3–

6months.

• Ahistoryofhypersensitivitytosulfonamides/co-trimoxazoleshoulddeteruse

ofthedrug.

• SSZcontainsinpartsalicylicacidthusitcanproduceaspirinandNSAID-like

sideeffects(e.g.pepticlesions,interstitialnephritis,tinnitus).

• SSZcanreducespermcountandviabilitydirectlyandcanaffectfertilityby

reducinggonadotrophinproduction.

• SSZincombinationwithAZAmaypotentiatetheriskofbonemarrowtoxicity

fromeitherdrug.

TargetedsyntheticDMARDs(tsDMARDs)

Tofacitinib

Tofacitinib is a JAK (Janus kinase) inhibitor that impairs the JAK-STAT

signallingpathwayandaffectsimmunecellfunction.

• Tofacitinib has been shown to be effective in RA as monotherapy or co-

therapywithMTX.Trialshavealsotakenplaceinpsoriasisandcolitis.

• IthasbeenapprovedintheUSAfortreatmentofRAanditisbeingreviewed

byNICEintheUK.

• Itisgivenorally5mgtwicedailyfortheimmediate-releasetabletor11mg

oncedailyfortheextended-releasetablet.

• Thedoseneedstobeadjustedinmoderaterenalandhepaticimpairmentto5

mgoncedailyandavoidedinsevereimpairment.

• It is not recommended to co-prescribe tofacitinib with strong CYP3A4

inducerssuchasrifampicinandthedoseshouldbereducedwithconcomitant

useofCYP3A4inhibitors.

• TestandtreatmentforlatentTBisrecommendedpriortocommencementof

tofacitinib.

• Lymphomaandothermalignanciesincludingskincancershavebeenreported.

• EBV-associated post-transplant lymphoproliferative disorders have been

reported in renal transplant patients treated with tofacitinib and concomitant

immunosuppressants.

• Bone marrow suppression, lipid abnormalities, and hepatotoxicity can occur

and hence monitoring should include FBC, lipid profile, and liver function

tests.

• GI perforation has been reported in clinical trials so use with caution in

patientsatincreasedrisksuchasdiverticulitis.

Apremilast

Apremilastisaphosphodiesterase4(PDE4)inhibitor,whichresultsinincreased

intracellularcAMP levelsand consequentlyaffectsthe regulationof numerous

inflammatorymediatorsincludingdecreasingtheexpressionofTNFα:

• ApremilastislicensedfortheuseofPsA.

• ItisapprovedintheUSAandEuropebutitisyettobeapprovedbyNICEas

‘cost-effective’intheUK.

• Apremilastisgivenorallyinitiallyat10mginthemorningonday1,titrate

upwardbyadditional10mgperdayondays2to5andmaintenancedoseof

30mgtwicedailyfromday6.

• Doseneedstobeadjustedwhencreatinineclearanceis<30mL/min.

• Apremilast maycauseweight lossanddiscontinuation should beconsidered

withsignificantweightloss.

• Neuropsychiatric effects such as depression and mood changes have been

reported.

BiologicalDMARDs

Anti-TNFαtherapy

TNFα is a potent pro-inflammatory cytokine and the levels are elevated in

autoinflammatory/autoimmuneinflammatoryconditions.

• Atpresent,therearefivemainanti-TNFαbDMARDsavailable:adalimumab,

etanercept,certolizumabpegol,infliximab,andgolimumab.

• Infliximab is a chimeric human–murine anti-TNFα monoclonal antibody,

etanerceptarecombinanthumanTNFαreceptorfusionprotein,certolizumab

pegol a pegylated Fab fragment of a fully humanized anti-TNF monoclonal

antibody, adalimumab and golimumab are both fully humanized anti-TNFα

monoclonalantibodies.

• InfliximabisadministeredbyslowIVinfusionat0,2,4,andevery4–8weeks,

thereafterdependingonresponse.

• Etanercept is administered by SC injection and can be given once (50 mg)

insteadoftwice(25mg)weekly.

• CertolizumabpegolisgivenbySCinjectionatadoseof400mginweeks0,

2,and4,followedbyadoseof200mgevery2weeks.

• Adalimumab is given by SC injection: 40 mg (20mg if the child weighs

<30kg)every2weeks.

• Golimumabis givenbySCinjectionatadoseof50mgevery4weeks.An

increaseindoseto100mgevery4weekscanbegiveninpatientswhoweigh

>100kg.

• Withallanti-TNFαagents,co-administrationwithMTXisrecommendedfor

treatingRAandJIAwhenMTXistoleratedasthishasbeenshowntoincrease

efficacy. Inaddition,MTX usewithinfliximabandadalimumab reducesthe

riskofantibodiestotheanti-TNFagent.

• ForefficacyalonethereappearstobenoadditionaleffectofaddingMTXto

anti-TNFαtherapyforPsAorAS/axSpA.

• For RA patients who cannot take MTX, adalimumab, etanercept and

certolizumabpegolcanbeusedasmonotherapy.

• Notably,andparticularlyinPsAandaxSpA/AS,thereisevidencethatpatients

mayrespondtoasecondanti-TNFαifthereisaninadequateresponsetoafirst

therapy.

• In the UK, anti-TNFα is restricted by criteria for use (NICE has published

guidelinesforNHSusebasedoncost-effectivenessassessments;Table23.9).

• Infliximab has been used to treat conditions (‘off-licence’) such as Behçet’s

disease(see Chapter18).

Table 23.9 Summary ofUK (NICE) guidelinesfor the useof the anti-TNFα therapyin RA in NHS

practice

1 PatientswithclinicaldiagnosisofRA:‘recentonset’(diseaseduration

ofupto2yearsandestablished(>2years)

2 ADiseaseActivityScore(DAS28)of>5.1

3 Adequatetrialofatleast2conventionalDMARDs,oneofwhichshould

bemethotrexate.Anadequatetrialisdefinedas:

Treatmentforatleast6months,withatleast2monthsatstandardtarget

dose(unlesstoxicity)

Treatment for <6 months where treatment was withdrawn due to

intoleranceortoxicity, normally after atleast 2 months oftherapeutic

doses

4 Exclusioncriteria:activeinfectionorhighriskofinfection.Malignantor

pre-malignantstates

5 Criteriaforwithdrawaloftherapy:adverseeventsorinefficacy

6 Analternativeanti-TNFαtherapymaybeconsideredforpatientsinwhom

treatmentiswithdrawnduetoanadverseeventbeforetheinitial6-month

assessmentofefficacy

Informationtakenfrom https://www.nice.org.uk/guidance/TA375and

https://www.nice.org.uk/guidance/CG79.

Anti-TNFα:cautionsandmonitoring

AlltheassessmentandmonitoringprinciplessetoutinTable23.7,Table23.8,

and Box 23.2 apply to bDMARDs as much as they do to csDMARDs,

particularlytheassessmentofinfectionandmalignancyrisk.

• Active bacterial or severe viral infection and current/recent malignancy are

exclusion criteria for treatment with anti-TNFα. Paediatric judgment is

requiredinchildren.

• Anti-TNFαshouldnotbegiventopatientswithahistoryofmultiplesclerosis

orsevereheartfailure(NYHAgrade3or4).

• Guidelines for using anti-TNFα therapy in pregnancy have recently been

published(Table23.10).

• Commonreactionsincludeheadache,nausea,andinjection-sitereactions.

• Serious bacterial infections have been reported, and patients with active

infectionshouldhavetheirtreatmentstopped.

• For patients at risk of recurrent infection (e.g. in-dwelling urinary catheter,

immunodeficiency states) it is usually recommended to avoid anti-TNFa

therapy.

• Otherreportedsideeffectsincludedemyelination,worseningofheartfailure,

lupus-likesyndromes,andblooddyscrasias.

• ReactivationofTBhasbeenreportedmainlywithinfliximabandadalimumab

use (3–4× increased risk compared with etanercept) and most commonly

within3monthsofbeginningoftreatment.PatientsshouldbeassessedforTB

risk.

• ThereareguidelinesforassessingriskandmanagingTBinfectioninpatients

duetostartanti-TNFαtherapy(e.g.BritishThoracicSocietyavailableat:

http://www.brit-thoracic.org.uk). Use of anti-TNFα therapy is not

contraindicatedbutpatientsmayrequireupto3–6months’treatmentforlatent

TB.

• Thelong-termsafetyofanti-TNFαespeciallywithregardtomalignancyisnot

known. It is well known that RA patients have a 2× risk of developing

lymphoma compared with the general population. Debate continues as to

whetherreports oflymphomainRA patientson anti-TNFαtherapyreflect a

realdrugeffectortheknownincreasedincidenceoflymphomainRApatients.

• There is no increased risk of developing solid tumours. However, there

appearstobeanincreasedriskofsomeskincancersespeciallymelanomaand

hencepatientshouldbeadvisedonpreventiveskincareandclosemonitoring

ofskin.

B-celldepletiontherapy

BcellsplayanimportantroleinthepathogenesisofRAandotherautoimmune

conditions generating antibodies and, through their surface receptors, in

processingandpresentingantigentoTcells.

Rituximab

RTXisachimericmonoclonalantibodyagainsthumanCD20thatispresenton

developingBcellspriortotheplasmacellstage.AdministrationofRTXleadsto

rapid CD20 positive B-cell depletion in the peripheral blood. Normal B-cell

repopulation (measured by monitoring the CD19 count) occurs variably but

typicallyoverthenext6–9months.

• RT.RCTshaveshownthatinRF-positiveRApatientswhohavefailedseveral

csDMARDs, a course of RTX (two infusions, 1 g 2 weeks apart with

methylprednisolone infusions) achieves a significant improvement in RA

diseaseactivityat6monthscomparedtoMTXalone.

• InRA,thetimetonextinfusionregimencanrangefrom6to18months,but

hasameanof9months.

• There is concern about persistent hypogammaglobulinaemia after repeated

courses of RTX. The possibility of increased risk of infection with

hypogammaglobulinaemia should be discussed with patients before re-

treatment.

• IntheUK,NICEallowsRTXtobeusedwithMTXinthetreatmentofsevere

RA forNHSpatients, wherethere hasbeenan inadequateresponseto other

DMARDsandoneormoreotheranti-TNFαtherapy.

• Open-labelstudiesin SLEinitiallysuggestedefficacyofRTX,withbenefits

extending to 6 months; however, a RCT failed to show that RTX was

beneficialtopatientswithmoderate-to-severeSLE.

• Repeated RTX infusions in SLE appear to increase BAFF/BLyS (see later),

whichisassociatedwith increasingseverityofpost-treatmentflaresinsome

patients.

• Rituximab is as effective as CYC in the treatment of AAV as induction or

maintenancetherapyandisusedifavoidanceofCYCispreferableorthereis

aninadequateresponsetoCYC.

• There is a growingliterature suggesting benefit ofRTX in other conditions,

e.g.polymyositisanddermatomyositis.

• Theseriousconditionprogressivemultifocalleucoencephalopathy(PML)has

been reported with RTX in a small number of patients. Patients should be

counselledappropriatelybeforetreatment.

• The assessment and monitoring recommended for RTX is similar to that

recommendedforanti-TNFαtherapy.

• A lymphocyte CD19 count can be checked before and 6 weeks after

administeringRTX.Theobservationofitfallingwithtreatmentandthenrising

asthe disease‘flares’ isevidenceinfavourofdrugefficacyandameansof

predictingneedforretreatment.

Belimumab

• Belimumab is monoclonal antibody that depletes B cell by blocking the

bindingofsolubleBAFF/BLyStoreceptorsonBlymphocytes,reducingthe

activity of B-cell-mediated immunity. BAFF/BLyS is a TNF superfamily

member(TNFSF13B)bestknownforitsroleinthesurvivalandmaturationof

Bcells.

• BelimumabmaybeusedinSLEresistanttootheragents.

• Belimumabisgivenasaninfusioninitiallyat10mg/kgevery2weeksfor3

dosesandmaintenanceof10mg/kgevery4weeks.

Interleukin-1receptorantagonists

Interleukin-1(IL-1)isapro-inflammatorycytokine.AnakinraisanIL-1receptor

antagonistthatcompeteswithIl-1forbinding.

• Anakinraisgivenby100mg(inchildren1–4mg/kg)SCinjectiondaily.

• RCTs have shown that anakinra is more effective than placebo in RA but

smallerdiseaseresponsesareevidentcomparedtoanti-TNFα.

• AnakinraisusedintreatingMAS,systemiconsetJIAandautoinflammatory

conditions, e.g. TNF receptor-1 associated periodic syndrome (TRAPS),

SAPHOsyndrome,andadult-onsetStill’sdisease(see Chapter18).

• Sideeffectsincludeinjection-sitereactions,blooddyscrasias,andinfection.

• Anakinrashouldnotbeusedtogetherwithanti-TNFαtherapies.

• Clearanceisreducedinrenalimpairment.

Interleukin-6inhibition

Interleukin-6(IL-6)isapotentpro-inflammatorycytokineandmediatorofthe

acute-phaseresponse.HighlevelsofIl-6havebeenfoundinserumandsynovial

fluidofRApatients.

• Recent work has shown that both upstream and downstream signalling

pathwaysforIL-6differbetweenmyocytesandmacrophages.

• ItappearsthatunlikeIL-6signallinginmacrophages,whichisdependenton

activation oftheNFκB signalling pathway, intramuscular IL-6expressionis

regulatedbyanetworkofsignallingcascades,includingtheCa

/NFAT and

glycogen/p38MAPKpathways.

• IL-6 signalling in monocytes or macrophages, creates a pro-inflammatory

response, whereas IL-6 signalling in muscle (independent of a preceding

TNFαresponseorNFκBactivation)isanti-inflammatory.

Tocilizumab

TocilizumabisahumanizedmonoclonalantibodyspecificfortheIl-6receptor.It

islicensedforuseintreatingRA,systemicJIA,andCastleman’sdisease.

• TocilizumabisgivenbymonthlyIVinfusionatadoseof8mg/kg.Itisalso

availableasSCinjectionat162mgeveryotherweekifweightis<100kgor

162mgeveryweekifweight>100kg.Inchildren>2ywithsystemicJIAthe

doseis:weight<30kg–12mg/kgeverytwoweeksbyinfusion;weight>30kg–

8mg/kg every two weeks. In children with polyarticular JIA the dose is 8–

10mg/kgevery4weeksbyinfusion.

• Tocilizumab is effective in controlling disease and limiting radiographic

progressioninRApatientsinwhomMTXandanti-TNFαtherapyhavebeen

ineffectiveornottolerated.

• Tocilizumab can be used as monotherapy if MTX is not tolerated or

contraindicated.

• Tocilizumab is currently under trial for use in large vessel vasculitis and

uveitis.

• Lipids should be monitored 6-monthly given the association with drug-

inducedhyperlipidaemia.

• Bone marrow side effects are more frequent in the first few months of

treatment.FBCandliverfunctiontestsshouldbemonitoredmonthly.

BiologicDMARDstargetingTh17cellactivation

Commontoanumberofconditions,Th17cellactivationisdrivenbyIl-12and

Il-23, which triggers the activated T-cell to produce Il-17 and elaborate other

cytokines, whichhavedownstream pro-inflammatory effects in varioustissues

then having tissue-specific effects. Diseases where Th17 cell activation is

pertinentincludepsoriasisandtheSpAs(see Chapter8).

Ustekinumab

Ustekinumab is a human monoclonal antibody directed against the pro-

inflammatory cytokines IL-12 and IL-23. Ustekinumab binds to the (common

sequence) p40 subunit of both cytokines so that they cannot activate their

receptorsonTh17cells.

• In PsA, ustekinumab has shown superior efficacy in treating synovitis,

dactylitis and enthesitis compared to MTX alone. Responses are positive in

bothanti-TNFαnaïveandanti-TNFαtreatedpatients.

• UstekinumabisgivenbySCinjection:dose45mg(weight<100kg)or90mg

(weight>100kg)atweek0,4,and12-weeklythereafter.

• IntheUK,NICEhasapproveduseforNHSpatientswithPsAwhendiseaseis

stillactivedespitetreatmentwithDMARDsandifanti-TNFαhasfailedoris

contraindicated.

• Commonsideeffectsincludeinfection,fatigue,andheadache.

• Uncommon side effects include exfoliative dermatitis, encephalopathy, and

facialpalsy.

Secukinumab

SecukinumabisarecombinantfullyhumanmonoclonalIgG1kantibodywhich

binds Il-17A inhibiting its receptor binding. It is licensed for use in treating

plaquepsoriasisandhasshownefficacyintreatingAS.

• For AS, the recommended dose is 150 mg once weekly subcutaneously at

weeks0,1,2,and3;followedbyamaintenancedosemonthlyfromweek4.

• Secukinumab may be effective in some adults with PsA whose response to

csDMARDshasbeeninadequate.Casereportssuggesteffectivityinpatients

definedashavingaxSpA.

• ItshouldbeusedwithcautioninpatientswithCrohn’sdiseaseasitcancause

exacerbationofinflammatorydisease.

OtherbiologicDMARDs

Abatacept(CTLA4-Ig)

Abatacept disrupts the CD80/86 co-stimulatory signal required for T-cell

activationbycompetingwithCD28forbinding.

• AbataceptiseffectiveinpatientswithRAwhosediseaseisnotcontrolledwith

oneormorecsDMARDsincludingMTXoranti-TNFα.

• AbataceptisadministeredIVatadoseaccordingtobodyweight;500mg(<60

kg),750mg(60–100kg),and 1000mg(>100kg)atweeks0, 2,and4and

thenmonthlythereafter.Inchildren<75kgthedoseis10mg/kgbyinfusionin

thesamefrequencyasadults.

• Abatacept can also been given SC at a dose of 125 mg once weekly. In

children25–50kgthedoseis87.5mgandif>50kganadultequivalentdoseis

used.

• Arecentsystematicreviewhasshownthattheincidenceofseriousinfections

waslow,andcomparedwithplacebowasequal.

TheuseofbDMARDsinpregnancyandbreastfeeding

There is a paucity of data on the effect of bDMARDs in pregnancy and in

women breastfeeding but consensus opinion is summarized in a number of

guidelines (e.g. UK BSR guidelines available at:

http://www.rheumatology.org.uk/resources/guidelines/default.aspx).

Table23.10Biologicsinpregnancyandbreastfeeding

Disclaimer: all readers should refer to their own local practice guidelines. Information here is

incompleteandbriefandaskeletonguideonly.

Drugs Effects

Infliximab Pregnancy: compatible peri-conception and with first

trimester,stopat16weeks

Breastfeeding:compatible

Etanercept

Adalimumab

Pregnancy: compatible peri-conception and with first and

secondtrimester,stopatthirdtrimester

Breastfeeding:compatible

Certolizumab Pregnancy: compatible peri-conception and throughout

pregnancy

Breastfeeding:compatible

Golimumab Pregnancy:nodatatorecommend

Breastfeeding:nodatatorecommend

Rituximab Pregnancy:stop6monthsbeforeconception

Breastfeeding:nodatatorecommend

Tocilizumab Pregnancy:stop3monthsbeforeconception

Breastfeeding:nodatatorecommend

Anakinra

Abatacept

Belimumab

Pregnancy:nodatatorecommend

Breastfeeding:nodatatorecommend

References

1.SmolenJS,vanderHeijdeD,MacholdKP,etal.Proposalforanewnomenclatureofdisease-modifying

antirheumaticdrugs.AnnRheumDis2014;73:3–5.

2.BaetenD,SieperJ,BraunJ,etal.Secukinumab,aninterleukin-17Ainhibitor,inankylosingspondylitis.

NEnglJMed2015;373:2534–48.

Othermedications

Drugsusedintreatingosteoporosis

The treatment of osteoporosis is described in  Chapter 6. A summary of

currentlylicensedosteoporosisdrugsisshowninTable23.11.

Table23.11Drugsusedinthetreatmentofosteoporosis

Drugs Dose Comments

Alendronic

acid

70mgorally

onceweekly

Fracture reduction broadly 20–40% for oral

bisphosphonates over 3–5 yrs and 70% for

vertebralfracturereductionforzoledronateat

3yrs.Initialtreatmentcourseis3–5yrs

Optimum response occurs if not calcium and

Risedronate 35mgorally

onceweekly

Ibandronic

acid

150mgoral

monthlyor3

mgIVevery3

months

vitaminDdeficient

Avoidallbisphosphonatesinrenalimpairment

(estimatedGFR<30mL/min)

Oral bisphosphonates can cause dyspepsia,

oesophagitis,andoesophagealulcers

Oral bisphosphonates must be taken with

water,fastingandatleast1hrbeforefoodor

liquid(otherthanwater)

Regularreviewforadherenceisadvisable

Atypicalfemoralfractures have been reported

—but rarely and chiefly with long-term

treatment

Osteonecrosisofthejawisveryrare

Zoledronic

acid

5mgIVonce

yearly

Denosumab 60mgSC

injectiononce

every6

months

Fracture reduction risk about 70% over 3 yrs

forvertebralfractures

Side effects include cellulitis, urinary tract

infection, and upper respiratory tract

infection

Hypocalcaemia can occur and the risk is

increased if estimated GFR <30 mL/min—

givecalciumsupplementsandmonitorserum

calcium

Atypicalfemoralfracturesandosteonecrosisof

jaw(advisedentalcheck-up)arerarebutcan

occur

Strontium

ranelate

2goraldaily;

avoidfoodfor

2hrsbefore

and2hrsafter

RCTsshowedfracturepreventionafter3yrsof

continuous use. Continued use to 8 yrs

suggestedmaintainedfractureprevention

Sideeffects:GI;nowusedsparinglybecauseof

increased risk of cardiovascular disease and

venous thrombosis. Use banned in some

countries

Teriparatide 20micrograms

SCinjection

dailyfor2

years

Side effects include GI disorders, palpitation,

hypercalcaemia,myalgia

Contraindicated in hypercalcaemia, skeletal

malignanciesorbonemetastases,Paget’s,and

previousradiationtotheskeleton

Avoidinsevererenalimpairment

DrugsusedinthetreatmentofRaynaud’sdiseaseandpulmonaryartery

hypertension

The treatment of Raynaud’s disease (RD) and pulmonary artery hypertension

(PAH)associatedwithSSclisdescribedin Chapter13.Table23.12providesa

summaryofthedrugsused.

Table23.12DrugsusedinthetreatmentofRaynaud’sdisease(RD)andpulmonaryarteryhypertension

(PAH)

Drugs Adverseeffects

Nifedipine:5–20mgthreetimesadayfor

RD.Startdoselowwithdoseadjustments

followingresponse

Amlodipine5–10mgdailyforRD

Oedema,hypotension,

headache,nausea

Losartan:25–50mgoraldailyforRD Hypotension,

hyperkalaemia

Fluoxetine:20–40mgoraldailyforRD SeeSNRIcautions, p.658

andTable23.5,p.657

TopicalGTN:availablein5mg/24hrs.For

RD.Applytoaffectedareaforuptill12hrs

Hypotension,headache,

applicationsitereactions

Sildenafil:25–50mgorallythreetimesaday

forRD,or

Tadalafil:40mgorallydaily.

Reducedosesinrenalandhepatic

impairment

Hypotension,priapism,

headache,flushing,diarrhoea,

visualdefects

Iloprost(prostacyclinanalogue)

NebulizedformforPAH.Firstinhaleddose

shouldbe2.5microgramsincreasedto5.0

microgramsiftoleratedandgiven3–4-

hourly.Typically,6–9doses/daybutnomore

than45micrograms/dayadvisable.

IVinfusionforPAHinitially0.5ng/kg/min

for30minsthenincreasedatintervalsof30

Hypotension,headache,jaw

orlimbpain.Monitorpulse,

bloodpressure,andoxygen

saturation.Ifeffectssevere

considerreducingdoseor

stoppinginfusiontemporarily

andrestartingatlowerdose

minsinstepsof0.5ng/kg/minupto2

ng/kg/min.Exactinfusionrateshouldbe

calculatedonbodyweighttoeffectinfusion

raterangeof0.5–2ng/kg/min.Finaldose

givenover6hrsdaily(e.g.over5days).

Bosentan:forPAH.Initially62.5mgtwice

dailyorallyincreasedafter4weeksto125

mgtwicedaily.

Macitentan:forPAHonly:10mgoraldaily.

Ambrisentan:forPAHonly:5mgoraldaily,

increasedifnecessaryto10mgdaily

Lowhaemoglobin(Hb)so

monitorHbbeforeandduring

treatment.AlsocheckLFTsat

startandatmonthlyintervals

ontreatment

Riociguat:forPAHonly;initially1mgthree

timesadaydailyfor2weeks,increasedby

0.5mgeachdoseevery2weeksupto

maximum2.5mgthreetimesaday

Hypotension—reducedoseif

systolicBPfalls<95mmHg

Drugsusedintreatinggoutandhyperuricaemia

The management of gout is described in Chapter 7. The treatment of acute

goutiswithNSAIDs,colchicine,andGCs.Urateloweringdrugsareusedifgout

issevere(e.g.chronic/tophaceous)and/orrecurrent.SeealsoCochranereview

CD010069( http://www.cochranelibrary.com).

Colchicine

• Colchicineisanti-inflammatoryandusedingoutandCPPDdiseaseforboth

acuteattacksandchronicdisease.

• ColchicinecanalsobeusedlongterminthetreatmentofBehçet’sdiseaseand

familialMediterraneanfever.

• Itisgiveninitiallyatadoseof0.5mgtwicedailyinacutegoutandCPPD.

Thedoseinchildrenis0.3–2.4mginonetotwodivideddosesincreasingin

0.3mg/dayincrementsastolerated.

• Dose should be adjusted with renal impairment and avoided completely in

severerenalimpairment(estimatedGFR<10mL/min).

• Dose is increased to three or four times daily but is limited by dose-related

diarrhoea.

• Colchicine frequently causes nausea, vomiting, and abdominal pain. Larger

doses may cause profuse diarrhoea, GI haemorrhage, skin rashes, and renal

andhepaticdamage.

• Theraresideeffectsaremyopathy,rhabdomyolysis,alopecia,withprolonged

treatment,bonemarrowsuppressioncanoccur.

Allopurinol

• Allopurinolisaxanthineoxidaseinhibitorwhichisusuallythefirst-lineurate-

loweringdrug.

• Initiate at 100 mg orally daily then adjust according to plasma uric acid

concentrationeachmonthby100mgtomaximum900mgdaily.

• The dose should be adjusted down in renal impairment, and in severe renal

impairment,reducedailydosebelow100mg.

• Thedoseshouldbechangedinversely (e.g.each4–6weeks)titrated against

urateleveltoatarget<360nmol/Lorinseveredisease<300.

• About 2% of patients develop a rash which is typically pruritic and

maculopapular.Ifmild,withdrawtherapyandre-challengecanbeundertaken

withcautionbutdiscontinuepromptlyifrecurrence.

• LifethreateninghypersensitivityreactionssuchasStevens–Johnsonsyndrome,

toxic epidermal necrolysis, or drug rash with eosinophilia and systemic

symptoms (DRESS) can occur rarely and re-challenge should not be

undertaken.

• GI disorders, e.g. nausea and diarrhoea, are uncommon and bone marrow

suppressionisrareeveninhighdoses.

• AllopurinolcaninterferewiththemetabolismofAZAand6-MP,potentiating

sideeffects.ThedoseofAZAor6-MPshouldbe~25%oftheusualdoseif

theyaregivenconcurrentlywithallopurinol.

• Otherinteractionsincludewarfarin(monitorINR),theophylline(monitordrug

level),andACEinhibitors(haematologicalreactions).

Febuxostat

Febuxostat is a non-purine xanthine oxidase inhibitor used to treat

hyperuricaemia.Itisappropriateforpatientswhoareallergictoallopurinol,do

not reach the target uric acid level with maximal allopurinol doses, or have

severerenalinsufficiency.

• Febuxostatisinitiatedat80mgorallydailythenincreaseto120mgdailyafter

2–4weeksifserumuricacid>6mg/dL.

• Themostcommonsideeffectsarediarrhoea,nausea,headache,liverfunction

testabnormalities,andrash.

• Severe hypersensitivity reactions such as Stevens–Johnson syndrome, toxic

epidermalnecrolysis,orDRESSoccurbutarerare.

• Mild liver function abnormalities were observed in 5% in clinical studies,

hence checking LFTs is recommended before starting febuxostat and

periodicallythereafter.Inknownmildhepaticimpairment,thedoseisreduced

to40–80mgdaily.

• Febuxostat is not advised for people with ischaemic heart disease or heart

failurebecauseinitialtrialsshowedahigherincidenceofcardiovascularside

effects fromfebuxostatcomparedwithallopurinol; however,theobservation

hasnotbeensubstantiatedinfurthertrials.

• Febuxostat can interfere with metabolism of AZA and 6-MP and hence

concomitantuseisnotrecommended.

Probenecid

Probenecidisauricosuricagent,whichiseffectivebyalteringrenalhandlingof

urate and increasing urine excretion. It has been used to increase the

concentrationofsomeantibiotics.

• The recommended dose is 250 mg oral twice dailyfor1weekand500mg

twicedailythereafter.

• Probenecidshouldnotbestarteduntilafteranacuteattackofgout.

• In some countries, including the UK, probenecid is only available from

‘special-order’manufacturersordistributors.

• Itisimportanttoensureadequatefluidintake.

• Probenecid is contraindicated in patients with a history of blood disorders,

renalstones,andrenalimpairmentwhereestimatedGFRis<30mL/min.

Sulfinpyrazone(sulphinpyrazone)

Sulfinpyrazoneisauricosuricagent.Itshouldnotbestartedduringanacutegout

attack.

• Sulfinpyrazone is initiated at 100–200 mg orally daily with food increasing

over2–3weeksto600mgdailyuntiltargetserumuricacidconcentrationis

reachedandthenreducedtomaintenancedosewhichmaybeaslowas200mg

daily.

• Dose shouldbe reducedin renalimpairment.Itshouldbeavoidedinsevere

renalimpairmentandisineffectiveifGFRis<30mL/min.

• Itiscontraindicatedinpatientswithhistoryofblooddisorders.

• RegularFBC/CBCmonitoringisadvisableassulfinpyrazonecancauseblood

disorders.

• Caution is advised in prescribing wherethereiscardiac,cerebrovascular, or

hypertensiondiseaseasthedrugmaycausesaltandwaterretention.

• Other side effects include GI disturbances and ulceration, allergic skin

reactions,acutekidneyinjury,andhepatitis.

• Seealso: http://www.medicines.org.uk/emc/medicine/26935.

Benzbromarone

Benzbromaroneisauricosuricagentandnon-competitiveinhibitorofxanthine

oxidase,availableinEurope.BenzbromaronealsoinhibitscytochromeCYP2C9,

whichisresponsibleformetabolizinganumberofdrugsincludingdrugswitha

narrowtherapeuticindexsuchaswarfarinandphenytoinandotherdrugssuchas

tolbutamide,losartan,andsomeNSAIDs.

• Benzbromarone offers advantages over some uricosuric drugs as it may be

saferandbettertoleratedinpatientswithrenalinsufficiency.

• Liverfunctionmustbemonitoredfordrug-inducedhepatitis;fulminantliver

failurehasbeendescribed.

• Given itseffectsonCYP2C9cautionwith co-prescribing,any medicationis

mandatory.

Rasburicase

Rasburicase is a recombinant uricase/urate-oxidase enzyme produced by

genetically modified Saccharomyces cerevisiae strain. Urate oxidase exists in

manymammalsbutdoesnotoccurinhumans.

• Rasburicase catalyses enzymatic oxidation of uric acid into a metabolite,

allantoin,whichis5–10×moresolublethanuricacid,withCO

andhydrogen

peroxideasby-productsinthechemicalreaction.

• Rasburicase is licensed in the USA and Europe for treatment of acute

hyperuricaemia associated with tumour lysis syndrome in patients receiving

lymphomaorleukaemiachemotherapy.

• Therecommendeddoseis0.2mg/kg/daygivenasaonce-daily30-minuteIV

infusionin50mLof0.9%saline.

• Thedurationoftreatmentmaybeupto7days,theexactdurationshouldbe

based upon adequate monitoring of uric acid levels in plasma and clinical

judgement.

• Long-termuseforhyperuricaemiaassociatedwith goutat dosesof 0.15–0.2

mg/kgisbeinginvestigated.

Pegloticase

Pegloticase is a recombinant porcine-like uricase and like rasburicase it

metabolizesuricacidtoallantoin.

• Pegloticaseispegylatedtoincreaseitseliminationhalf-lifefromabout8hours

to 10–12 days and to decrease the immunogenicity of the foreign uricase

protein.Sopegloticaseisgivenevery2–4weeks.

• Pegloticasemightbeconsidered*forpatientswithseveregoutinwhomother

urate-loweringagentshavebeenineffective.

• Pegloticaseproducesrapidreductioninsignsandsymptomsofgout.

• PegloticaseisgivenasanIVinfusion,8mgevery2weeks,infusedover>2

hours with premedication to decrease infusion reactions including oral

paracetamol,hydrocortisone,andantihistamine.

• Allpatientsshouldbegivenprophylaxisforpreventionofacutegoutduring

thefirst6monthsoftreatment.

• Trials haveshown thattheurate-lowering effect canbe attenuatedorlost in

somepatientsduetohightitreanti-pegloticaseantibodies.

• IntheUK,pegloticasehasnotbeensanctionedforuseingoutbyNICEfor

NHS-treated patients, citing poor cost-effectivity but also noting reported

severeanaphylaxisreactionshaveoccurredwithit.

• * In 2016, the European Commission withdrew the marketing authorization

forpegloticaseintheEU.

Pooledintravenousimmunoglobulin(IVIg)

Pooled IVIg is primarily used as replacement therapy in primary

immunodeficiencyconditions. However,IVIgcan havean immunosuppressive

effect though the mechanism of effect is not precisely known. A number of

theoriesexist.

• Apartfromimmunodeficiency,themainindicationsforIVIgareinGuillain–

Barrésyndrome,myastheniagravis,immunethrombocytopenicpurpura,SLE

(see  Chapter 10), dermatomyositis (see  Chapter 14), and Kawasaki

disease(see Chapter15).

• The typical dosing regimen is 400 mg/kg/day as a single infusion over 2–4

hoursastoleratedandfor5days;or1g/kg/dayfor2days.Thisisrepeated

every4–8weeksforupto6monthsinthefirstinstanceaccordingtoefficacy.

• Side effectsoccur in <5% ofpatientsand most often within 24hoursofan

infusion.

• However, the FDA (USA) requires IVIg products to carry a black box

warning, cautioning that IVIg has been associated with renal dysfunction,

acutekidneyinjury,osmoticnephrosis,anddeath,especiallyintheelderlyor

withsimultaneoususeofothernephrotoxicdrugsorotherpre-existingissues

thataffectthekidneys.

• Sideeffectsatthetimeofinfusionincludeheadache,flushing,chills,myalgia,

wheezing, tachycardia, lower back pain, nausea, and hypotension. If these

occur,theinfusionshould beslowedorstopped.Mostcaseswillrespond to

antihistaminesandIVhydrocortisoneifsymptomspersist.

• Other significant, but rare complications include acute kidney injury,

arteriovenous thrombosis, disseminated intravascular coagulation, transient

serum sickness, transient neutropenia, aseptic meningitis, post-infusion

hyperproteinaemia with pseudohyponatraemia, eczematous dermatitis, and

alopecia.

Resources

AllUK-licenseddrugSPCsareavailableatEMC: http://www.medicines.org.uk

Patientdruginformationavailableat: http://www.arthritisresearchuk.org

Selectivetherapymeta-analysesat: http://www.cochranelibrary.com

Chapter24
Glucocorticoidinjectiontherapy
Introduction
Principlesofinjectiontechniques
Theshoulder
Theelbow
Thewristandhand
Thehipandperiarticularlesions
Thekneeandperiarticularlesions
Theankleandfoot
Relevant anatomical drawings for each region of the body are found in
Chapter3
Introduction
Local anaesthetic and glucocorticoid (GC; ‘steroid’) injection into joints,
tendons,bursae,andsofttissuesisaveryeffectivetreatmentforlocalizedpain
andinflammation.
• Injection offers a local maximal anti-inflammatory effect with minimal
systemicabsorption.
• Asageneralrule,itisrecommendedthatanyonejointshouldnotbeinjected
more than four times in 12 months and there are at least 6 weeks between
injections.
• Theindicationsforlocalsteroidinjectioninclude:
• reductionofinflammation.
• reliefofpainfrominflammatorylesions.
• reliefofinflammationatsitesofnervecompression.
• reducethesizeofnodulesandganglia.
• Thecontraindicationsare:

• absolute: septic arthritis/sepsis, a febrile patient with cause unknown,

seriousallergytopreviousinjection,sicklecelldisease.

• relative: unknown cause of lesion, neutropenia, thrombocytopenia,

anticoagulation,orbleedingdisorder.

• Commonsteroidpreparationsusedinclude:

• hydrocortisone acetate—a short-acting, weak steroid useful for superficial

lesionssuchastendonsandbursae:25mgistypical.

• methylprednisoloneacetate40mg/mL.

• prednisoloneacetate25mg/mL.

• triamcinoloneacetonide10and40mg/mL.

• Thelatterthreeagentsarelong-actingsyntheticglucocorticoids.

• Choiceofstrengthofsteroidremainsempiric.

• Volumeofsteroid/anaesthetic‘accepted’byjointsvaries:

• Smalljointsacceptonlyasmallvolume;thus,forIPJs,MCPJs,MTPJs,and

temporomandibularjoints,0.5mLonlyisappropriate.

• Allotherjointsshouldacceptatleast1mL.

• There may be merit in diluting the steroid in sterile saline, to increase

volumeforbetterdistributioninlargerjoints.

• alternatively,largervolumelevobupivacaine(10mL)isofvalue.

• Potential,thoughuncommon,sideeffects(seealso Chapter23)are:

• exacerbationofpainfor24–48hours.

• septicarthritisandreactivationofTB.

• tissueatrophy(lesslikelywithhydrocortisonethanothers).

• depigmentationofskin.

• anaphylaxis.

• nervedamage.

• tendonrupture.

• osteonecrosis.

• cartilagedamage.

• softtissuecalcification.

• temporaryexacerbationofhyperglycaemiaindiabetes.

Principlesofinjectiontechniques

Theprocedureneednotnecessarilybedoneinasterileenvironment.However,

thereisaneedtomaintainanaseptictechnique.Efficacymaybegreaterusing

US-guided injection but will be more accurate. US should only be done by

appropriatelyqualifiedclinicians.

• Marktheexactspotofneedleinsertion.

• Washhands.Usesterileglovesfortheprocedure.

• Cleantheskinwithpovidone-iodineandallowittodry.

• Anaesthetize the skin (either with local anaesthetic or refrigerant alcohol

spray).Childrenandsomeadolescentsmayrequirealightgeneralanaesthetic

giventheprocedurecanbetraumatic.Analternativeistouselocalanaesthetic

gelpads(e.g.EMLA

patch).

• Insertacleanneedlewithemptysyringeandaspirateback.

• Leavetheneedleinplace,detachthesyringe,andplacethesyringecontaining

steroid/localanaestheticontotheendofanewneedle.

• Insertneedleintositetobeinjected.

• Pull back the syringe plunger again before injecting to confirm placement,

ensuringtheneedleisnotinabloodvessel.

• Introductionofsteroidshouldbeeffortless.Resistanceimpliestheendofthe

needleisinthewrongspace.Stopifitcausesmorepain.

• On completion of the procedure, remove the syringe and needle and throw

awaythe‘sharps’.

• Covertheinjectionsitewithcleangauzeorabandage.

• Restthejointfor24hours(considerupto48hoursforaweight-bearingjoint),

includingusinganon-rigidsplint(e.g.Velcro

attachedsemi-rigidsplintfor

wrist,ormodifiedRobert-Jonesbandagingfortheknee).

• Advisethaticingthearea/jointmayreducepost-injectiondiscomfort,andre-

emphasizepossiblesideeffectsandbenefits.

Theshoulder

Theglenohumeraljoint(forglenohumeraljointsynovitisoradhesive

capsulitis)

US-guidedinjectiontechnique

Itisdifficulttobeconfidentaneedleisplacedintheglenohumeraljointspace

withoutconfirmationimagingwithUS.Thedefaulttechniqueforinjectingthe

glenohumeraljointshouldbewithUS.

• US-guided injection is the gold standard for comparing therapy options in

researchstudies(e.g.steroidinjectionvshydrodilationforadhesivecapsulitis).

• USisprobablynotrequired,however,whenaninjectionisdoneasthesecond

partofalinkedprocedurewhenthefirstpartisaspiratingalargeeffusion(e.g.

inCPPD-pseudogout).

Non-US-guidedinjectiontechnique

SometimesitisnotpossibletoobtainUSanda‘blind’injectionmayneedtobe

done.Itisessentialthatanyoneundertakingtheinjectionshasbeenappropriately

trained or is supervised and is knowledgeable about anatomy and functional

anatomy.

• Theapproachmaybeanteriororposterior.

• The anterior approach is favoured for adhesive capsulitis given the

predominant pathology involves the anterior part of the joint complex

includingcoracoacromialligamentandsubscapularisbursa.

• Theanteriorrouteisundertakenthus:

• Palpatethecoracoidprocessanteriorlyandacromionposteriorly.

• The injectionismade just lateraltothe coracoid withtheneedle pointing

towardstheacromion(see Plate4).

• Theposteriorrouteisdonethus:

• Theclinicianpalpatesthespineofthescapulawiththethumbtoitslateral

endwhereitbendsforwardastheacromion.

• Withtheforefinger,palpatethecoracoidanteriorly.Thelinebetweenfinger

andthumbthenmarksthepositionofthejointline.

• Theneedleisadvancedfrombehind,1cmbelowtheacromion,andtowards

thecoracoid.Thereshouldbenoresistance.

• By either approach, the joint can be injected with relatively large volumes

such as 1 mL (40 mg) methylprednisolone acetate mixed with 5 mL 1%

lidocaine.

• Alongneedleisneeded.

• Withdrawingtheneedleslightlyandredirecting30°upwardwillallowoneto

reachtherotatorcuffwiththesameprocedure.

Subacromialspace(forsubacromialimpingementdisorders)

US-guidedinjectiontechnique

Itisdifficulttobeconfidentaneedleisplacedinthesubacromialspacewithout

confirmationwithUS.Thedefaulttechniqueforinjectingthesubacromialspace

shouldbewithUS.

• USmaybeuseddiagnosticallyand,withappropriatesonographerexperience

andskill,calcificsupraspinatuslesionsandtearscanbeidentified.

• Radiologicalexpertisevariesfromdepartmenttodepartmentandlocaladvice

onchoosingMRIorUSforspecificlesionidentificationwouldbeappropriate.

Non-US-guidedinjectiontechnique

SometimesitisnotpossibletoobtainUSanda‘blind’injectionmayneedtobe

done. It is essential that anyone undertaking such an injection has been

appropriatelytrainedorissupervisedandisknowledgeableaboutanatomyand

functionalanatomy.

• Thesubacromialspaceisinjectedmosteffectivelyfromthelateralaspectof

theshoulder.

• The arm is placed in a neutral position, hanging to the side, and the gap

betweentheacromionandthehumeralheadispalpated.

• A long, narrow-gauge (e.g. 23) needle is directed medially and slightly

posterior(butonahorizontalplane)forabout2–3cm(see Plate5).

• Usuallyavolumeof3–4mLcanbeaccepted(e.g.40mgmethylprednisolone

acetatein1mLwithupto5mL1%lidocaine).

• Advise avoidance of overarm activity or heavy lifting for a few days and

considerarrangingphysiotherapytostart2weeksaftertheinjectiontowork

onrestoringrotatorcufffunction.

Acromioclavicularjoint(ACJ)

TheACJissometimesvery difficulttolocate soUS tohelpmarkthejoint is

desirable. US is somewhat limited in its utility however, given the amount of

bonepresent—usuallyanACJwhichneedsinjectingissomewhatarthriticwith

osteophytesandperiarticularsclerosis—thusinterferingwithUSimagingdata.

• TheACJislocatedbyfollowingtheclaviclelaterallytoaridgeinthebone.

Thejointisoftentendertopalpate.

• Markingthebonyedge/landmarkswithapenwillbehelpful.

• Withthepatient eithersitting orlyingsupine, asmall-gauge needlewith20

mgmethylprednisolone(orequivalent)in0.5mLmixedwith0.5mLof1%

lidocaineisdirectedintothejoint.

Theelbow

Lateralepicondylitis/‘tenniselbow’/commonextensortendonorigin

enthesitis

Pleasesee Chapter3foradviceonclinicalassessmentandmakingadiagnosis.

ThislesionmaybesecondarytotraumaorassociatedwithaSpAconditionor

PsA.

• US imaging is not required. The injection is best placed at the point of

maximumtenderness.Thetargetisusuallyverysuperficial.

• The lateral humeral epicondyle and surrounding tissue is injected with the

elbowrestingonapillow—orsimilar—ontheexaminationtableandflexedat

90°.

• Use hydrocortisone initially 25 mg because other steroid preparations may

causelocalfatatrophyanddepigmentation(asthisisnecessarilyoftenavery

superficialinjectionjustundertheskin).

• Use0.5–1mL1%lidocainemixedwiththehydrocortisone.

• Theinjectionisaimedat45°totheendofthetendonorigin.

• A fair amount of pressure is required for this injection. Efficacy of the

injectionmayrelypartly on disruption oftheperiosteum of the epicondylar

bone.Itisoftenpainful(see Plate6).

• Adviserestandicingpostprocedure.

• Autologousbloodinjectionhasbeenreportedanecdotallyaseffective,though

thetechniqueiscontroversial,convincingdataonefficacyislackingandinthe

UKNHS,thetechniqueisnotrecommended.Guidanceonthisproceduremay

befoundat: https://www.nice.org.uk/guidance/ipg438/.

Medialepicondylitis/‘golfer’selbow’/commonflexortendonoriginenthesitis

Pleasesee Chapter3foradviceonclinicalassessmentandmakingadiagnosis.

ThislesionmaybesecondarytotraumaorassociatedwithaSpAconditionor

PsA.

• US imaging is not required. The injection is best placed at the point of

maximumtenderness.Thetargetisusuallyverysuperficial.

• The medial humeral epicondyle and surrounding tissue is injected with the

elbow extended and resting on a pillow—or similar—on the examination

table.

• Use hydrocortisone initially 25 mg because other steroid preparations may

causelocalfatatrophyanddepigmentation(asthisisnecessarilyoftenavery

superficialinjectionjustundertheskin).

• Use0.5–1mL1%lidocainemixedwiththehydrocortisone.

• Theinjectionisaimedat45°totheendofthetendonorigin.

• The needle is directed to the flexor tendon origin. However, care should be

takentoavoidthegroovejustbehindthemedialepicondyle—thesiteofthe

ulnarnerve.

• Adviserestandicepostprocedure.

Olecranonbursitis

AnolecranonbursacanbeaspiratedandinjectedwithoutUSguidance.Needle

positionisconfirmedbytheaspirationoffluid.

• Theusualcausesofbursitisaregout,infection,andRA.

• Fluid aspirated may reasonably be sent initially for microscopy and culture

andinfectionruledoutbeforesteroidisinjected.

• Alwayssendfluidforpolarizedlightmicroscopy.

• Usetriamcinoloneacetonideormethylprednisoloneatadoseof20–40mgand

adviseicingandrestfor48hours.

• Arrange appropriate follow-up as the olecranon bursa is prone to develop

infectionandmayneedpromptreassessment—advisethepatientaccordingly.

Elbowjoint(e.g.RAsynovitis)

USguidancemayhelpthoughoften,whenthereisaneffusion,needleplacement

isrelativelystraightforwardandcanbeconfirmedbyfluidaspiration.

• Theelbowjointismosteasilyreachedbyaposteriorapproach.

• Use40mgmethylprednisoloneorequivalent,with2–3mL1%lidocaine.

• Injection into a swollen elbow joint after fluid aspiration, when there is a

distendedcapsuleis relativelystraightforward;however, aneffusionmaybe

present and not readily clinically identified—so landmark identification is

necessary.

• Placethethumbonthelateralepicondyleandthethirdfingerontheolecranon.

Thegroovebetweenthetwofingersidentifiesthejointline.

• Injectat90°totheskin,justaboveandlateraltotheolecranon.

• Alternatively,theradialheadcanbepalpated(byfeelingforitduringforearm

pronation/supination)andtheneedlesitedtangentiallyjustunderthecapsule

(ananterolateralapproach).

• Advise rest and icing postprocedureand advise to avoid lifting orgripping

withthearmforafewdays.

• Considerarrangingphysiotherapytoencourage/exercisetheelbowbacktofull

range. There is a high chance, with persistent inflammatory disease in the

elbow,ofprogressiontopermanentlossofelbowextension.

Thewristandhand

Lesionsofthewrist

Radiocarpaljoint

(Pleaseseealso Chapter3.)

• Theradiocarpaljointisbestidentifiedforinjectionwiththepatient’sforearm

supportedandtheirhand—alsosupported—palmdownwiththewristthenin

slightflexion.Atriangulargapisfeltbetweentheradiusscaphoidandlunate.

• Theneedle(smallgauge)ispointeddirectlydownintothespace.

• For most causes of wrist joint inflammation and synovitis, 40 mg

methylprednisoloneacetatewith2mL1%lidocaineisappropriate.

• Image-guidedinjectiontechniqueisnotusuallyneededforthisinjectionasthe

wristspaceiseasilygained.

Carpaltunnelsyndrome

For anatomy and clinical assessment see  ‘Upper limb peripheral nerve

lesions’,pp.124–127.

• The carpal tunnel is injected on the palmar surface of the wrist in the first

crease,midline. Positionthepatient’ssupportedarm,volar sideup andwith

gentleextensionatthewrist;handsupportedalso.

• USguidanceforthisinjectionisnotneeded.

• Sitoppositethepatientsotheir armand handispointingtowardsyourown

position.

• Advancetheneedleat30–45°totheskintowardsthehandforabout2cm(i.e.

towardsyou).

• Improvementofneurogenicsymptomscanbegainedwithhydrocortisone25

mg but most rheumatologists will use triamcinolone 20 mg or

methylprednisoloneacetate20mg.

• Donotuselidocaine.

• Ifthepalmaristendonispresent,theinjectionshouldbesitedjustmedial(i.e.

closertothe‘littlefinger’)tothemidline,byabout1cm.

• Thereshouldbenoresistanceoninjectionornervepain(see Plate12).

Extensorpollicisbrevis/abductorpollicislongus

De Quervain’s tenosynovitis should be injected at the point of maximal

tenderness, advancing the needle through the tendon sheath at a very shallow

angletotheskin,alongthelineofthetendonratherthanat90°tothetendon.

• For functional anatomyandclinical assessment please, see  ‘Wrist pain in

adults’,pp.106–110.

• Inject25mghydrocortisoneinitially.Ifasecondinjectionisrequired,consider

eitherusingmethylprednisoloneoraskingforaUS-guidedinjection.

• AUScanalsoruleoutotherlesionsofthewristandtendonarea(e.g.ganglia,

carpal bone disruption, lateral wrist compartment synovitis, 1st CMCJ

synovialcyst,etc.).

Thesmallhandjoints

Thesmalljointsofthehandarefrequentlyaffectedbysynovitisinpatientswith

chronic inflammatory arthritis. Excess joint fluid and capsule extension and

thickeningcanbeconfirmedbyUS.Effusionsareusuallyunderhighpressure,

thoughcannoteasilybeaspiratedwithoutalarge-gaugeneedle.Useofthelatter,

however,issomewhatbrutalandisbestnotattemptedexceptunderanaesthetic.

• US to confirm joint synovitis is often very useful and there are specific

diagnostic signs potentially available with it (e.g. double contour sign in

detectingMSUcrystalsingoutandcalciumpyrophosphatedepositsinCPPD

arthritis).

• TheMCPJsandPIPJswillnormally‘accept’0.5–1mLofinjectedfluid(e.g.

0.5 mL triamcinolone acetonide or methylprednisolone(20mg)and0.5 mL

1%lidocaine).

• ForMCPJinjection,ensurethepatient’sforearmandhandaresupported.Sit

oppositethepatient.

• Useasmall23-or25-gaugeneedleand‘run’theneedleundertheskinparallel

tothefingerjusttothesideofthemetacarpalhead(Fig.24.1),awayfromyou

butaimingveryslightlytowardsthemetacarpalhead—envisageenteringthe

needleunderthedistendedjointcapsuleandinthisway,avoidcontactingthe

bone(whichwillbepainful).Lookforasubcutaneousblebappearing(asign

ofnotgettingtheinjectionintothejoint).

• Usingthesameneedleaccesspointbutanglingtheneedleappropriately,two

MCPJscanbeaccessedintheoneprocedure(butplanthisandfillthesyringe

withappropriateamountofsteroid/lidocaine).

• TheapproachtoaPIPJisprobablybestundertakenfromtheulnarsideofthe

digitbutthetechniqueissimilartoMCPJinjection.

• The small joint injections can cause discomfort and so advise icing and

NSAIDuseinthepost-injectionperiodfor2–3days.

• Asalwayswithjointinjections,adviseagainstmobilizingthejointtoomuch

inthefirstfewdaysafterinjection.

Fig.24.1Directionofneedleaccesstoaswollenmetacarpophalangealjoint(MCPJ)orproximal

interphalangealjoint(PIPJ).Synovitisswellsthejointcapsulewhichcanbeaccessedbyrunningtheneedle

virtuallyparallelwiththedigitbutslightlyangled.

Thehipandperiarticularlesions

Hipjoint

Hipinjectionis notaroutineoutpatientprocedure.Aspirationandinjectionof

thejointeitherunderUSorfluororadiographicguidanceisrecommended.

Greatertrochanterpainsyndrome

Pain at and around the greater trochanter may be due to referred lumbosacral

pain,gluteusmedius(orothertendon)tearorinsertionaltendonitis/enthesitis,or

alocalbursitis.Lesionscancoexist.

• Imagingtoconfirmthelesionandtoruleoutatendontear—whenaninjection

wouldbecontraindicated—isadvisable.

• Trochantericbursitisorenthesitisatthissite,however,oftenrespondswellto

localsteroidinjection.

• US-guided injection is preferable as the inflamed tissue is deep and ‘blind’

injectionplacementmaybequiteinaccurate.

• However,occasionally‘blind’injectionisappropriate.

• Thepatientshouldlieontheirsidewithkneesdrawnupandthemosttender

arealocatedwithmarkers—e.g.withpenontheskin.

• The usual point of maximum tenderness in gluteus medius enthesitis is just

posteriorandhightothegreatertrochanterapex.

• Thesiteofinjectionisatthepointofmaximaltenderness.

• Theinjectiontargetisdeepandthereforeapragmaticapproachusingalarge

volumeissensible(e.g.5–10mL).

• Use20–40mgtriamcinoloneormethylprednisolone(thus1–2mL)andthen

dilutedwithsterilesalineor1%lidocaine.

• InjectionfailureshouldraisethepossibilityofpoorneedlepositionthusUS-

guidanceonasecondinjectionattemptisadvisable.

Otherlesionsaroundthepelvisandhip

• Meralgia paraesthetica occurs as a consequence of lateral cutaneous nerve

entrapment(see Chapter3)asittraversesthefascia10cmbelowandmedial

to the anterior superior iliac spine. If this spot can be clearly demarcated

because of localized tenderness, steroid injection has a greater chance of

success.

• Theischialtuberositiesarelocateddeepinthemedialsideofthebuttocks.The

hamstringenthesesoroverlyingbursaecanbecomeinflamed,causingpainon

sitting. These tender points can be injected. The differential diagnosis is

coccidynia.

• Thecoccyxcanbepalpatedwiththepatientproneorlyingontheirside)andis

amenabletolocalanaestheticandsteroidinjection.

• Adductorenthesitis/insertionaltendonitisisamenabletosteroidinjectionbut

is technicallydifficult. Imaging initially isessentialas there is adifferential

diagnosis—which includes symphysitis, osteitis pubis, ischiopubis fracture,

inguinalhernia,andmedialhipjointlesions.Aninflamedsymphysispubisis

bestinjectedunderUSguidance.

Thekneeandperiarticularlesions

Thekneejoint

Knee joints are, with appropriate training and experience, straightforward to

accesswithaneedlewithoutimagingguidance.

• Accesstothejointisperhapssimplestbythelateralapproachsotheprocedure

doesnothavetotakeplace‘over’thepatient’sotherleg/knee,andtheperson

undertaking the procedure can sit comfortably without having to reach over

thepatient.

• The patient should be supine and comfortable with support under the knee

(whichmaynot,whenthereisaneffusion,beabletoextendfullyandreston

thecouch).

• Markapointaboutathirdofthewaydownthepatellabutmidwaybetween

the upperandlower parts of theleg—thisshould be whereaneffusion will

‘balloon’ out because of pressure distribution within the joint, and thus be

mosteasilyaccessed.

• Awide-gaugeneedleismostappropriategivenaspirationofsynovialfluidis

oftenalsorequiredforsymptomreliefanddiagnostics.

• If theprocedure maybelongbecauseof anticipationthat alargevolume of

fluid will need to be aspirated, then consider anesthetizing the skin and

subcutaneoustissuesfirst.

• Theneedleisadvancedat90°totheskinsurface(see Plate19).

• Ajointeffusionshouldbereached,inallbutthemostobesepatients,within2

cm.Acommonmistakethatinexperiencedoperatorscanmakeistoinsertthe

needle too far and cause pain by hitting the femur or patella bone with the

needle.

• Ifsepsisorcrystalarthritisissuspected,sendasampleoffluidformicroscopy

andculture,andpolarizedlightmicroscopy,respectively.

• If a sample is needed to assess for infection, take great care to harvest the

sampleinasterileway—withtheaidofanassistanttohelpcollectthesample

inasterilepot.

• Aspiratethe jointtodrynessor untilaspirationbecomesdifficult.Trynotto

repositiontheneedletoomanytimesasthiswillcausetraumaandbleeding—

effusionswithPsAandinfectioncanbelarge(e.g.author’spersonalrecordis

300mLfromaTBeffusion!).

• Access to the joint space may be improved, and greater fluid removal

facilitated, by pressing on the medial side of the knee and pressing on, and

tilting,thepatellawithyourotherhand.

• Disengage the needle from the syringe and re-attach the syringe containing

steroid: 40 mg triamcinolone or methylprednisolone is appropriate for most

sizejointsandconditions—butaddperhaps5mLofeithersterilesalineor1%

lidocainebecausethejointspaceispotentiallyquitelarge.

• Theefficacyofasteroidinjectionmayrelatetotheamountofrestfollowing

the procedure—avoidance of weight-bearing on a flexed knee for example.

Advise48hoursrestideally.

• Icing and NSAIDuse for 24 hoursafterthe procedure mayeasediscomfort

associatedwiththeprocedure.

• Consider follow-up physiotherapy if there is poor extension range and/or

quadricepswastingassociatedwithchronicityofthekneesynovitis.

Kneeperiarticularinjections

• Prepatellar bursitis, patellar ligament enthesitis, pes anserinus enthesitis or

bursitis,andtriggerpointsaroundthekneemayallrespondtolocalsteroidand

anaesthetic.

• US scanning to confirm diagnosis may reasonably be combined with a US-

guidedprocedurebutthedetailsofthisneedtobeagreedwithanappropriate

radiologistinadvance.

• Popliteal cysts can be directly aspirated and injected but due to the risk of

damaging superficial neurovascular structures, should be done under US

guidance.

Theankleandfoot

Ankleandsubtalarjointsandtarsaltunnel

The ankle joint can sometimes be accessed without US guidance though the

techniqueisdifficultwhenaffectedbythecommonoccurrenceofsubcutaneous

oedema.

• Theanklejointislocatedmosteasilywiththepatientsupineonacouchand

wholelegrestedandsupported.

• Thejointlinecanbepalpatedjustlateraltotheextensordigitorumtendonasit

crossestheanklecrease.

• The needle is initially advanced downwards over the dome of the talus and

paralleltothesoleofthefootforabout1–2cminmostcases—whenthereis

aneffusion,theswellingwillballoonout/forwardtowardsthispoint.

• Itisquitefrequenttohitbonewiththeneedlesocautioninneedleplacement

isadvised(see Plate20a).

• It is unusual to be able to aspirate fluid from an ankle joint though a small

volumeisaccessiblewithalarger-gaugeneedle.Theankleisacommonjoint

tobeaffectedbygoutandCPPDarthritissosendinganysampleforPLMis

appropriate.

• For an inflammatory ankle arthritis, 40 mg of triamcinolone or

methylprednisoloneacetatewith2–3mLof1%lidocaineistypical.

• Adviseelevation,rest,andicingpostprocedureandavoidingallbutnecessary

weight-bearingfor48hours.

• Subtalarjointcanbeaffectedbysynovitisandinfectionbutaccessingthejoint

withoutUSguidanceisverydifficult.

• The tarsal tunnel (see  Plate 20b) is injected under the flexor retinaculum

betweenthecalcaneumandthemedialmalleolus.

Plantarfasciitis

Theoriginoftheplantarfasciaatthemedialcalcanealtubercleoftheoscalcisis

frequently affected by recurrent trauma and inflammation. The latter occurs

commonlyinaxSpA,PsA,reactive(SpA-associated)arthritis,and IBD-related

arthritis.

• The plantar fascia origin is injected from the medial side after carefully

localizingthepositionofmaximalpain(see Plate20c).

• Neverinjectthroughthesoleofthefoot(i.e.at90°totheskin)butapointof

needle entry at the medial edge of the foot, angled towards the point of

maximaltendernessmaybeoptimal.

• Some clinicians will numb the area with local anaesthetic injection of the

posteriortibialnerve,inthetarsaltunnel(see Plate20b).

• Use40mgtriamcinoloneacetonideormethylprednisolonemixedwith1–2mL

of1%lidocaine.

• Advisepost-procedurefootelevation,restrictingofweight-bearing,andicing

iftheheelissore.

• Manyrheumatologistswillconsideritappropriatetoofferasecondinjectionif

thefirstisonlypartlyhelpful.Allow4–6weekstotellifthefirstinjectionhas

beensatisfactorilyeffectiveornot.

Smalljointsofthefeet

• The MTPJs are injected most easily via the dorsal approach (20 mg

triamcinoloneormethylprednisolone)throughthetoeweb.

• Theneedleisdirectedtowardstheappropriatemetatarsalhead.

• Thesametechniqueisusedtoinjectaroundaninterdigitalneuroma(Morton’s

neuroma).

• Careshouldbetakenwithsterilizingtheskinpriortotheprocedureasthereis

aparticularriskofinfectionaftertheprocedure.

Chapter25
Rheumatologicalemergencies
Septicarthritis
Infectionsinpatientsonbiologics
Acutesystemiclupuserythematosus
Systemicvasculitis
Systemicsclerosis‘crises’
Methotrexate-inducedpneumonitis
Macrophageactivationsyndrome
Paediatricosteomyelitis
Malignanciespresentingwithmusculoskeletalsymptomsinchildren
Septicarthritis
Infectionina joint can progressrapidly, causingtissuedestruction, permanent
deformity, and disability. When septic arthritis is suspected, investigation and
antibiotic initiation should be prompt, and where feasible, infected tissue
resected.Theepidemiologyandaetiopathogenesisofsepticarthritisisreported
in Chapter17.
Septicarthritis:inadults
• Patients may not appear systemically unwell, so a high index of clinical
suspicionisrequired.
• Septic arthritis is more common in patients with established joint disease,
prostheticjoints,andwheretherearecomorbiditiessuchasdiabetes,chronic
renaldisease,immunosuppression,andIVdrugabuse.
• Staphylococcus and Streptococcus are the most common pathogens. Septic
arthritis from Haemophilus influenzae type b is becoming rare due to
vaccinationprogrammes.
• Crystalarthropathyandcellulitisaredifferentialdiagnoses.
• Considerprimaryorsecondaryinfectiveendocarditisinhigh-riskcases,(e.g.

IVdrugusersandprosthetic/diseasedcardiacvalves).

• Gonococcalarthritisisthemostcommoncauseofmonoarthritisinayoung,

sexually active adult; women during menstruation may be at particular risk.

Disseminatedgonococcalinfectionmaypresentasaclinicaltriadofpustular

skin lesions, tenosynovitis, or migratory arthralgias. The cutaneous

manifestationsarefleetingandarenotrequiredtomakethisdiagnosis.

Septicarthritis:inchildren

• Diagnosisisconsideredifthereishighorspikingfever,lossofweightbearing

or limp, or joint swelling. There may be focal bony tenderness if there is

associatedosteomyelitis(especiallyininfants).

• Mostcasesoccurinyoungchildren(50%ofcasesaged<2years).

• Thelowerlimbisinvolvedin75%ofcases(knee>hip>ankle).Theshoulder

isacommonlyaffectedsite.

• Presentationdependson organismand hostimmunity.Infants mayhavefew

signsandnotappearunwellorpyrexial.

• Although >2 joints may be affected, this is rare, and alterative diagnoses

shouldbeconsidered,e.g.JIA.

• Theyieldfromjoint/boneaspirateandbiopsyispoor.

• Staphylococcusaureusisthemostcommoncauseinchildren,butcommunity-

acquired methicillin-resistant Staphylococcus aureus (MRSA-CA) is

increasinglycommon.Considerotherpathogensbyage:

• Neonates:EscherichiacoliandgroupBstreptococci.

• 2monthsto5ygroupAStrep,andStrep.pneumoniae.

• Adolescents:Neisseriagonorrhoeae.

• Mycobacteriumtuberculosisisanincreasinglyrecognized,albeitrarecauseof

chronicpyogenicarthritis.MantouxandanIFNγreleaseassay(IGRA)should

bedoneinhigh-riskcases.

• ConsiderHaemophilusinfluenzaetypeBinnon-vaccinatedchildren.

• Viral-induced transient synovitis of the hip is an important differential

diagnosis.Itisabenigncondition,farmorecommonthansepticarthritisofthe

hip, presenting with hip pain, impaired mobility, apyrexia, and without

systemicupset.

Immediatemanagementofsepticarthritisinadults

• Jointimmobilization,analgesia,andfluidresuscitationifseptic.

• Laboratory testing (FBC, U&E, creatinine, LFT, ESR, and CRP) and blood

cultures.

• CompletejointdrainagesynovialfluidanalysiswithGramstain,culture,and

polarizedlightmicroscopy.

• Joint fluid with a white blood cell count >50,000/mm

 (mainly neutrophils)

andaglucose<400mg/Lishighlysuggestiveofinfection(see Chapter17).

• Ifcrystalsareevident,andculturesarenegativeafter48hours,adiagnosisofa

crystalarthropathyshouldbeconsidered(see Chapter7).

• Antibiotic therapy initiation immediately after joint samples have been

obtained.Cultureandsensitivityresultsmaychangeantibiotictherapyasthey

becomeavailable,butbroad-spectrumIVtherapyshouldbegiveninitially.

• Joints with implants or prostheses should not be aspirated without prior

discussion with an orthopaedic specialist, and should only be aspirated in

steriletheatreenvironments;ideallypriortoantibioticadministration.

• Foranon-gonococcalsepticarthritis,seekorthopaedicinputforjointwashout,

and microbiology input to arrange a Gram stain of joint fluid and set up

cultures/special tests for atypical organisms (especially for a septic arthritis

resistanttoempiricantibiotics).

• EmpiricantibiotictreatmentintheabsenceofapositiveGramstaininadults

inastraightforwardclinicalscenarioshouldbeguidedbylocalpolicies;some

examplesregimensaredetailedasfollows:

• Common regimens include flucloxacillin 2 g IV four times a day ±

gentamicinIVorathird-generationcephalosporin.

• In cases of suspected MRSA infection, discussion with microbiology and

considerationofvancomycinisadvised.

• Pseudomonas spp. should be suspected in IV drug users (Table25.1) and

treatedwithcephalosporinIVwithanaminoglycoside(e.g.gentamicin3–5

mg/kgIV).

• Forfurtherinformationsee Chapter17.

Managementofsepticarthritisinchildren

Followsasimilarlinetoadultsandincludesahipultrasoundinchildrenifthe

cause of the limp is not obvious. IV antibiotics and analgesia will depend on

localpolicies,butasaguideaccordingtoage(seeTable25.1andTable25.2)the

followingarerecommended

Table25.1Post-immediatemanagementofsepticarthritisinchildren

Diagnosticstatus Management

Diagnosisnotconfirmed

Clinicallyimproved

SplintandcontinueIVantibiotic1–2weeks

Then switch to oral co-amoxiclav for a total

treatmentof4–6weeksaccordingtoclinical

condition

Confirmeddiagnosis

(pus ± 50,000 leucocytes ±

pathogenisolatedinblood

orsynovialfluid)

Splint and continue IV antibiotic 1–2 weeks

andadjustbasedonculture/susceptibility

Then switch to oral co-amoxiclav for a total

treatmentof4–6weeksaccordingtoclinical

conditionandpathogen

Weeklyclinicalandlaboratoryfollow-up

Diagnosisnotconfirmed

Clinicallynotimproved

Reviewantibiotics

Obtain paediatric infectious disease specialist

advice

Further evaluation to consider other types of

non-infectiousarthritis

Table25.2Summaryofantibioticsbyagegroup

Neonate(<3

months)

Benzylpenicillinandgentamicin

Orcefotaxime

Addamoxicilliniflisteriasuspected

Oralswitchtoco-amoxiclav

3months–5

years

Cefuroxime

Oralswitchtocefalexinorco-amoxiclav

>5years Flucloxacillinorclindamycin

Considerceftazidimeorciprofloxacinifpseudomonas

suspected

Oralswitchtoco-amoxiclavsuspensionorflucloxacillinor

clindamycintablets

ReproducedfromWattsetal.(2013)OxfordTextbookofRheumatologywithpermissionfromOxford

UniversityPress.

• <3monthsold:IVcefotaximeandamoxicillin.

• 3months:5yearsold:IVcefuroxime.

• >5yearsold:IVflucloxacillin

Post-immediatemanagementofsepticarthritisinadults

• Regularanalgesiareview.

• Assessformultiplefociofinfection.

• Discontinueanyimmunosuppressants,butconsiderstress-doseglucocorticoids

(GCs)ifthepatientissystemicallyunwellandhasbeenonlong-termGCs.

• Adjustantibioticsaccordingtoculturesensitivitiesandindiscussionwithan

infectiousdiseasespecialist.

• For affected weight-bearing joints, keep non-weight-bearing until there is

obviousimprovementinpainandswelling,andyouareconfidentthepatientis

onappropriateantimicrobials.

• Physical therapists should be involved early to help passive mobilization of

jointbeforepatientweight-bears.

• The evidence for routine duration of antibiotic course is not strong and the

regimen should be tailored to the individual. A common protocol is IV

antibioticsfor1–2weeks,followedbyoralantibioticsfor2–4weeks.

• Reasonsforlimited/noresponsetotreatmentcaninclude:

• Alternative diagnosis. Consider crystal-induced MSK disease (see

Chapter7),RA(see Chapter5),andspondyloarthritis(see Chapter8).

• Concomitantcrystal-inducedMSKdisease,reactivearthritis,foreignbody,

orflareofunderlyingarthritis,e.g.RA.

• Inappropriate antimicrobial choice for an atypical organism (e.g.

Mycobacteriummarinum,Borrelia,fungus)ormultipleinfectingorganisms

(see Chapter17).

• Secondary osteomyelitis—especially if treatment had been delayed (see

Chapter17).

• Surgical lavage may need to be repeated, and surgical synovectomy

considered. Recalcitrant cases may require joint excision ± subsequent

arthroplasty.

Gonococcalsepticarthritis

• Synovial fluid and blood cultures can be negative. If gonococcal infection

suspected,re-culturebloodbutalsourethra,cervix(80–90%positive),rectum,

pharynx,anyskinpustules,andjointfluid.

• UrinecanbetestedforgonococcalnucleicacidbyPCR.

• Treatment should be guided by local policies but a common regimen is

ceftriaxone1g IM orIV every24hours. An oralswitch can beconsidered

after 24–48 hours when clinical improvement is seen. Treatment should

continuefor7days.

• Duetoincreasingorganismmicrobialresistance,treatmentwithciprofloxacin

isnolongeradvisable.

• ConsiderempirictherapyforChlamydiawithdoxycycline100mgfor7days

oronedoseofazithromycin1g,andconcurrenttestingforHIVandsyphilis.

• All sexual partners should receive one dose of ceftriaxone 125 mg IM and

empirictreatmentforChlamydia.

Infectionsinpatientsonbiologics

• Overthelast10years,immunosuppressantsthatspecificallyinhibittheactions

ofTNFα, Il-6,and Tcells,anddeplete Bcells havebecomewidelyusedto

treatmultiplerheumaticdiseases(see Chapter23).

• Theriskofinfectionsisincreasedwithuseofthese‘biologic’drugs,although

isprobablygreaterwithanti-TNFαagentsthanotherclasses.Patientswitha

history of serious infections should be treated with this class of drug with

extremecautionandvigilance.

• Theriskandseverityofinfectionsmaybeincreasedinthosealsotakingother

immunosuppressants,typicallyMTXorGCs.

Commonpathogens

• Patientsareatparticularriskfortuberculosis(TB).

• Disseminatedfungalandviralinfectionscanoccur(Table25.3).

• Reactivationoflatentinfectionsmaybeaparticularproblem.

• Latenthistoplasmosisshouldbeconsideredinpatientsfromendemicregions

orwithahistoryofpotentialexposure(e.g.caving/potholing,construction).

• Listeriosis should be considered in the context of unpasteurized dairy

consumption.

Tuberculosisanditsrisk

ReportsofTBoccurringwithbiologicsadvocatetakingprecautions:

• ScreenforlatentTBpriortoinitiationoftherapy.

• Screenpeoplewhotraveltoendemicareasandhealthcareworkers.

• Screenusingintradermalinjection ofPPDandCXRgiven thepossibilityof

anergy.

• With PPD injection, induration of ≥5 mm should be considered a positive

responseformostpatientswithrheumaticdisease.

• If active TB is found, patientsshouldbetreated as per the British Thoracic

SocietyGuidelineandtreatmentshouldbepostponeduntil≥2monthsofanti-

TBtherapyhasbeenreceived.

• Reactivation of TB should be considered in biologic-treated febrile patients

andthosenotscreenedforTBbeforebiologictreatment.

• Patientsmayneedalongerthannormalcourseofantibioticsandneedcareful

reassessmentbeforerestartingtherapy.

Varicellainfections

• Ifapatientonabiologic,orahouseholdcontact,developsprimaryvaricella

(chickenpox),thenvaricellaimmunityshouldbechecked.

• People not immune and at significant risk of infection should be given

varicellazosterimmunoglobulinwithin72hours.Thiswillprovidetemporary

immunity.

• If a patient develops shingles, standard treatment should be given and the

biologicwithheld.

Table25.3Organismsandinfectionsreportedwithbiologics

Organisms Natureofinfection

Bacteria Mycobacteriumtuberculosis Disseminated

Pulmonary

Atypicalmycobacteria

Listeria Septicaemia

Septicarthritis

Meningitis

Staphylococcus Septicaemia

Cavitatingpneumonia

Salmonella Septicaemia

Septicarthritis

Moraxella Septicarthritis

Actinobacillus Septicarthritis

Nocardia Respiratorytract

Viruses Varicella

Herpessimplex

HepatitisB/C

CMV

Disseminated

Severe

Reactivation

Disseminated

Fungi/yeasts Candida

Cryptococcus

Aspergillus

Sporothrix

Pneumocystis

Septicaemia

Pneumonia

Disseminated

Skin

Pneumonia

Histoplasmosis Disseminated

Parasites Leishmania Visceral

Acutesystemiclupuserythematosus

Acute systemic lupus erythematosus (SLE) will manifest either as a flare in

patientswithanestablisheddiagnosisorasthefirstpresentationofthedisease.

Declining C3 and increasing dsDNA titres may predict acute disease flares in

somepatients.Thereaderisreferredto Chapter13forSLEandto Chapter

11forantiphospholipidsyndrome(APS)andcatastrophicAPS.

DiagnosingSLEinanacutemedicalcontext

• Consider SLE as a diagnosis in all young and middle-aged women who

presentwithahistoryofjointpain,photosensitiverash,orpleuriticchestpain.

• Raynaud’sdisease(RD)andrecurrentmouthulcersarenon-specific,butmay

alsoappearinassociationwithSLE.

• ANA serology and complement levels may not be available at initial

assessment.

• InflammatorymarkerssuchastheESRorCRParenotreliableindicatorsof

SLEactivity.

• Although pericardial effusions are common with SLE, they are generally

trivial. Cardiac tamponade is found in <1% of patients. Since the effusion

tendstoreflecttheoveralldiseasestate,generallytreatmentoftheunderlying

disease is adequate to resolve the effusion. Rarely, therapeutic

pericardiocentesisisrequired.

AcuterenalSLE(adults)

• ChecktheBP,sendbloodforcreatinine,U&E,sendurineforculture,aspot

urine protein/creatinine ratio (as an estimate of proteinuria) and organize a

renaltractUStoruleoutpost-renalobstruction.

• Quantification of urinary protein and creatinine grades severity of the renal

lesionandguidesmanagementapproach(Fig.25.1).

• Control BP aggressively. Use an ACE inhibitor or ARB for those with

proteinuria.

• Biopsy can inform treatment decisions. Induction treatment is usually given

withGCsandoralmycophenolatemofetil(titrateto1–1.5gtwicedaily)orIV

cyclophosphamide.

• GC-inducedosteoporosisandcardiovascularriskshouldbemanagedfromthe

outset.Considergettingthefollowingdoneearly:DXAscan,ECG,andfasting

lipidpanel.

• Daily calcium (1000–1500 mg) and vitamin D (800 IU) should be

administeredtoallpatientsreceivingGCs.

• Withcyclophosphamide,thereisaneedtocounselpatientsabouttherisksof

infertility, malignancy, and haemorrhagic cystitis, the dosing schedules (e.g.

using mesna), monitoring (FBC at day 10 after and prior to IV pulse), and

Pneumocystisprophylaxischemotherapy(e.g.trimethoprim-sulfamethoxazole;

Fig.25.1).

Fig25.1Flowdiagramofthemanagementofrenalsystemiclupuserythematosusbasedonourown

practice.ReproducedfromWattsetal.(2013)OxfordTextbookofRheumatologywithpermissionfrom

OxfordUniversityPress.

AcutecardiorespiratorySLE(adults)

• CardiacandisolatedpulmonarymanifestationsofSLEarerare andinmany

patientswithSLE,acutecardiacandpulmonaryfeaturesmaybeduetoother

commonconditions(Table25.4).

• CRP elevation may reflect infection or significant pleuropericardial SLE.

Lupus pericarditis alone without evidence of cardiac compromise can be

treated with NSAIDs and prednisone 20–40 mg daily for 2–4 weeks with

subsequentGCdosetaper.

• Ifnotduetocardiacfailure,acutedyspnoeainSLEmaybeduetointercurrent

infection, pneumonitis, pulmonary vasculitis, pulmonary embolism,

pulmonaryhypertension,ordyspnoeafromthepainofpleuralserositis.

• Cyclophosphamide should be considered for severe or life-threatening

manifestationsofSLE.

AcutehaematologicalSLE(adults)

• ManypatientswithSLEareCoombs(directantiglobulin)testpositivewithout

havinghaemolysis(anddonotneedtreatingassuch).

• Features of haemolysis include fever, shivers, pyrexia, anaemia, elevated

bilirubininserumandurine,lowserumhaptoglobins,andreticulocytosis.

• Acutethrombocytopeniaisarelativelyfrequentpresentation.

• If severe, both haemolytic anaemia (Hb <70 mg/L) and thrombocytopenia

(platelets<25,000)require high-doseprednisone60–80 mg/day andAZA or

CYC(pulsedIVororal).

AcuterenalSLE(paediatrics)

• ThemostcommonlesionisClassIVdiffuseproliferativeglomerulonephritis

(30–45%ofcases),andcarriestheworstprognosis.

• One-third of children with acute renal SLE have hypertension which often

needsaggressivemanagement.

• All have microscopic haematuria and proteinuria >3 mg/kg/day. Most have

>25mg/kg/dayproteinuria.Upto33%haveserumalbumin>35g/L.About

50%maintainGFR>100mL/min/1.73m

• PrognosisandtherapyofnephritisisguidedbythehistopathologyactiveISN-

grade pathological lesion and chronicity index, thus obtaining a biopsy is

important.

• Management shouldbe ina specialistunit,andincludeshigh-doseGCsand

MMF600mg/m

BD.InsomecasesIVCYCuitilisingthelow-orhigh-dose

Eurolupusprotocolisusedforinductionorflareoflupusnephritis.

• The value of plasma exchange and IVIg in crescenteric or fulminant renal

disease is unclear but its often considered, and dialysis may ultimately be

necessary.

Table25.4Importantaspectsinmanagementofacutecardio-respiratorySLE(adults)

Initialclinical

cardiacassessment

ECG,bloodforCK,troponinT,echo

Initiallung

assessments

ABGs,CXR,spirometry,HRCTchest,VQscan

Consider

pulmonaryembolus

Considerempiricalanticoagulationearlyandcheckfor

lupusanticoagulant,APLantibodies,andcomplete

thrombophiliascreen

Pulmonary

vasculitis(very

rare)

Features:severedyspnoea,CXRabnormal.Requires

ICUandrespiratoryphysiciansupportandconsider

plasmaexchange

Interstitiallung

disease

Requireshigh-dosesteroidsandeither

cyclophosphamide,azathioprine,ormycophenolate

mofetil

Antiphospholipid

syndrome

PE-associatedwithAPLsyndromeinSLErequires

lifelonganticoagulation

Specifictherapies

Glucocorticoids Assumingnon-viralinfectionsexcludedortreated

mostcardiopulmonarySLEfeaturesrespondtooral

prednisone0.5–1mg/kg/day.Consider

methylprednisolone1gIV×3daysifclinicalsituation

extreme

Mycophenolate Mycophenolatemofetil(0.5mgtwicedailyinitially

increasingafter1–2weeksto1–1.5gtwicedaily)can

beconsideredifAZAorcyclophosphamide

contraindicatedorpatientintolerant.Itisincreasingly

beingusedinsteadofcyclophosphamideforinducing

remissioninlupusnephritis

Anti-CD20 Thoughevidenceminimal,rituximab(anti-CD20)1g

infusionrepeatedafter2weeksmaybeconsideredif

otherimmunosuppressantsarecontraindicatedorcause

sideeffects

Fragility AllpatientstreatedwithGCsrequiredailycalcium(1

fracture/osteoporosis

prevention

g)andvitaminD(800IU).Forall>50yrsa

bisphosphonateshouldbeofferedinitially(and

withdrawnifDXAscanandoverallfracturerisk

assessment(e.g.FRAX)suggestsfractureriskislow.

Localguidelinesmayexist

AcutehaematologicalSLE(paediatrics)

• Overthaemolysisoccursin<10%,thrombocytopeniain15–45%.

• Bleedingisuncommon.

• AutoimmunehaemolyticanaemiaistreatedwithoralGCs,but,whenthereis

rapidlyprogressinganaemia,IVmethylprednisoloneandIVIgmaybeneeded.

• Most patientswiththrombocytopenia respondtooral GCs.Ifthere is active

haemorrhage or no response to oral GCs, then IV methylprednisolone and

IVIgmaybeneeded.

• Splenectomyshouldbeavoided.

• A high index of suspicion is needed to diagnose catastrophic APS. It is

characterizedbymultipleorganthrombosesandmicroangiopathy.

• Leucopeniausuallyresolvesasdiseaseactivityimproves.

• If there is neutropenia with infection, granulocyte colony stimulating factor

can be used to increase the neutrophil count. If neutropenia is due to drug

toxicity and infection is absent, this usually improves with stopping or

decreasingthedoseoftheoffendingmedication.

• Close working with haematologists will assist interpretation of coagulation

studiesandadviseonanticoagulantuseincludingfactor10ainhibitors.

Systemicvasculitis

A vasculitis flare should be treated aggressively because permanent damage

from tissue ischaemia may occur rapidly. Patients diagnosed with pulmonary

capillaritisorglomerulonephritiswilltypicallybenefitfromtreatmentwithpulse

GCs. The specific management of each type of vasculitis is outlined in

Chapter 15. See  Table 4.2 p. 212 for precipitants and associations of

leucocytoclasticsmallvesselvasculitisand Table4.3p.214fortherangeof

laboratorytestsneededinpatientswithsuspectedvasculitis.

Giantcell(temporal)arteritis

• Sincegiantcellarteritis(GCA)canleadtocranialischaemiceventsincluding

blindnessandstroke,treatempiricallyifsuspected.

• TheprevalenceofGCAincreaseswithage.Visualchanges,jawclaudication,

and diplopia in the setting of B-type symptoms all support the diagnosis of

GCA.

• Empirictherapyiswithprednisone40–60mgdailyfor1monthbutifthereare

visualsymptoms,urgentophthalmologyexaminationisessential.

• IschaemicGCA-relatedocularpathologyistreatedwithmethylprednisolone1

gIVfor3days.

• Daily low-dose aspirin decreases the risk of cranial ischaemic events, and

should be used as part of standard therapy unless there is a clear

contraindication.

• Treatmentshouldnotbedelayed.Biopsyisdiagnosticallyusefulupforsome

weeksafterGCtherapyisinitiated.

• To optimize yield, temporal artery biopsy should be bilateral, with samples

>1.5cminlength.

‘Severe’vasculitis

• Patientswithactivevasculitiscanquicklydevelopmanifestationsthatthreaten

lifeorthefunctionofavitalorgan.

• Patients with a potential flare of vasculitis, already on immunosuppression,

needthoroughassessmenttoruleoutinfectioninitially—see Tables4.2and

4.3(p.212andp.214).

• Severe manifestations of the small vessel vasculitides include pulmonary

haemorrhage(orcapillaritis)andglomerulonephritis.Severemanifestationsof

mediumvesselvasculitisincludemononeuritismultiplex(e.g.footdrop/wrist

drop)andmesentericangina/ischaemia.

• When glomerulonephritis is suspected, renal biopsy should always be

considered.

• Severevasculitisisgenerallytreatedwithpulsemethylprednisolone1gIVfor

3days,followedbyprednisone1mg/kg/day.

• Most patients with severe vasculitis will also be treated with

cyclophosphamide 1.5–2.0 mg/kg/day. Lower doses should be used in the

elderlyorinpatientswithrenalinsufficiency.

• Plasmapheresis can belife-savingfor AAV-related pulmonary vasculitis;not

allcentreshaveafacilitytogiveplasmapheresisthough.

• Cyclophosphamide places patients at risk for Pneumocystis infection, and

appropriatechemoprophylaxisshouldbeinstituted.

• Inpatientswhodeclineonclinicalgrounds,despiteimmunosuppression,then

infectionsmimickingvasculitisshouldbeconsidered.

Systemicsclerosis‘crises’

Renalcrisis

• Thismaymanifestasanacuteorsubacutehypertensivecrisis,usuallywithin

thefirst4yearsafterdiagnosisofdiffusesystemicsclerosis(dcSScl).Itcanbe

thepresentingfeatureofSScl(see Chapter13).Itrarelyoccursinlimited

cutaneousSScl(lcSScl).

• AnabruptincreaseinBP>150/85andnewrenalinsufficiencyareconsistent

with this diagnosis. Very occasionally patients are normotensive, and

paradoxicallysubjecttoapoorerprognosis.

• Other manifestations include those of a hypertensive emergency:

microangiopathic haemolytic anaemia, encephalopathy, and hypertensive

retinopathy.

• Urinalysisisusuallynormal.

Management

• ACEinhibitorsarethecornerstoneofrenalcrisismanagement.

• The patient should be treated with escalating doses of captopril until BP is

broughtundercontrol.Calciumchannelblockerscanbeaddedsequentiallyif

captoprilisinadequate.

• FastdropsinBPshouldbeavoided,aslowperfusionpressuresinabnormal

renalvesselsmayworsenrenalfailure.

• Early consulting with a nephrologist about the potential need for

haemodialysisisprudent.

• Promptinitialtreatmentcanleadtoreturnofgoodrenalfunction.

Pulmonaryhypertensioncrisis

(Seealso Chapter13.)

• Primary pulmonary arterial hypertension (PAH) occurs as a complication of

lcSScl, although it can also occur in dcSScl (both as a primary feature and

secondarytopulmonaryfibrosis).

• Echocardiography can be used to screen for PAH. A RVSP estimate of >40

mmHg is suggestive, but the diagnosis must be confirmed by right heart

catheterization.

• Decompensated PAH presents with dyspnoea, syncope, raised JVP, loud P2

heartsound,andankleoedema.

Management

• Intensivecoronarycareunitmonitoringisessential.

• Patients withrapidly decompensatingheart failuresecondary toPAHshould

betreatedwithsupplementaloxygen,diuresis.

• ContinuousIVepoprostenolcanbeconsideredbutdecreasingcardiacpreload

toomuchcanreduceoverallpulmonaryperfusionifthePAisnotresponsive.

• Diuretics decrease right ventricular preload, and can lead to significant

symptomaticrelief.

• AlargepulmonaryembolismcanalsoresultinrapidlyworseningofPAH,and

should be considered contributory if the PAH was known to be high

previously,ifthereisAPSandintheappropriatesetting.

Methotrexate-inducedpneumonitis

Thisisrarebutcanoccurinanypatienttakingmethotrexate(MTX).

Epidemiologyandriskfactors

• Incidence5–70 per1000patientsperyeartakingMTX.Itis probablymuch

rarerinchildren/adolescentscomparedwithadults.

• Life-threatening pneumonitis requiring hospital admission occurs in <1%

patientstakingMTX.

• Mildpneumonitislikelyresolvesondrugwithdrawalalone.

• Mostpatientssufferingfrompneumonitisdosowithinthefirstfewmonthsof

startingMTXorafterasignificantdosechange.

• In patients on stable-dose MTX, blood levels may change in the setting of

progressiverenalinsufficiencyorlowlevelsoffolate.

• ConsiderthediagnosisinallpatientsonMTXwithacuteonsetofdrycough,

dyspnoea,headache,andfever.

• The differential diagnosis lies between chest infection, acute pulmonary

oedema, or acute interstitial lung disease associated with the underlying

condition.

Managementofseveretoxicity

• StopMTX.

• Intensiverespiratorycareisnotoftenneededbutshouldbeconsidered.Severe

casesneedsupplementaloxygenandbloodtransfusion.

• Assessforinfection.Considerbronchoalveolarlavagefor samplesandhigh-

resolutionlungCT.Itmaybenecessarytotreatempiricallyforthemostlikely

pathogens,whileawaitingresults.

• Optimal therapy for MTX-induced pneumonitis has not been well defined.

Folinicacid(15–25mgorallyfourtimesaday)mayreverseMTXtoxicity.

• Anecdotally, GCs accelerate recovery. In cases of severe respiratory

decompensation,treatwithmethylprednisolone1gIVfor3days,followedby

prednisone1mg/kg/day.Prednisonecanbetaperedoverthesubsequent1–6

months,dependingondiseaseseverity.

• Most patients with MTX-induced lung injury will recover, but may have

chroniclungdamageasaresult.

Macrophageactivationsyndrome

Macrophageactivationsyndrome(MAS)israrebutislife-threatening(mortality

is8–22%).MAScancomplicateotherdiseases.MASisalsotermedsecondary

haemophagocytic lymphohistiocytosis (HLH). For a summary, see

http://www.the-rheumatologist.org/article/macrophage-activation-syndrome/6/

Pathology

• Activatedmacrophagesengulfotherhaematopoieticcellsinthebonemarrow,

liver,andspleen.

• PolyclonalT-andNK-cellactivationisassociatedwithacytokine‘storm’with

consequentextensiveimmunologicalabnormalities.

Presentationandclinicalfeatures

• A high level of suspicion remains key to MAS diagnosis as it may present

insidiouslyinanalreadyunwellchild.

• Unremitting fever and high levels of persistent inflammation despite broad-

spectrumantibioticsoranunexpectedfallinESRassociatedwithnew-onset

cytopeniaandhyperferritinaemiashouldraisesuspicionofMAS.

• MAScanbetheinitialpresentationoracomplicationofoncologic,infectious,

and rheumatic disorders, including systemic-onset JIA, SLE, and Kawasaki

diseaseandlesscommonlyjuvenileDM,PAN,polyarticularJIA,MCTD,and

otherautoimmuneandautoinflammatoryconditions.

• Sepsisshouldbeconsideredasacause.

• Infective triggers of MAS include EBV, VZV, CMV, coxsackievirus,

parvovirusB19,hepatitisA,Salmonella,andenterococcus.

• If MAS is the initial presentation of an inflammatory illness, assessment

shouldbemadeformalignancy.

• BycontrasttoMAS/secondaryHLH,primaryHLHisusuallyseeninchildren

<2yearsold,withconsanguineousparents.Theremaybeahistoryofdeathof

youngfamilymemberwithunexplainedfever,andaprimarycentralnervous

systempresentation.

Diagnosis

Clinicalfeaturesarenotspecificfordiagnosis.Combinationsoftypicalfeatures

are often present and high suspicion for the diagnosis remains important; see

Table25.5.

• NewdiagnosticcriteriaforMASinthecontextofactiveSoJIA

include:

• Ferritin>684ng/mL.

• Plus ≥2 of the following: platelet count <181 × 10

/L, AST >48 U/L,

triglycerides>156mg/dL,fibrinogen<360mg/dL.

• The valueoftesting forCD25 andCD163positive circulatinglymphocytes,

low NK-cell activity, haemophagocytosis in bone marrow, liver, spleen, or

lymphnodes,highD-dimer,andabnormalperforinexpression,isdebatable.

Table25.5Clinicalandlaboratoryfeaturesofmacrophageactivationsyndrome

Clinicalsigns Laboratoryfindings

• High, persistent, unremitting

fever or change in pattern of

fever

• New-onsethepatosplenomegaly

• Neurological manifestations

includingirritability

• Lymphadenopathy

• New-onsetheart,lung,orkidney

failure

• Petechiaeorhaemorrhages

• Low/falling ESR in context of active

inflammatorydiseaseorhighCRP

• Low/rapidlyfallingwhitebloodcells,

Hb,orplateletcount

• Low/falling or unexpectedly normal

plateletcount

• Low/falling or unexpected normal

fibrinogen

• Rising AST, ALT, GGT, bilirubin,

triglyceridesandLDH

• Ferritinhigherthanwouldbeexpected

forpatient’sdiagnosis

Haemophagocytosisinthebonemarrowaspirateispresentin60%ofMAScases,andtendstobea

relativelylatesign.AbsenceofhaemophagocytosisdoesnotruleoutMAS.

Treatment

• Treatmentshouldbestartedpromptlyasdelayedtreatmentisassociatedwith

poorprognosis.

• Broad-spectrumantibiotictreatmentisusuallystartedincasesotherthanthose

withactiveautoimmuneconditions.

• First-line treatment of IV then oral GCs is effective in >50% of cases. For

example:methylprednisolone30mg/kg/day(maximum1g)for3consecutive

days,followedbyoralprednisolone1mg/kg/dayandthendosetapering.

• Ifthereisapoorresponsetosteroids,IVIg1–2g/kgisrecommended.

• IL-1 inhibition (e.g. anakinra) is dramatically effective in MAS associated

with SoJIA (and increases survival rate vs placebo in adult sepsis + MAS

features).AnakinraisgivenSCorIV2–8mg/Kg/day(max100mg/dose)in1–

4divideddoses.

• In refractory disease other options include anti-IL-6r (tocilizumab), anti-

TNFα, etoposide, rituximab (anti-CD20+ B-cell therapy) for EBV-driven

MAS,andcyclophosphamideinSLE-associatedMAS.

Reference

1. RavelliA,MinoiaF,DavìS,etal.2016ClassificationCriteriaforMacrophageActivationSyndrome

Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against

Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials

OrganisationCollaborativeInitiative.AnnRheumDis2016;75:481–9.

Paediatricosteomyelitis

Inchildren,osteomyelitisismostcommonininfants;50%ofcasesoccurbefore

5yearsofage.

• Thereisusuallyahistoryoftrauma,typicallyinvolvingthemetaphysisoflong

bones.

• Osteomyelitis can arise from haematogenous spread of pathogens from a

primarysite(e.g.lung,skinear,nose,orthroat)orbydirectinoculationfrom

openfracturesorpenetratingwounds.

• Thereareacute,subacute(2–3weeks’delay),chronic(rareinchildren),and

non-bacterial (e.g. CRMO or SAPHO) forms of osteomyelitis (see also

Chapter17).

Malignanciespresentingwithmusculoskeletal

symptomsinchildren

Causes

The annual incidence of primary malignant tumours of bone, synovium, or

muscle is 6 per 1 million children. The main causes are osteosarcoma (about

50%ofcases)andEwingsarcoma(40–45%ofcases).

• Widespread MSK symptoms may of course be from bone metastases from

osteosarcomaorEwingsarcoma.

• Bone marrow infiltration by different lymphoproliferative disorders can

presentwithMSKsymptoms.

Presentationandclinicalfeatures

• Malignancy should be suspected, particularly in an adolescent if there is

persistentpainoflongbonesorvertebraeof>2weekswithassociated:

• pointtenderness.

• nightawakening.

• painoutofproportionforclinicalfindings.

• Otherfeaturescanincludebonyswellingorenlargement,weightloss,malaise,

pathologicalfracture(5–10%),andrarely,lunginvolvement.

• A mass increasing in size, extending deep into soft tissues, or a presumed

exostosis>5cm,shouldraisethepossibilityofmalignancy.

• The associated arthritisusually involves large joints, ismild,migratory, and

oftenwithoutmorningjointstiffness.

Investigationandmanagement

• Earlyreferraltoapaediatriconcologistisessential.

• Making a diagnosis prior to metastasis greatly enhances the prognosis.

Mortalityratefollowingmetastasisis40%.

• BloodtestsmayshowincreasedinflammatorymarkersandLDH.FBCisoften

normal initially, but there may be a reduction trend in platelet count and

haemoglobin.Alowleucocytecountisalatesign.

• Abloodfilmshowingblastcellsispathognomonicforleukaemia.

• Abonemarrowaspirateortissuebiopsyprovidesahistologicaldiagnosisand

canfacilitatetumourgrading.

• Tumour staging is dependent on the diagnosis, histological grade, and both

sizeandlocationofthetumour.

Imaging

• Plainradiographscharacterizetheprimarybonetumour.

• US is important to screen for hepatosplenomegaly, lymphadenopathy, and

furtherdefinesofttissuemassessuchaslipomaorvascularmalformation.

• MRIprovidesspecificinformationregardingthetumournatureandsizeand

thesurroundingsofttissueinvolvement.

• MRIimagesfacilitatetheplanningofabiopsy.

• CT helps define tumour anatomy prior to surgery and to evaluate for

metastases locally, though bone scintigraphy or whole-body MRI are useful

investigationstogetanoverviewofanyskeletalmetastases.

Treatment

• Therapy measures are beyond the scope of the text here. However, for

overviews see references 2 and 3 for osteosarcoma and Ewing sarcoma

managementrespectively.

Othermalignancies

ManychildhoodmalignancieshaveMSKfeaturesatpresentation,inparticular

acutelymphoblasticleukaemia(ALL),lymphoma,andneuroblastoma.

• Isolated hip or back involvement in a young child raises the suspicion of

leukaemia in the absence of sepsis. Risk factors for leukaemia include

conditionssuchasDown’ssyndrome.

• Backpaincanbeapresentingfeatureofneuroblastomainyoungchildrenand

toddlers and is attributable to metastases which occur in 75% of patients at

diagnosis.

• Limb pain in leukaemia and lymphoma is due to marrow invasion. Pain is

usually intense and continuous and associated with night awakening. Local

signs,suchasarthritisorerythema,maybeabsent.

• All malignancies can be associated with systemic features such as pallor,

petechiae,bruising,weightloss,andfever.

• In lymphoma, there may be hypertrophic osteoarthropathy associated with

painfulperiostitisandlymphadenopathy.

• Investigations should include checking FBC, LDH, LFTs, a blood film,

measuringurinarycatecholamines/metadrenalines,CXR,andabdominalUS.

• Bone marrow aspirate and whole-body MRI are then more definitive

investigations.

References

2. LindseyBA,MarkelJE,KleinermanES.Osteosarcomaoverview.RheumatolTher2017;4:25–43.

3. KridisWB, Toumi N, Chaari H, et al. A review of Ewing sarcoma treatment: is it stilla subject of

debate?RevRecentClinTrials2017;12:19–23.

Plates

Plate1Increasedgrowthoftheleftlowerlimbduetochronickneeinflammationin(rheumatoidfactor-

negative)juvenileidiopathicarthritis.

Plate2Magneticresonancescanoftheneckshowinglossofheightandsignalaffectingseveraldiscswith

multisegmentalspondyloticbars,compressionofthecordfromprotrusionoftheC5/6disc,and

myelopathicchanges(highsignal)inthecord.

Plate3Patternsofradiographicabnormalityinchronicsubacromialimpingement:sclerosisandcystic

changesinthegreatertuberosity.

Plate4Injectionoftheglenohumeraljointviatheanteriorroute.

Plate5Injectionofthesubacromialspace.

Plate6Injectionoftenniselbow(lateralhumeralepicondylitis/enthesitis).

Plate7Nodulesassociatedwithjointdiseases.(a)RA:typicallyoverextensorsurfacesandpressureareas.

(b)Chronictophaceousgout:tophicanbeindistinguishableclinicallyfromRAnodulesthoughmayappear

aseccentricswellingsaroundjoints(imageprovidedcourtesyofDrR.A.Watts).(c)Multicentric

reticulohistiocytosis:nodulesareintheskin,aresmall,yellowish-brown,andareoftenaroundnails.(d)

NodalOA:swellingisbony,typicallyatPIPJsandDIPJs.

Plate8Dactylitis,nailchanges,andDIPJarthritisinpsoriaticarthritis.

Plate9(a)Normalnailfoldcapillaries.(b)Nailfoldcapillariesinsclerodermashowingavascularareasand

dilatedcapillariesinanirregularorientation(originalmagnification×65).

Plate10Diffusearmandhandswellinginchronicregionalpainsyndrome(osteodystrophy)ina13–year–

oldgirl.

Plate11Slightflexionoffourthandfifthfingersasaresultofanulnarnervelesionattheelbow.Thearea

ofsensorylossisindicatedbythedashedline.

Plate12Injectionofthecarpaltunneltotheulnarsideofpalmarislongustendon.

Plate13Psoriaticspondylitis:non-marginaland‘floating‘(non-attached)syndesmophytes.

Plate14Spondylolysis.Thedefectintheparsinterarticularis(blackarrows)mayonlybenotedonan

obliqueview.Thepatienthashadaspinalfusion(openarrows).

Plate15Testingpassivehipflexionandrotationalmovements(a)andhipabduction.(b)Thepelvisshould

befixedwhentestingabductionandadduction.

Plate16Bonescintigraphy(

99m

Tc-MDP)ofa65-year-oldmanwithwidespreadbonepainandweakness

suspectedtohavemetastaticmalignancy.Anteriorview(left);posteriorview(right).Undecalcified

transiliacbonebiopsyconfirmedsevereosteomalacia.TherewascoincidentalrightfemoralPaget’sdisease

(arrowedlesions).

Plate17Bonescintigraphyshowingosteonecrosisoftheleftfemoralhead(ontheright-handsideasthisis

ananteriorview).Hightracerlocalisationindicatesincreasedboneturnoverthoughinsomeinstancesthere

maybephotopenia(anearlysign)whichcorrespondstoischaemia.

Plate18The‘patellartap’test.Anyfluidinthesuprapatellarpouchissqueezeddistallybythelefthand.

Thepatellaisdepressedbytherighthand.Itwillnormallytaptheunderlyingfemurimmediately.Any

delayinelicitingthetaporafeelingofdampingasthepatellaisdepressedsuggestsajointeffusion.

Plate19Injectionoftheknee.CourtesyofMrsCareyTierney.

Plate20(a)Injectiontoanklejoint,(b)tarsaltunnel,and(c)plantarfascia.ImagescourtesyofMrsCarey

Tierney.

Plate21Lupusperniopresentingasabluish–redorviolaceousswellingofthenoseextendingontothe

cheek.

Plate22Calciumpyrophosphatedepositiondisease(CPPD).ThisisatypicalaxialskeletalCPPDlesion:

calcificationofperiodontoidligamentsandsoft-tissue(termed‘crowned-denssyndrome’)shownonCT

scan:(a)axialview;(b)sagittalview;(c)coronalview.

Plate23Psoriaticarthritis(PsA).Lesionsat/aroundadistalgreattoeinterphalangealjoint.Inearlydisease

thearticularsurfacesoftenappearnormalandthereis‘fluffy’juxta-articularnewbone.SeeCASPAR

criteriafordiagnosisand‘Investigations’forPsAinEChapter8.

Plate24Osteitisinaxialspondyloarthritis(axSpA).Vertebral(corner)osteitisisseenashighsignalonthis

fat-suppressedsagittalspinalmagneticresonanceimage,indicatingcurrentinflammationonfour

contiguousvertebrae(T12–L3)andfaintlyinL5.Intervertebraldiscsappearnormal(highsignalindicating

wellhydrated)sonotdegenerate—suggestingagainstthevertebralhighsignalbeing‘Modiclesions’

(associatedwithdegeneratediscdisease).

Plate25Raynaud’sdisease(RD)insystemicsclerosis(SScl).Noteclearmarginstoischaemic(white)

areas.

Plate26ContiguousCT(a)and

F-FDG-PET(b)imagesshowingaortitis(arrowedin(b)andinCT-PET

registeredimage(c))andvasculitisofsubclavianarteries(arrowedin(d)innon-contiguous

F-FDG-PET

scanimage)invasculitis(ina75-year-old,treatedasgiantcellarteritis).

Index
Note:Tables,figures,andboxesareindicatedbyanitalict,f,andbfollowing
thepagenumber.
A
abaloparatide492,581
abatacept680
rheumatoidarthritis258,259b
juvenileidiopathicarthritis329
polymyositisanddermatomyositis440t
pregnancyandbreastfeeding676t
abdominalpain63
abductordigitiminimi115t
abductorpollicislongus696
acetaminophenseeparacetamol
Achillesperitendonitis199
aciclovir637
acitretin312
acromegaly227,409t
acromioclavicularjoint90,597t
acropachy,thyroid226
activemind–bodytechniques641
acuteorsubacutebackpain,conditionscausing608–613
facetjointarthritis/syndrome610–611
lumbarcanalspinalstenosis611–612
lumbardiscprolapse611t
mechanical608–609,609t
nerverootlesions609–610
non-septicdiscitis613
non-traumaticvertebralfracture612
post-surgical612–613,613t
therapies609t
adalimumab674–675,676
axialspondyloarthritisandankylosingspondylitis305–306
juvenileidiopathicarthritis329
polymyositisanddermatomyositis440t
pregnancyandbreastfeeding676t
psoriaticarthritis312
rheumatoidarthritis262b
Still’sdisease571
adductorapophysitis162
adhesivecapsulitis(frozenshoulder)88,224–225,600

adolescents
assessment32–45
backpain618–621
chronicpain44–45,638–641
conditionsnottobemissed28b
elbowpain104
endocrinemanifestations224t
fatigue23
fever23
handpain122
hypermobility592–593
inflammatoryarthritis33–37
jointpainswithsystemicfeatures40
kneepainandlowerlimbdevelopment184–186
limpandgaitconcerns22
lowbackpain154–155
lowerlegandfooddisorders200–203
musclepainandweakness39–40
neckpain82
non-inflammatorymusculoskeletalconditions40–44
normalmusculoskeletalvariants32–33
painassessment20
pelvic,groin,andthighpain168–169
pyrexia23
referralforfurtherassessment,triggeringfeatures28–30
regionalmusculoskeletalpain4
shoulderpain96
thoracicbackandchestpain136–138
unexplainedacute-phaseresponse23
wristpain122
airways219
Albrighthereditaryosteodystrophy504
alemtuzumab440t
alendronicacid682t
allergic(hypersensitivity)vasculitis471
allopurinol667,684
ambrisentan417,683t
aminosalicylates667
amiodarone669–670
amitriptyline615t,631–632,637,657
amlodipine683t
amyloid55
amyloidosis50,222,247,409t,566–567,567t
amyopathicjuveniledermatomyositis446
anakinra678
macrophageactivationsyndrome723
polymyositisanddermatomyositis440t
pregnancyandbreastfeeding676t
SAPHOsyndrome513
Still’sdisease571
systemic-onsetjuvenileidiopathicarthritis336
analgesia

analgesicescalation649–650
opioidanalgesics651–653,652t
rheumatoidarthritis252
aneurysm217
aneurysmalbonecyst622b
angina131t
angiotensin-convertingenzyme(ACE)inhibitors667,684
ankle18t,147t,195,198–199
glucocorticoidinjectiontherapy704–705
ankylosingspondylitis298–306
BathAnkylosingSpondylitisDiseaseActivityIndex(BASDAI)302–304,303b
classifying297b
clinicalfeatures300–301
diagnosticcriteria296
diseaseactivityscore302–304,303b
diseasestatusandprognosticindicators302–304,303b,304b
enthesitisindices303t
epidemiology298
treatment304–306
anserinetendonitis173–174
antalgicgait38–39
anteriorcruciatefunctiontests178f
anteriordrawtest177,178f
antibioticsforsepticarthritis710t
anticonvulsants667
antidepressants656
antiepileptics660
antihypertensives660
anti-interleukininhibitors258,259b,678–679
antimalarialdrugs361,669–670
antineutrophilcytoplasmicantibody(ANCA)450
-associatedvasculitides464–469,481
antinuclearantibodies67t
antiphospholipidsyndrome356
anticoagulation383–384
cardiacfeatures380
catastrophic378,386–387
centralnervoussystem380
classification376–377
clinicalfeatures378–380
differentialdiagnosis377
endocrinefeatures379
epidemiology377
fetalloss379
kidney380
laboratoryfeatures380–381
liverandgastrointestinaltract379
musculoskeletalfeatures379
pathophysiology377
pregnancy378t,384t
pulmonaryfeatures380
skinlesions379

thrombocytopenia378t,380
thrombosis378
treatment381–384
antirheumaticdrugs206
seealsodisease-modifyingantirheumaticdrugs
anti-TNFαtherapy674–675
axialspondyloarthritisandankylosingspondylitis305–306
cautionsandmonitoring675–677
chronicnon-bacterialosteomyelitis511
inflammatoryboweldisease-relatedspondyloarthritis317
juvenileidiopathicarthritis329
juvenilespondyloarthritis320
macrophageactivationsyndrome722
NICEguidelines675t
polymyositisanddermatomyositis439
psoriaticarthritis312
rheumatoidarthritis256,257b,259b,260,262b
SAPHOsyndrome513
spondyloarthritis-associatedreactivearthritis315
Still’sdisease571
systemic-onsetjuvenileidiopathicarthritis336
Takayasuarteritis455
α1-antitrypsindeficiency560–561
aorticdissection131t
aorticregurgitation217
apixaban384
apremilast313,674
arachnoiditis613t
argatroban382t
arthralgias392t
arthritis
calciumoxalate291
calciumpyrophosphatedeposition48t
crystal174
facetjoint610–611
gonococcal48t,529t,530–531
followinginfection324t
andjuvenileidiopathicarthritis,differencesbetween326
Lyme49,50
microorganisms527t
monoarthritis,acute46–47
non-gonococcal529t
oligoarticularjuvenileidiopathic334
post-streptococcal34
reactive33–34,51,206–207
andrelapsingpolychondritis565t
rheumaticfever539
andSjögren’ssyndrome392t
spondyloarthritis48t,230t
seealsoinflammatoryarthritis;juvenileidiopathicarthritis;osteoarthritis;psoriaticarthritis;rheumatoid
arthritis;septicarthritis;skinconditionsassociatedwitharthritis
arthropathy

sarcoid54–55
seealsocrystalarthropathies;entericinfection;spondyloarthropathies
articulardisorders108t,290t
articularlesions87t
aspirin653–656
antiphospholipidsyndrome381t,383,384t
giantcellarteritis460
Still’sdisease570–571
atacicept364–365
ataxicgait39
auranofin255,669
autoantibodiesinsystemiclupuserythematosus355t
autoimmunediseases
ascausesofmyopathiesandmyalgia59t
andskinvasculitis212t
autoimmunehepatitis392t
autoimmunerheumaticdisease67t,160t
autoinflammatorybonediseases,childhood510–511
axialspondyloarthritis296,298–306
classification298b
clinicalfeatures300–301
diseasestatusandprognosticindicators302–304,303b,304b
epidemiology299
HLA-B27andgenetics299–300
immunopathology300
investigations301–302
pathogenesis299–300
treatment304–306
azathioprine673,685
ANCA-associatedvasculitides468,469
immunoglobulinG4-relateddisease574
inflammatoryboweldisease-relatedspondyloarthritis317
juvenileidiopathicarthritis329
lupusnephritis362f
polymyositisanddermatomyositis438–439
pregnancyandbreastfeeding665t
psoriaticarthritis311–313
relapsingpolychondritis564
rheumatoidarthritis254b,255,262b,667
Still’sdisease570–571
systemiclupuserythematosus361t,363
Takayasuarteritis455
azithromycin530–531
azoles660
azotaemia220–221
B
Bcelldepletors677–678
Bcelltherapyseerituximab
backpain605–621
acutenon-specific607

adults614–617
categorization607
causesinchildren618t
childrenandadolescents618–621
chronic607,614–617,615t
congenitalandneuromuscularscoliosis620
herniateddisc621
idiopathicscoliosis619
neuropathic607
non-specificlowbackpain618
non-spinal607
‘red’and‘yellow’flags607
Scheuermann’sosteochondritis620
spinaltumours621,622b
spondylolysisandspondylolisthesis620,621f
seealsoacuteorsubacutebackpain,conditionscausing;lowbackpain;thoracicbackandchestpain
backschool615t
baclofen659
bacteria527t,712t
Baker’scyst173–174
balanitis51
balneotherapy(backpain)609t
barbiturates660
Barlow’smanoeuvre162
basiccalciumphosphatecrystal-associateddisease290
Bazin’sdisease473
Beal’ssyndrome584
behaviouralprogrammes(backpain)609t
Behçet’sdisease51,550–554
clinicalfeaturesandmanagement550–554,551t
diagnosticcriteria551t
epidemiologyandpathophysiology550
gutandhepatobiliarymanifestations231t
skindisorders206–207
belimumab364,387,398,676t,678
benignmyositisofchildhood39–40
benignnocturnallimbpainofchildhood45,32t,184–185
Bennett’sfractures106–108
benzbromarone686
benzylpenicillin540
biliarycirrhosis,primary228t
biologicaltherapies647t,674–677
abatacept(CTLA4-Ig)680
anti-TNFαtherapy674–675,675t
axialspondyloarthritisandankylosingspondylitis305–306
Bcelldepletors677–678
belimumab678
infectionsinpatientson712–714
juvenileidiopathicarthritis329
polymyositisanddermatomyositis439,440t
pregnancyandbreastfeeding676t,680
relapsingpolychondritis564

rheumatoidarthritis257b,258,259b
rituximab677
secukinumab679
Sjögren’ssyndrome398
Still’sdisease571
systemic-onsetjuvenileidiopathicarthritis336
Takayasuarteritis455
targetingTh17cellactivation679
ustekinumab679
biomechanicalconditions
ofback132t
ofchestwall132t
differentialdiagnosis324t
kneepain182
biomechanicalpaininchildrenandadolescents41
bisphosphonates
chronicnon-bacterialosteomyelitis511
non-septicdiscitis613
osteogenesisimperfecta581
osteoporosis490–491
SAPHOsyndrome513
Blausyndrome542,549
bleomycinexposure409t
blindloopsyndrome228t
blisters208
bloodvesselsandrelapsingpolychondritis565t
Blountdisease515t
bonedisorders/manifestations
backpain141t
hand/wrist120t
sarcoidosis558
shoulderpain87t
seealsometabolicbonediseases
bonelesions75t
bonemarrowmanifestationsandsarcoidosis557t
bonepathology60–61,108t
bonetumours524
chondrosarcoma524
osteoidosteoma524
osteosarcoma524
bosentan417,683t
brachialplexuslesions75t
breastfeeding
biologicaltherapies676t,680
DMARDs663,665t
NSAIDs655
rheumatoidarthritis261,262b
bronchiectasis416t
Brown’stumours227
Buerger’sdisease116
buprenorphine610,653
bursitis173–174

children184–185
Busche–Ollendorfsyndrome523
buttockpain158t
C
calcanealfractures198
calcaneovalgus201
calcificsupraspinatustendonitis,acute89–90
calcitonin507–508,612
calcium489
calciumchannelblockers668
calciumoxalatearthritis291
calciumpyrophosphatedepositionarthritis47,48t,50
calciumpyrophosphatedihydratedisease286–289
definitions286b
inflammation,triggeringfactorsof287b
investigations288
management288–289,289f
pseudogout,triggeringfactorsof287b
calf14t
Camurati–Engelmanndisease522
canakinumab336
CANDLEsyndrome549
capsaicin659
carbamazepine637
carcinoidsyndrome409t
carcinomatousneuromyopathy235t
cardiactamponade216,714
cardiopulmonarydisorders/manifestations,systemiclupuserythematosus715,716t
cardiovasculardisorders/manifestations216–217
antiphospholipidsyndrome380
Behçet’sdisease553
conductionabnormalities217
coronaryarterydisease217
immunoglobulinG4-relateddisease575t
Lymedisease537t
myocardium216–217
non-steroidalanti-inflammatorydrugs654–655
pericardium216
polymyositisanddermatomyositis429,432t
relapsingpolychondritis565t
rheumaticfever539
andsarcoidosis557t
Sjögren’ssyndrome395
systemiclupuserythematosus349,360
systemicsclerosis415–417
valvulardisease217
carditis537t
carpaltunnelsyndrome116,127,224–225,225–226
glucocorticoidinjectiontherapy696
caudaequinasyndrome142–143

cavitatingapicallesions218
cefotaxime536
ceftriaxone530–531,536
Lymedisease536
celecoxib653–656
centralnervoussystem
antiphospholipidsyndrome380
non-steroidalanti-inflammatorydrugs654t
cerebrovascularlesions238–239
certolizumab305–306,676t
certolizumabpegol262b,312,674–675
cervicaldystonia(torticollis)77
cervicalnerves74f
cervicalradiculopathy87
cervicitis51
chemonucleolysis611t
cherubism510–511,511t
chestpain62
seealsothoracicbackandchestpain
children
assessment32–45
autoinflammatorybonediseases510–511
backpain154–155,618–621
chronicpain44–45,638–641
conditionsnottobemissed28b
elbowpain104
endocrinemanifestations224t
fatigue23
fever23
gait,arms,legs,spine(GALS)screen14–19,24
gaitassessment37–39
gaitconcerns22
handpain122
hypercalcaemia501–502,502t
hypermobility592–593
idiopathicinflammatorymyopathy444–446
idiopathicosteoporosis485–486
inflammatoryarthritis33–37
jointpainswithsystemicfeatures40
juvenilespondyloarthritis318–320
kneepainandlowerlimbdevelopment184–186
limp22,37–39
lowbackpain154–155
lowerlegandfootdisorders200–203
malignanciespresentingwithmusculoskeletalsymptoms726–727
musclepainandweakness39–40
neckpain82
non-inflammatorymusculoskeletalconditions40–44
normalmusculoskeletalvariants32–33
osteogenesisimperfecta581
osteomyelitis724
painassessment20–21

pelvic,groin,andthighpain168–169
primaryvasculitides474–481
pyrexia23
rareautoinflammatorydiseases545
referralforfurtherassessment,triggeringfeatures28–30
regionalmusculoskeletalpain4
sarcoidosis556–557
septicarthritis708–710
shoulderpain96
systemiclupuserythematosus368–370,717
thoracicbackandchestpain136–138
unexplainedacute-phaseresponse23
wristpain122
seealsojuvenileidiopathicarthritis
chlorambucil439,567
chloroquinephosphate669–670
chondrocalcinosis225–227
chondromalaciapatella184–185
chondrosarcoma524
choreaandrheumaticfever539
chronicatypicalneutrophilicdermatosiswithlipodystrophyandelevatedtemperature(CANDLE)
syndrome549
chronicgraftvshostdisease409t
chronickidneydisease-mineralandbonedisorders504–505
chronicnon-bacterialosteomyelitis510–511
chronicpainsyndromes623–642
childrenandadolescents44–45,638–642
chronicwidespreadpain626,628–632,639–641
complexregionalpainsyndromeinchildrenandadolescents642
fibromyalgiaand‘syndromic’fibromyalgia626–632,628b,629b
generalized626–632
localizedpainsyndromes634–637
withoutidentifiablemusculoskeletalabnormalities44–45
seealsochronicregionalpainsyndrome;chronicwidespreadpain
chronicrecurrentmultifocalosteomyelitis510–511
chronicregionalpainsyndrome634–637
Budapestdiagnosticcriteria636t
clinicalfeatures634–635
epidemiologyandaetiology634
investigation,staging,anddiagnosis635
management635–637
chronicwidespreadpain626
activemind–bodytechniques641
careprogrammes640
causative/associatedconditions626b
childrenandadolescents639–641
management628–632,639–640
parentcoaching641
pharmacotherapy641
psychologicaltherapies640
Churg–Strausssyndromeseeeosinophilicgranulomatosiswithpolyangiitis
ciclosporin667–668,669–670

juvenileidiopathicarthritis329
macrophageactivationsyndrome722
polymyositisanddermatomyositis439
pregnancyandbreastfeeding665t
psoriaticarthritis311–313
relapsingpolychondritis564
Still’sdisease570–571
systemic-onsetjuvenileidiopathicarthritis336
citalopram631–632
clawtoe203
clicks12
clomipramine657
clozapine669
clumsygait39
clunks12
coccidynia163–164
coccyx700
codeine651
codeinephosphate610
coeliacdisease228t
cognitivebehaviouraltherapies630
colchicine513,668,684
colitis232,316–317
collagenandfibrillin,molecularabnormalitiesof578
seealsohereditarydisordersofconnectivetissue
Colles’fracture106–108
commonextensortendonoriginenthesitis694
compartmentsyndrome198
complementaryandalternativemedicine263,616t
complexregionalpainsyndrome28,44–45
childrenandadolescents642
management642
conductionabnormalities217
congenitalscoliosis620
conjunctivitis240
connectivetissueseealsohereditarydisordersofconnectivetissue
constitutionalsymptoms12–13
cornealdisease240
coronaryarterydisease217
cortex,lossof149t
corticosteroidsseeglucocorticoidinjectiontherapy;glucocorticoids
costochondritis133
co-trimoxazole672,673,667
cough62
coupdesabre210t,422
coxibs/COX-2inhibitors656
creatinekinase,raised434t
Crohn’sdisease228t,316–317
cruciateligamentdeficiency185
cryoglobulinaemia213,231t,472
cryopyrin-associatedperiodicsyndromes545
crystalarthritis174

crystalarthropathies277–291
basiccalciumphosphatecrystal-associateddisease290
calciumoxalatearthritis291
calciumpyrophosphatedihydratedisease286–289
seealsogoutandhyperuricaemia
CTLA4-Igseeabatacept
curlytoes,congenital203
cutaneousdisease428–429
cutaneousmanifestations
immunoglobulinG4-relateddisease575t
rareautoinflammatorydiseases543
cutaneouspolyarteritisnodosa478–479
cutaneousvasculitis392t
cyclophosphamide664,668–669
amyloidosis567
ANCA-associatedvasculitides467–469
catastrophicantiphospholipidsyndrome387
giantcellarteritis460
lupusnephritis362f
polymyositisanddermatomyositis439
pregnancyandbreastfeeding665t
relapsingpolychondritis564
systemiclupuserythematosus361t,363
systemicsclerosis420
Takayasuarteritis455
cytokines404
D
dabigatran384
dactylitis(sausagetoe)51,117
danaparoid382t
danazol383
dantrolene659
dapsone564
DeQuervain’stenosynovitis99,109,110,115
defibrotide387
deficiencyofinterleukin-1receptorantagonist510–511,549
features511t
degenerativecausesofbackpain141t
degenerativeconditionsofspineandchestwall132t
degenerativedisease78
degenerativelesions75t
deltoid92t
denosumab492,508,682t
dermatomes
cervicalandupperthoracicnerves74f
upperlimb128f
dermatomyositisseepolymyositisanddermatomyositis
developmentalcausesofbackpaininchildren618t
diabetes210t,224–225
jointandtissuehypomobility/stiffness224t

diabeticamyotrophy225
diabeticneuropathy225
diarrhoea63,231
diazepam610,615t,659
diclofenac327,653–656,668
diffuseconditionsandshoulderpain87t
diffuseidiopathicskeletalhyperostosis(DISH)134
digoxin668,669–670
dihydrocodeine651
discspace,narrowed149t
discectomy611t
discitis143,613
disease-modifyingantirheumaticdrugs647t,662–680
abatacept680
anti-interleukin6inhibitors678–679
anti-TNFαtherapy674–675,675t
apremilast674
axialspondyloarthritisandankylosingspondylitis305–306
azathioprine667
Bcelldepletors677–678
belimumab678
biological674–680
ciclosporin667–668
co-administerednon-steroidalanti-inflammatorydrugs655
conventionalsynthetic662–673
cyclophosphamide668–669
familyplanning,pregnancy,andbreastfeeding663,665t
gold(auranofinandsodiumaurothiomalate)669
hydroxychloroquineandchloroquinephosphate669–670
immunizationandassessmentofinfectionriskbeforecommencement663b
interleukin-1receptorantagonists678
juvenileidiopathicarthritis328–329
leflunomide670
malignancy664
methotrexate671–672
monitoring664t,666b
mycophenolatemofetil672
polymyositisanddermatomyositis438–439
pregnancyandbreastfeeding680
psoriaticarthritis311–313
rheumatoidarthritis248,250–258,253b,254b,259b
rituximab677
SAPHOsyndrome513
secukinumab679
sharedcareinformation665–667
sideeffects666b
Sjögren’ssyndrome398
spondyloarthritis-associatedreactivearthritis315
sulfasalazine672–673
surgeryandinfectiveillness663
systemic-onsetjuvenileidiopathicarthritis336
targetedsynthetic673–674

tocilizumab678–679
tofacitinib673–674
ustekinumab679
uveitis341
distalarthrogryposes582
diuretics660,668
dorsalinterossei114f
dosulepin657
doxycycline536
D-penicillamine570–571
drug-inducedlupuserythematosus(DILE)359
drugsascauseofmyopathiesandmyalgia59t
drugsusedinrheumatology645–687
antidepressants656
biologicaltherapies647t
glucocorticoids660
goutandhyperuricaemia684–687
non-steroidalanti-inflammatorydrugs653–656
opioidanalgesics651–653,652t
osteoporosis682–683
pharmacotherapy647t
pooledintravenousimmunoglobulin687
pulmonaryarteryhypertension683–684
Raynaud’sdisease683–684
seealsobiologicaltherapies;disease-modifyingantirheumaticdrugs;painrelief
dryeye240
duloxetine615t,631–632,658
Dupuytren’scontracture115,119,224–225
dysphagia63
dyspnoea62
dysrhythmias217
systemicsclerosis416t
E
ears
andgranulomatosiswithpolyangiitis465
andrelapsingpolychondritis565t
andskindisorders206–207
Eaton–Lambertmyasthenicsyndrome234–235,235t
ectopiccalcificationandossification505
eculizumab364–365,383
edoxaban384
Ehlers–Danlossyndrome230t,586–589
classical587
classification586
genotypingandclinicaldiagnosis586–589
hypermobile587,588t,592–593
vascular589
elbow
glucocorticoidinjectiontherapy694–695
joint695

lateralepicondylitis/tenniselbow694
medialepicondylitis/golfer’selbow694
olecranonbursitis695
physicalexamination14t,17t
seealsoelbowpain;lateralepicondylitis(tenniselbow);medialepicondylitis(golfer’selbow)
elbowpain98–104
activeflexionandsupination/pronation100
acuteorchronic(overuse)trauma,historyof98–99
adults98–102
bonyconfigurationatelbow98f
causesinchildrenandadolescents104t
childrenandadolescents104
distalarmsymptoms101
distalradiation99
electrophysiology102
examination100–101
exclusivepaininelboworreferredfromelsewhere98
flexingandextension,passive101
functionalanatomy98
historytaking98–99
lateralepicondyleofhumerus,palpationof100
locking99
medialhumeralepicondylepalpation100
needlearthrocentesis/olecranonbursocentesis102
peripheralnervefunctiontesting101
prominentstiffness99
radiographsandotherimaging101
supinationandpronationofforearm101
symptomsinotherjoints99
treatment102
unremittingandsevere99
visualinspection100
emergencies,rheumatological707–727
infectionsinpatientsonbiologicaltherapy712–714
macrophageactivationsyndrome722–723,723t
malignanciespresentingwithmusculoskeletalsymptomsinchildren726–727
methotrexate-inducedpneumonitis721
paediatricosteomyelitis724
septicarthritis708–711
systemiclupuserythematosus,acute714–717
systemicsclerosiscrises720
systemicvasculitis718–719
emptycantest91f
‘end-feel’101
endocrinedisorders/manifestations224–227
acromegaly227
antiphospholipidsyndrome379
diabetes224–225
hyperparathyroidism226–227
hypothyroidism225–226
myopathiesandmyalgia59t
thyroidacropachy226

thyrotoxicosis226
endocrineglands575t
endostealhyperostosis522–523
entericinfection228t
enthesitis134,173–174,597t
children184–185
indices303t
oligoarticular47
spondyloarthritis297b
trochanteric158–159
enthesitis-relatedarthritis318–319
juvenile335
enthesophytes101
entrapmentneuropathies238
eosinophilicfasciitis209,210t,235,409t,422,572
eosinophilicgranuloma622b
eosinophilicgranulomatosiswithpolyangiitis213,217,231t,467
treatment469
eosinophilicmyalgiasyndrome409t

eperisone615t
epiduraletanercepttherapy616t
epiduralsteroidinjections616t
epiphysealdysplasia157,160t
epratuzumab364–365,398
erythemaelevatumdiutinum472
erythemamarginatumseerheumaticfever
erythemanodosum52,560
erythromycin540,660
etanercept674–675,676
ANCA-associatedvasculitides468
axialspondyloarthritisandankylosingspondylitis305–306
backpain616t
juvenileidiopathicarthritis329
polymyositisanddermatomyositis440t
pregnancyandbreastfeeding676t
psoriaticarthritis312
rheumatoidarthritis262b
Still’sdisease571
etidronate507–508
etodolac655
etoricoxib656
Eurofevertool548t
Ewingsarcoma622b
inchildren726
exercise490,615t
chronicpainsyndromes630
extension145
extensorhallucislongus147t
extensorpollicisbrevis696
externaltibialtorsion186
extraglandulardisease392t
extramusculardisease,treatmentof440–441
eyedisorders/manifestations240
Behçet’sdisease552
dryeye(xerophthalmia)240
granulomatosiswithpolyangiitis466
immunoglobulinG4-relateddisease575t
ischaemicophthalmiclesions240
relapsingpolychondritis565t
sarcoidosis557t
scleralandcornealdisease240
systemiclupuserythematosus352t
uveitis240
F
Faber/Patricktesttest169t
face206–207
FacesPainScale20–21
facetjointarthritis/syndrome610–611
familialcoldautoinflammatorysyndrome542–543

familialMediterraneanfever546
late-onset547
familyplanninganddisease-modifyingantirheumaticdrugs663
Fanconisyndrome497
fatpadsyndrome184–185
fatigue226
childrenandadolescents23
Sjögren’ssyndrome395
febuxostat685
Felty’ssyndrome247
femaletriadsyndrome200–201
femoralanteversion32t,185
Fenbid
®
653–656
fetalloss379
fever23
fibrillinseecollagenandfibrillin,molecularabnormalitiesof
fibromyalgia626–628
ACR(revised)2010criteria629b
diagnosis627–628,628b
historyofuseofterm627
juvenile44–45,639–641
management628–632
sitesoftendernessin65f
‘syndromic’626–627
fibrosis
nephrogenicsystemic422–423
systemicsclerosis405
fibrousdysplasia520
fingers17t,112f,117
Finkelstein’stest110
flatfeet(pesplanus)32t,201–202
flexordigitiminimiBrevis115t
flexortendinopathy119
fluoxetine631–632,657,683t
fluvastatin383
folicacid671–672
folinicacid671–672
fondaparinux382t
foot18t
forefoot193,196,199
glucocorticoidinjectiontherapy704–705
hindfoot14t,189f,191–192,195,198–199
midfoot14t,192–193,195–196
smalljoints705
seealsolowerlegandfootdisorders
forefoot193,196,199
foreignprotein212t
fractures
Bennett’s106–108
calcaneal198
Colles’106
hip161–162

non-traumaticvertebral612
andosteoporosis489–493
stress191
Freibergdisease515t,516
Froment’ssign125–126
frozenshoulder(adhesivecapsulitis)88,224–225,600
fungi527t,712t
G
gabapentin615t,636,637,641,658
gait,arms,legs,spine(GALS)screen14–19,15–16f,17t,19f
paediatric14–19,24
gaitconcerns,childrenandadolescents22
gaitpatterns144–145
children37–39
gametogenesis668–669
ganglia116,118
gastritis232
gastrocnemiusandsoleus(ankleplantarflexion)147t
gastrointestinaldisorders/manifestations228t
antiphospholipidsyndrome379
Behçet’sdisease554
non-steroidalanti-inflammatorydrugs654t
polymyositisanddermatomyositis429,432t
sarcoidosis557t
Sjögren’ssyndrome394
systemiclupuserythematosus352t
systemicsclerosisandrelateddisorders414–415
gastrointestinalhaemorrhage229–231,232
genitalia418t
genitourinarymanifestations,immunoglobulinG4-relateddisease575t
genuvalgum(knockknees)32t,175
childrenandadolescents186
genuvarum(bowlegs)32t,175
childrenandadolescents186
giantcellarteritis457–460,458t,718
gingivalhyperplasia232
glandulardisease392,393t
glenohumeralinstabilityduetolabraltrauma597t
glenohumeraljoint90,692
glomerulonephritis220
glucocorticoidinjectiontherapy689–705
acromioclavicularjoint693
ankleandfoot704–705
carpaltunnelsyndrome696
elbow694–695
extensorpollicisbrevis/abductorpollicislongus696
glenohumeraljoint692
greatertrochanterpainsyndrome700
hipandperiarticularlesions700
kneeandperiarticularlesions702–703

lateralepicondylitis/tenniselbow694
medialepicondylitis/golfer’selbow694
olecranonbursitis695
plantarfaciitis704
principlesofinjectiontechniques691
radiocarpaljoint696
shoulder692–693
subacromialspace693
subtalarjoints704
tarsaltunnel704
wristandhand696–698
glucocorticoids256,262b,647t,660
ANCA-associatedvasculitides467–469
cautionsandcomplications661t
chronicnon-bacterialosteomyelitis511
chronicpainsyndromes631–632
chronicregionalpainsyndrome636
interactions660
juvenileidiopathicarthritis327
lobularpanniculitis560–561
macrophageactivationsyndrome722
osteoporosis487–488
pelvicorhiplesions160t
polymyositisanddermatomyositis438
post-herpeticneuralgia637
rheumaticfever540
SAPHOsyndrome513
Still’sdisease570–571
systemiclupuserythematosus360
systemic-onsetjuvenileidiopathicarthritis336
Takayasuarteritis455
seealsoglucocorticoidinjectiontherapy
glutealgroupmuscles14t,156–157
glyceryltrinitrate683t
gold(auranofinandsodiumaurothiomalate)669
pregnancyandbreastfeeding665t
psoriaticarthritis311–313
rheumatoidarthritis254b,255
golfer’selbowseemedialepicondylitis
golimumab305–306,312,674–675,676t
gonococcalarthritis48t,529t,530–531
Goodpasture’ssyndrome221
goutandhyperuricaemia48t,225–226,278–284
acuteattackofgout281–282
causesandriskfactors278t
chronicgout282–284
classificationcriteria279
clinicalconditionsmimickinggout280b
clinicalfeatures279–280
drugs684–687
epidemiology278
imaging280–281

investigation280
management281–284
tophaceousgout282–284
gradedactivityprogrammes(backpain)609t
granulomafaciale472
granulomatosiswithpolyangiitis
classificationcriteria464b
ear,nose,andthroatsymptoms465
eosinophilicseeeosinophilicgranulomatosiswithpolyangiitis
epidemiology464
eyedisease466
investigation466
musculoskeletalsymptoms464–465
nervoussystem466
presentationandclinicalfeatures464
pulmonarydisease465
renaldisease465
skindisease465
treatment466,468
grapefruit668
Graves’disease226
greatertrochanterpainsyndrome700
Guillain–Barrésyndrome39–40
gutandhepatobiliarydisorders/manifestations228–232
immunoglobulinG4-relateddisease575t
rheumaticdiseases229–231
sideeffectsfromdrugsusedintreatment231–232
Sjögren’ssyndrome394
H
haemarthrosis46–47,48t,174
haematologicaldisorders/manifestations
non-steroidalanti-inflammatorydrugs654t
systemiclupuserythematosus351,716–717
haematuria213
haemochromatosis54,228t,229
haemophagocyticlymphohistiocytosis,secondaryseemacrophageactivationsyndrome
haemoptysis62,219
haloperidol540
hammertoe203
hamstrings(kneeflexion)147t
hand112–122
adults112–121
bonescintigraphy119
childrenandadolescents122
conditions/featuresdiagnosedonradiograph120t
deformityofdigits118
diffuseswelling118
dorsalinterossei114f
dorsum118
Dupuytren’scontractureandflexortendinopathy119

examination117–119
extensorexpansionoffinger112f
functionalanatomy112–115
glucocorticoidinjectiontherapy696–698
grip113–115
historytaking115–117
hypermobile32t
hypothenareminencemuscles114f,115t
immobilityandstiffness,painassociatedwith115
intrinsicmuscles113
ischaemicpain116
jointsandnodules,palpationof118
laboratorytests120–121
longtendons112–113
lumbricalmuscles114f
magneticresonanceimaging119
musclewasting118
nailsandfingers,examinationof117
neurologicalqualitiestopainorcommonnervelesions115
painarisingfrombone116
painfulconditions108t
palm118
palmtendons,palpationof119
physicalexamination17t
radiographs119,120t
skindisorders207
smalljoints697–698
stiffness,localordiffuse115
‘swelling’116
thenareminencemuscles113t,114f
tingling/pinsandneedles/numbness116
treatmentofdisorders121
triggerfinger117,224–225
ultrasound119
‘weakness’117
Hashimoto’sthyroiditis226
headache239
helminths527t
Henoch–Schönleinpurpura213,231t,471,476–478
heparin381t,383,384t,387
hepaticmanifestationsandsarcoidosis557t
hepatitis58t,228t,229,392t
hepatitisCosteosclerosis523
hepatobiliarydisordersseegutandhepatobiliarydisorders/manifestations
hepatosplenomegaly229–231
hereditarydisordersofconnectivetissue577–594
Beal’ssyndrome584
distalarthrogryposes582
Ehlers–Danlossyndrome586–589
hypermobilityspectrumdisorderinadults590–591
hypermobilityspectrumdisorderinchildrenandadolescents592–593
Loeys–Dietzsyndrome584

Marfansyndrome584
molecularabnormalitiesofcollagenandfibrillin578
osteogenesisimperfecta580–581
Sticklersyndrome594
herniateddisc621
herpeszoster132t
Hibernianfeverseetumournecrosisfactor(TNF)receptor-associatedperiodicsyndrome
highsteppinggait39
hilarlymphadenopathy218
hindfoot14t,191–192,195,198–199
tendons,retinaculae,andbursae189f
hip
flexion/internalrotation147t
functionalanatomy157
glucocorticoidinjectiontherapy700
osteoarthritis276
andperiarticularlesions700
physicalexamination18t,162
Hoffman’ssyndrome226
hormonereplacement490
housemaid’sknee175
hydrotherapy(backpain)609t
hydroxychloroquine668,662–663,664,669–670
antiphospholipidsyndrome381–384,382t
dermatomyositis440–441
juvenileidiopathicarthritis329
lupusnephritis362f
pregnancyandbreastfeeding665t
psoriaticarthritis311–313
rheumaticarthritis254b,255,262b
Sjögren’ssyndrome398
Still’sdisease570–571
systemiclupuserythematosus361t
hypercalcaemia500–501
causes501t
childhood501–502,502t
familialbenign503
familialhypocalciuric502t
idiopathicinfantile502t
treatment501t
hypergammaglobulinaemicpurpura472
hyper-IgDsyndrome546–547
hypermobilityseejointhypermobilitysyndrome
hyperparathyroidism54,226–227
familial503–504
neonatalprimary502t
primary502–503
secondaryandtertiary503
hypertension654t
seealsopulmonaryarteryhypertension
hypertrophicosteoarthropathy
primary522

pulmonary(secondary)235,522
hyperuricaemiaseegoutandhyperuricaemia
hyperviscosity220
hypophosphataemicosteomalacia234–235
hypothenareminencemuscles114f,115t
hypothyroidism225–226
hypovitaminosisD496
I
ibandronicacid682t
ibuprofen327,641,653–656
idiopathicarthritisseejuvenileidiopathicarthritis
idiopathiccausesofmyopathiesandmyalgia59t
idiopathicinflammatorymyopathiesseepolymyositisanddermatomyositis
idiopathicscoliosis619
iliopsoas(hipflexion/internalrotation)147t
iliotibialband172f
iloprost683t
imipenem536
imipramine657
immunecellactivation404
immunoglobulin,intravenous687
ANCA-associatedvasculitides468–469
polymyositisanddermatomyositis439
Still’sdisease570–571
immunoglobulinG4-relateddisease574,575t
immunologicalfeatures,systemiclupuserythematosus352t
immunosuppressivetherapies259–260
impingement89–90
indomethacin655
infection
acutepolyarthritis58t
arthritisfollowing324t
backpain141t,151,618t
enteric228t
kneepain174
managementwhileonimmunosuppression259–260
non-osseous75t
skinvasculitis213
seealsoinfectionandrheumaticdisease
infectionandrheumaticdisease541–576
autoimmune67t,160t
Lymedisease536,537t
Mycobacteriumtuberculosis532–533
osteomyelitis534–535,535t
pathogenesis526t
rheumaticfever538–540
septicarthritis528–531
inflammatoryarthritis
characteristicrashes36
childrenandadolescents33–37

examination35
familyhistory34
imaginginvestigations36
infectiousfeatures33–34
jointaspirationandsynovialbiopsy37
jointinvolvement,typicalpatternsof33t
laboratorytests36–37
regionalmusculoskeletalexamination35
responsetomedication35
systemsenquiryandpastmedicalhistory34
trauma,historyof34
travelhistoryandinfectiouscontacts35
inflammatorybackpain
differentialdiagnosis324t
spondyloarthritis296b
inflammatoryboweldisease-relatedspondyloarthritis316–317
clinicalpresentation316
management317
inflammatorydisorders/manifestations75t
backpain141t,618t
skinvasculitis212t
systemicsclerosis405
inflammatoryperipheralneuropathy238
infliximab674–675,676
axialspondyloarthritisandankylosingspondylitis305–306
polymyositisanddermatomyositis440t
pregnancyandbreastfeeding676t
psoriaticarthritis312
rheumatoidarthritis262b
infraspinatus92t
interleukin-1receptorantagonistsseeanakinra
internaltibialtorsion186
interstitiallungdisease219
interstitialnephritis222
intestinalbypasssurgery228t
in-toeing32t,203
ischaemicophthalmiclesions240
ischialtuberosities700
Iselindisease515t
seealsoosteochondritis
J
Jack’stest196
januskinaseinhibitors259
jointhypermobilitysyndrome29,64t,99,206,230t
adults46,590–591
Beightonhypermobilityscale590–591,592
childrenandadolescents41,592–593,639–641
hands32t
knees32t
jointinjectiontherapies182–183

seealsoglucocorticoidinjectiontherapy
joints
painswithsystemicfeatures40
polymyositisanddermatomyositis429
sarcoidosis557–558
Sjögren’ssyndrome393
synovitis177
juveniledermatomyositis231t,444–445
amyopathic446
juvenileenthesitis-relatedarthritis335
juvenileidiopathicarthritis321–341
andadultarthritis,differencesbetween326
classification323
diagnosis324–326
differentialdiagnosis324t
epidemiology322–323
gutandhepatobiliarydisease231t
investigations326–327
keysigns325t
macrophageactivationsyndrome338,722
management324–330
nationalguidelinestoaidmanagement324
oligoarticular334
outcomeandprognosis329–330
polyarticular334
rheumatoidfactor-negativepolyarticular334–335
subtypes322t,334–336
systemic-onset40,326t,335–336
transitionservices332
treatment327–329
uveitis340–341
juvenileidiopathicinflammatorymyopathy444–446
juvenileidiopathicosteoporosis485–486
juvenilemandibularchronicosteomyelitis510–511
juvenilepolymyositis446
juvenilepsoriaticarthritis335
juvenilespondyloarthritis318–320,335
clinicalpresentation319
diagnosticapproach319
epidemiologyandclassification318–319
management319–320
outcome320
juvenilesystemiclupuserythematosus368–370
K
Kawasakidisease207,231t,475–476
childrenandadolescents40
Kennedy–Hawkinstest91f
keratodermablennorrhagica52
ketoprofen655
kidneysseerenaldisorders/manifestations

Kienbockdisease515t
knee
extension147t
flexion147t
glucocorticoidinjectiontherapy702–703
hypermobile32t
osteoarthritis276
periarticularlesions703
physicalexamination18t,14t
seealsokneepain
kneepain170–186
adults170–183
anatomy170–173
anteriorcruciatefunctiontests178f
anteriorpain,causesof173t
anteriorstructures171f
axialsection171f
biomechanicalfactors182
capsaicincream183
childrenandadolescents184–186
computedtomography181
drugs183
examination175–179,185
examinationandobservationofpatientstanding175
examinationforjointsynovitisandeffusion177
examinationofsittingpatient175–177
femoralanteversion,retroversion,andtibialtorsion180f
historytaking173–175,184–185
iliotibialband172f
initialonset174
injury174
jointaspirationandperiarticularfluidcollections181
jointinjectiontherapies182–183
laboratoryinvestigations181
lidocainepatches183
locking174
magneticresonanceimaging181
meniscusdamagetesting178
pastmedical,family,occupationalandleisurehistory174–175
patellaQangle172f,177
patternandtypeof174
positioningofkneeforpalpation176f
proximalmusculoskeletalexamination179
radiographs179
siteofpain173–174
stabilitytesting177
steroidinjection,local182–183
surgery183
treatment181–183
ultrasound181
yttrium-90radiationsynovectomy183
Köhlerdisease515t,516

kyphoplasty493
L
Lachmanntest177,178f
lacrimalglands575t
lactationseebreastfeeding
largevesselvasculitis452
causes452t
laryngealobstruction219
Laseague’stest146
laserlumbardiscectomy611t
lateralepicondylitis(tenniselbow)100,602–603,603f
glucocorticoidinjectiontherapy694
leflunomide662–663,664
amyloidosis567
ANCA-associatedvasculitides468
juvenileidiopathicarthritis329
juvenilespondyloarthritis320
pregnancyandbreastfeeding665t
psoriaticarthritis311–313
rheumatoidarthritis254b,255,262b,670
Takayasuarteritis455
legdisorders
developmentalfactors185
femoralanteversion185
genuvalgum(knockknees)186
genuvarum(bowlegs)186
internaltibialtorsion186
seealsolowerlegandfootdisorders
leglengthdiscrepancy169
Legg–Calvé–Perthesdisease514,515t
leisureactivities/history77,109,174–175
leucocytoclasticvasculitis470,478
associatedconditions470t
precipitantsandassociations212t
leukaemia622b,727
Libman–Sacksendocarditis217
lichenplanus207
lidocaine615t
limp
assessment38–39
causes38t
childrenandadolescents22,38–39
linearscleroderma402,422
lipodermatosclerosis561,210t,409t
lipogranulomatosis560–561
livedoreticularis209
livedoidvasculitis473
liver418t
antiphospholipidsyndrome379
non-steroidalanti-inflammatorydrugs654t

localizedpainsyndromes634–637
chronicregionalpainsyndrome634–637,636t
post-herpeticneuralgia637
temporomandibularjointdysfunction637
trigeminalneuralgia637
Loeys–Dietzsyndrome584
Lofgren’ssyndrome556
longheadofbicepstendonitis597t
losartan361t,683t
lowbackpain140–155
adults140–152
assessment140–141
bonescintigraphy150
childrenandadolescents154–155
commonand/orseriouscauses141t
computedtomography150
descriptionofpain143
epidemiology140
examination144–147,148–151
extensionandlumbarrotation145
familyhistory143
gaitpattern144–145
historytaking141–143
lumbarandsacralspineanatomy140
lumbarnerverootlesions148t
magneticresonanceimaging150
musclestrengthtestinginlowerlimbs147t
nerveroottensiontest146
neurologicalexamination146
observationofactivemovementswhilepatientstanding144
occupationalhistory143
previousbackpainandtrauma143
pronepatient146
radiationofpainandsymptomsinlegs142–143
radiographs148–150,149t
sacroiliacjointsandhips145
screeningforinfection,malignancy,ormetabolicbonedisease151
slumptest145f
straightleg(Laseague’stest)146
treatment151–152
visualinspection144
lowerlegandfootdisorders188–203
adults188–199
anatomyofbonesandjoints188–189
anatomyofintrinsicfootstructure190
anatomyoflongmusclesandtendons189–190
ankleandhindfootexamination195
childrenandadolescents200–203
conditions191,201–203
conditionscausinglocalizedfootpain192t
descriptionofpain193
examination194–196,200

footbones188f
footimaging197
forefootexamination196
forefootpain,causesof193
functionalanatomy190–191
gaitpatterns194
hindfootpain,causesof191–192
historytaking191–194,200
investigations197–198
joint/bursafluidaspiration198
laboratorytests198
lowerlegimaging197
lowerlumbarnerverootlesions197t
midfootandfirstMTPpain,causesof192–193
midfootlesionsexamination195–196
neuroanatomy190
neurologicalexamination196
neurophysiology198
observation194
relevantproximalmusculoskeletalexamination196
siteandqualityofpain191
steroidinjections199
surgery199
tendons,retinaculae,andbursaeofhindfoot189f
trauma,historyof200–201
treatment198–199
treatmentforankleandhindfootdisorders198–199
treatmentforforefootdisorders199
treatmentforlowerlegdisorders198
weakness194
lucentlesions,localized149t
lumbarcanalspinalstenosis611–612
lumbardiscprolapse611t
lumbarflexionmeasurement15–16f
lumbarnerverootlesions148t,197t
lumbarpedicles,short149t
lumbarrotation145
lumbarspine17t,140
lumbosacralanomalies149t
lumbricalmuscles114f
lunateosteochondritis(Kienbock’sdisease)515t
lungsseecardiopulmonarydisorders/manifestations;pulmonarydisorders/manifestations
lupusnephritis362f,364–365
lupuspernio206–207
lupusprofundus561
Lymearthritis49,50
Lymedisease58t,536,537t
lymphadenopathy392t
hilar218
lymphaticdisorders/manifestations
immunoglobulinG4-relateddisease575t
sarcoidosis557t

lymphoblasticleukaemia,acute727
lymphocyticthyroiditis226
lymphocyticvasculitis(non-leucocytoclastic)470t,473
lymphoedema,dependent210t
lymphoma622b,727
lymphoproliferativediseaseandSjögren’ssyndrome392t,395
M
McCune–Albrightsyndrome520
McGillpainscale7t
McGregor’sline78–79
macitentan417,683t
McKenzieexercises609t
McMurraytest178,179f
macrophageactivationsyndrome338,722–723
clinicalfeatures722,723t
diagnosis722
laboratoryfeatures723t
pathology722
treatment723
macularrashes207
Majeedsyndrome510–511,542–543
features511t
malignancy75t,234–236
causingmusculoskeletalsymptoms234
disease-modifyingantirheumaticdrugs664
lowbackpain151
myopathy235t
neoplasticdiseases,primaryandsecondaryofbonesandjoints234
non-myopathyparaneoplasticsyndromes235
paraneoplasticmyopathies234–235
polymyositisanddermatomyositis430
presentingwithmusculoskeletalsymptomsinchildren726–727
rheumaticdiseasesassociatedwithincreasedincidenceof236
rheumatoidarthritis-associatedrisk260
rheumatologicaldrugs236
secondary622b
skinvasculitis212t
systemiclupuserythematosus352
andwidespreadpain69–70
seealsotumours
malletfinger118
mallettoe203
manifestationsandsarcoidosis557t
manipulation(backpain)609t,615t
Marfansyndrome230t,584
Ghent1996criteria585t
mechanicaldisorders/manifestations
backpain141t,160,618t
hip157
seealsobiomechanicalconditions

mechanicallesions75t
medialepicondylitis(golfer’selbow)98–99,100
glucocorticoidinjectiontherapy694
mediannerve101,126–127,128f
mediastinalconditions131t
mefloquine669–670
meloxicam656
mepacrine361
mepolizumab469
meptazinol652
meralgiaparesthetica158–159,700
mesalazine317
mesna668–669

metabolicbonediseases483–524
bonetumours524
childhoodautoinflammatorybonediseases510–511
fibrousdysplasia520
lowbackpain151
osteochondroses514–516
osteonecrosis518–519
Paget’sdisease506–508
SAPHOsyndrme512–513
sclerosingbonedisorders522–523
seealsoosteomalaciaandrickets;osteoporosis;parathyroiddiseaseandrelateddisorders
metaboliccausesofmyopathiesandmyalgia59t
metabolicsyndromes225
metatarsalheadosteochondritis(Freiberg’sdisease)515t
metatarsalphalangealjoint192–193
metatarsusadductus201
methocarbamol659
methotrexate660,662–663,664,669–670,671,674–675,677
amyloidosis567
ANCA-associatedvasculitides467–469
axialspondyloarthritisandankylosingspondylitis305
chronicnon-bacterialosteomyelitis511
eosinophilicfasciitis572
giantcellarteritis460
immunoglobulinG4-relateddisease574
-inducedpneumonitis721
inflammatoryboweldisease-relatedspondyloarthritis317
juvenileidiopathicarthritis329
juvenilespondyloarthritis320
polymyositisanddermatomyositis438–439
pregnancyandbreastfeeding665t
psoriaticarthritis311–313
relapsingpolychondritis564
rheumatoidarthritis253,254b,262b
SAPHOsyndrome513
spondyloarthritis-associatedreactivearthritis315
Still’sdisease570–571
systemiclupuserythematosus361t,363
systemic-onsetjuvenileidiopathicarthritis336
systemicsclerosis420
Takayasuarteritis455
methylprednisolone660,677
antiphospholipidsyndrome381t
giantcellarteritis460
lupusnephritis362f
macrophageactivationsyndrome722
polymyositisanddermatomyositis438
Still’sdisease570–571
systemiclupuserythematosus360
mevalonatekinasedeficiency546–547
microdiscectomy611t
microscopicpolyangiitis213,466–467,468

midfoot14t,192–193,195–196
milnacipran631–632,658
Milwaukeeshoulder/kneesyndrome50,89
miscellaneousconditionsseerareautoinflammatoryandmiscellaneousdiseases;skinconditionsassociated
witharthritis
mitralvalveprolapse217
mixedconnectivetissuedisease230t,231t
mixedserotonin-norepinephrinereuptakeinhibitors658
monoarthritis,acute46–47
monoarticulardisease324t
monoarticularpain46–47
mononeuritismultiplex213
morphinesulfate610,653
morphoea210t
circumscribed422
generalized402,422
guttate422
Morton’smetatarsalgia192t,196
Muckle–Wellssyndrome542–543
mucocutaneousmanifestations,systemiclupuserythematosus348
mucosalinvolvementandBehçet’sdisease550–552
multicentricreticulohistiocytosis562
muscleactivationtests162–163
musclebiopsyandpolymyositisanddermatomyositis435–436
muscleenzymelevelsandpolymyositisanddermatomyositis434–435
musclerelaxants659
musclesandsarcoidosis558
musculardystrophies59t
musculoskeletalassessmentandpatternsofdisease25–70
adults46–70
childrenandadolescents32–45
featuresnottobemissed26
normalvariants32–33,46
musculoskeletaldisorders/manifestations
antiphospholipidsyndrome379
Behçet’sdisease552
granulomatosiswithpolyangiitis464–465
Lymedisease537t
sarcoidosis557–558
systemiclupuserythematosus348
musculoskeletallesionsseeupperlimbmusculoskeletallesions
musculoskeletalsymptoms,evaluationof3–24
clunks,snaps,andclicks12
constitutionalsymptoms12–13
elicitedpainonexamination10
fatigueinchildrenandadolescents23
feverinchildrenandadolescents23
gait,arms,legs,spine(GALS)screen14–19,15–16f,17t,19f
inflammatorymusculoskeletalpain8
limpandgaitconcernsinchildrenandadolescents22
McGillpainscale7t
mechanicalpain8

painassessmentinchildrenandadolescents20–21
paininadults6–13
painlocalization6–7
physicalexamination14t,15–16f,17t,19f
pyrexiainchildrenandadolescents23
qualityofpain7
rashes13
stiffness12
swelling12
unexplainedacute-phaseresponseinchildrenandadolescents23
myalgias59t,60,65–67
myastheniagravis235t
mycobacteria527t
Mycobacteriumtuberculosis532–533
mycophenolatemofetil672
ANCA-associatedvasculitides468
eosinophilicfasciitis572
immunoglobulinG4-relateddisease574
juvenileidiopathicarthritis329
lupusnephritis362f
polymyositisanddermatomyositis439
pregnancyandbreastfeeding665t
systemiclupuserythematosus361t,363
systemicsclerosis420
Takayasuarteritis455
myeloma236
myocardialfibrosis416t
myocardialinfarction131t
myocarditis216–217,416t
myocardium216–217
myocrisin(gold)254b,255
myofascialpain87
myopathy59t
drug-induced431t,443
idiopathicinflammatory426,430–431,440t,444–446
andmalignancy235t
paraneoplastic234–235
proximal226
screeningexamination66f
myositis392t,428
autoantibodiesin436–437
benignmyositisofchildhood39–40
chronic39–40
inclusion-body438,442
infectious59t
overlap446
-specificautoantibodies445
N
nails63,117,207
naproxen327,653–656

navicularosteochondritis(Köhler’sdisease)515t
neck,physicalexaminationof14t,17t
neckpain
acutewithtrauma76
adults74–79
backgroundepidemiology74
bonescintigraphy79
causesinadults75t
causesinchildren83t
childrenandadolescents82
computedtomography79
dermatomaldistributionofcervicalandupperthoracicnerves74f
examination77–78,82
functionalanatomy74–76
historytaking76–77
magneticresonanceimaging79,80f
newand/orassociatedsymptoms76–77
occupationalandleisureactivities77
radiographs78–79
site,radiation,anddescriptionof76
trauma,previous77
treatment79,80f
Neertest91f
neonatallupuserythematosus372–373
neoplasmsascausesofbackpain141t,618t
neoplasticdiseases,primaryandsecondaryofbonesandjoints234
nephriticsyndromes221
nephritis,interstitial222
nephrogenicfibrosingdermopathy409t
nephrogenicsystemicfibrosis422–423
nerveentrapment124
nerveirritation132t
nervelesionsseeupperlimbperipheralnervelesions
nerverootlesions609–610
nervoussystemdisorders/manifestations
granulomatosiswithpolyangiitis466
sarcoidosis557t
systemiclupuserythematosus351–352
systemicsclerosis418t
seealsoneurologicaldisorders/manifestations
neuroblastoma727
neurologicalconditions238–239
cerebrovascularlesions238–239
entrapmentneuropathies238
headache239
inflammatoryperipheralneuropathy238
neuromyopathy239
spinalcordlesions238
neurologicaldeficit,rapidlyprogressive151–152
neurologicaldisorders/manifestations
Behçet’sdisease553–554
immunoglobulinG4-relateddisease575t

Lymedisease537t
shoulderpain87t
wristandhand108t
neurologicalexaminationandlowbackpaindisorders146
neuromusculardiseaseandSjögren’ssyndrome394
neuromuscularscoliosis620
neuromyopathy239
neuropathy
entrapment238
inflammatoryperipheral238
neutrophilicdermatoses208,561–562
non-infectious561t
Sweet’ssyndrome561–562,562t
nifedipine683t
nodularvasculitis473
non-accidentalcausesofbackpaininchildren618t
non-bacterialosteomyelitis,chronic510–511
non-gonococcalarthritis529t
non-gonococcalsepticarthritis47
non-Hodgkin’slymphoma236
non-inflammatorymusculoskeletalconditions
childrenandadolescents40–44
contributoryfactorsandtheirimpact42
diagnosis,principlesof40–41
examination43
history42–43
laboratorytests44
magneticresonanceimaging44
radiographs44
typicaldisordersinchildrenandadolescents41b
ultrasound44
non-myopathyparaneoplasticsyndromes235
non-osseousinfections75t
non-septicdiscitis613
non-steroidalanti-inflammatorydrugs653–656,660,672
adverseeffects654–655
axialspondyloarthritisandankylosingspondylitis305
backpain610,615t
cautions655
chronicnon-bacterialosteomyelitis511
chronicpainsyndromes631–632
andco-administereddisease-modifyingantirheumaticdrugs655
inflammatoryboweldisease-relatedspondyloarthritis317
juvenileidiopathicarthritis327
non-traumaticvertebralfracture612
psoriaticarthritis311–313
rheumaticfever540
rheumatoidarthritis252,262b
SAPHOsyndrome513
spondyloarthritis-associatedreactivearthritis315
Still’sdisease570–571
systemiclupuserythematosus361t

systemic-onsetjuvenileidiopathicarthritis336
non-traumaticvertebralfracture612
norepinephrinereuptakeinhibitors657–658
nortriptyline615t,657
nose
andgranulomatosiswithpolyangiitis465
andrelapsingpolychondritis565t
O
Obertest169t,178
occupationalactivities/history77,109,174–175
oculardisordersseeeyedisorders/manifestations
odanacatib492
oesophagealdysmotility229–231
oesophagealreflux131t
olecranonbursitis695
oligoarticularjuvenileidiopathicarthritis334
oligoarticularpain
adults47–55
affectedjoints50,51
associatedfeatures51
commoncausesandtypicalpatternsofpresentation48t
examination49,51–52
familyandsocialhistory50–51
generalexamination51
history48–49,50
inflamedjoint,assessmentof47
investigations52
jointaspiration52–53
jointfluidcharacteristics53t
laboratoryinvestigations54
magneticresonanceimaging54
musculoskeletalstructures,examinationof51
precedingfactors50
radiographs53–54
skinrashesandinflammation52
synovialbiopsy54–55
ultrasound54
oncogenicosteomalacia235t
hypophosphataemic498
onycholysis207
ophthalmicsymptomsseeeyedisorders/manifestations
ophthalmoplegia240
opiates,intrathecal615t
opioidanalgesics651–653
cautionsandsideeffects652t
opponensdigitiminimi115t
orthopaedicconditions,differentialdiagnosis324t
Osgood–Schlatterdisease514,515t
osteitispubis159,162
osteoarthritis48t,265–276

aetiology268
clinicalfeatures270–271
epidemiology266
facetjoint149t
futuretherapeuticstrategies275
generalizednodal270–271
hip276
inflammatory/erosive271
investigation272
knee276
largejoint271
management274–275,275b
pathology267
pharmacotherapies274
prognosis276
radiographic-pathologycorrelates267t
secondary271
osteochondritis514–516
childrenandadolescents42–43,184–185
dissecans42–43,174,514–516
Scheuermann’s132t,134,620
osteochondroses514–516
childrenandadolescents42–43,184–185
conditions515t
Freiberg’sdisease516
Köhlerdisease516
Legg–Calvé–Perthesdisease514
Scheuermann’sdisease514
Sinding–Larsen–Johanssondisease516
osteogenesisimperfecta580–581
Sillenceclassification580t
osteoidosteoma524,622b
osteolysis225
osteomalaciaandrickets494–498
fromalteredphosphatehomeostasis497
classification494t
clinicalandlaboratoryfindings495–496
hypophosphataemic234–235
management496
oncogenichypophosphataemic(tumour-induced)498
oncogenicosteomalacia235t
ricketyrosary132t
thoracicbackandchestpain132t
vitaminD-dependentrickets496
X-linkedhypophosphataemicrickets497
osteomyelitis225,534–535,535t
chronicnon-bacterial510–511
osteonecrosis106–108,518–519
causative/associatedconditions519t
osteopenia352
generalized149t
osteopetrosis522

osteopoikilosis523
osteoporosis484–493
abaloparatide492
bisphosphonates490–491
calcium489
causative/associateddiseases486t
clinicalfeatures488
denosumab492
drugs682–683
endocrinemanifestations226
exercise490
fractureprevention489–493
glucocorticoid-induced487–488
guidelinesformanaging493
hormonereplacement490
idiopathic485–486
investigations488–489
juvenileidiopathic485–486
kyphoplasty493
odanacatib492
pathogenesisandclassification484–488
rheumatoidarthritis247
riskoffracturewithsite484t
romosozumab492
strontiumranelate491
systemiclupuserythematosus352
teriparatide491
thoracicbackandchestpain133
vertebroplasty492–493
osteosarcoma524
inchildren726
out-toeing32t
overlapmyositis446
oxicams653–656
oxycodonehydrochloride653
P
pachydermoperiostosis522
paediatricgait,arms,legs,spine(pGALS)screen14–19,24
paediatricsystemiclupuserythematosus,acute717
Paget’sdisease132t,157,198,506–508
clinicalfeatures506t
investigationandtreatment507–508
pain624–625
acute624–625
inadults6–13
elicitedpainonexamination10
gatecontroltheory625
hypermobilityandchronicpaininchildren593
inflammatorymusculoskeletalpain8
localization6–7

McGillpainscale7t
mechanical8
monoarticular46–47
neurophysiology624
pathophysiology625
qualityof7
referred75t,87t
siteof88
seealsochronicpainsyndromes;chronicregionalpainsyndrome;painrelief
painconditions,differentialdiagnosis324t
painrelief647t,648–659
analgesicescalation649–650
antidepressants656
gabapentin658
musclerelaxants659
non-steroidalanti-inflammatorydrugs653–656
opioidanalgesics651–653
pregabalin658
rheumatoidarthritis252
serotoninandnorepinephrinereuptakeinhibitors657–658
simpleandcompoundanalgesics650,651t
topicalagents659
painfularctest91f
palpitations62
pamidronate305,511,581,613,636
Pannerdisease515t
panniculitis560–561
calcifying561
lobular560–561
septal560
withvasculitis561
paracetamol(acetaminophen)650
backpain610,615t
cautionsandsideeffects651t
chronicwidespreadpaininchildrenandadolescents641
compounds650
non-traumaticvertebralfracture612
post-herpeticneuralgia637
paraesthesias124
paraneoplasticmyopathies234–235
paraneoplasticsyndromes,non-myopathy235
paraproteinaemia236
parasites712t
parathyroiddiseaseandrelateddisorders483–524
chronickidneydisease-mineralandbonedisorders504–505
ectopiccalcificationandossification505
familialhyperparathyroidsyndromes503–504
familialhypocalciurichypercalcaemia503
hypercalcaemia500–502,502t
hyperparathyroidism,primary502–503
hyperparathyroidism,secondaryandtertiary503
parathyroidhormoneresistantsyndromes504

renalosteodystrophy504–505,505t
parathyroidhormoneresistantsyndromes504
parentcoaching641
paroxetine657
parsinterarticularis/defect/fracture149t
parvovirusB1958t
patellaQangle172f,177
patellofemoralsyndrome42,184–185
patternsofdiseasepresentationseeoligoarticularpain;widespreadpain
peg-leggait38–39
pegloticase686–687
Pellegrini–Stiedaphenomenon173–174
pelvic,groin,andthighpain156–169
adults156–166
ageofpatient157
areaswithinwhichsensorychangesmaybefound161f
boneandsofttissuepain,distributionandtypeof158–159
bonescintigraphy165
bonyanatomyofposteriorhipandpelvis163f
causesinchildrenandadolescents168t
childrenandadolescents168–169
computedtomography165
diagnosticultrasound164
examination160–164,168–169,169t
hip,functionalanatomyof157
hipexamination162
historytaking157–160
laboratoryinvestigations165
leglengthdiscrepancy169
magneticresonanceimaging165
muscleactivationtests162–163
musculardistribution,painin159
nervepain,qualityanddistributionof159–160
neuroanatomy157
observationandpalpation161–162
painpatternsandcausesaroundproximalleg158t
pelvicandhipregion,anatomyof156
pelvicmusculature,anatomyof156–157
pelvicorhiplesions,riskfactorsfor160t
pelvicphysicalexamination14t
posterolateralstructures,palpationof163–164
previoustrauma,lowback,andmusculoskeletalproblems160
radiographs164
surgery166
thigh,posterior,painin158t
treatment165–166
pemphigoid208
pemphigus208
penicillamine311–313,665t
penicillin536,540
pepticulcerdisease131t,231–232
percutaneousadhesiolysis616t

percutaneousdiscectomy611t
periarticulardisorders108t,290t
periarticularinjections
hip700
knee703
periarticularlesions87t,700–703
pericarditis416t
pericardium216
effusions216
inflammation131t
periodicfever,aphthousstomatitis,pharyngitis,adenitis(PFAPA)syndrome547
periostitis227,191
peripheralneuropathy392t
peripheralspondyloarthritis299b
peritendonitiscrepitans99
Perthesdisease160t
children42–43
pescavus32t,202
pesplanus(flatfeet)32t,201–202
Phalen’smanoeuvre127
phantomlimbpain637
phenoxymethylpenicillin540
phenylketonuria409t
phenytoin669
photosensitivityreaction667
physicalexamination14–19,15–16f,17t,19f
physiotherapy640
pigmentedvillonodularsynovitis576
Pilates615t,630
piriformissyndrome157,163–164
piroxicam655,656
pityriasislichenoides473
plantarfasciitis51,195,200–201
glucocorticoidinjectiontherapy704
plantarspur198
plaques208
plasmaexchange
ANCA-associatedvasculitides467–469
systemiclupuserythematosus364
pleura/pleuraleffusion218
pleurisy416t
pleuriticinflammation131t
pneumonitis,methotrexate-induced721
pneumothorax416t
POEMS409t
polarizedlightmicroscopy53
polyangiitis,microscopic213,466–467,468
polyarteritisnodosa231t,462
aetiology462
clinicalfeatures463t
cutaneous478–479
presentation462

systemic479–480
treatment462
polyarthropathy68
polyarticularabnormalityinwrist/hand120t
polyarticularjuvenileidiopathicarthritis334
rheumatoidfactor-negative334–335
polychondritis,relapsing52,206–207,564,565t
polydactyly203
polymyalgiarheumatica159,456–457,457b,459–460
polymyositisanddermatomyositis206–207,226,234–235,235t,425–446
antibodies436t
assessmentofdiseaseimpact431–432
autoantibodies436–437
biologictherapies439,440t
BohanandPeter’sclassification426b
cardiovascularfeatures429,432t
children444–446
clinicalassessments430–432
clinicalfeatures428–430
creatinekinase,raised434t
diagnosticcriteria427b
electromyography437
extramusculardisease,treatmentof440–441
gastrointestinalfeatures429,432t
glucocorticoids438
gutandhepatobiliarymanifestations230t,231t
idiopathicinflammatorymyopathy430–431
imaging437
inclusion-bodymyositis438,442
withinterstitiallungdisease443
intravenousimmunoglobulin439
investigations434–437
joints429
juveniledermatomyositis231t
keyfeatures427t
malignancy235t,430
musclebiopsy435–436
muscleenzymelevels434–435
myopathy,drug-induced431t,443
myositis428
pathogenesis428
prognosis441
pulmonaryfeatures429,432t
skinandcutaneousdisease428–429
systemicmanifestations432t
treatment438–441,445–446
pooledimmunoglobulin365,687
posteriordrawtest177
post-herpeticneuralgia637
post-renalazotaemia221
post-streptococcalarthritis34
posturetraining615t

prednisolone660
ANCA-associatedvasculitides468
lupusnephritis362f
macrophageactivationsyndrome722
polymyalgiarheumatica459–460
polymyositisanddermatomyositis438
relapsingpolychondritis564
Still’sdisease570–571
systemiclupuserythematosus360,361t
systemicsclerosis420
Takayasuarteritis455
prednisone459–460
pregabalin615t,631–632,636,658
pregnancy
antiphospholipidsyndrome378t,384t
biologicaltherapies676t,680
disease-modifyingantirheumaticdrugs663,665t
multiple,andpelvicorhiplesions160t
non-steroidalanti-inflammatorydrugs655
rheumatoidarthritis261,262b
systemiclupuserythematosus357
Takayasuarteritis455
prepatellarbursitis(housemaid’sknee)175
pre-renalazotaemia220
presentationofrheumaticdisease205–240
cardiacconditions216–217
endocrineconditions224–227
gutandhepatobiliaryconditions228–232
malignancy234–236
neurologicalconditions238–239
ophthalmicconditions240
pulmonaryconditions218–219
renalconditions220–222
skindisorders206–209
skinvasculitis212–214
primaryangiitisofcentralnervoussysteminchildren480–481
primaryvasculitides447–481
ANCA450
ANCA-associatedvasculitides464–469,481
childhood-onset474–481
cutaneouspolyarteritisnodosa478–479
eosinophilicgranulomatosiswithpolyangiitis467
giantcellarteritis457–460,458t
granulomatosiswithpolyangiitis464–466
Kawasakidisease475–476
largevesselvasculitis452
leucocytoclasticvasculitis470,478
microscopicpolyangiitis466–467
polyarteritisnodosa462
polymyalgiarheumatica456–457,457b,459–460
primaryangiitisofCNSinchildren480–481
smallvesselvasculitis470–473

systemicpolyarteritisnodosa479–480
systemicvasculitis,classificationof448t
Takayasuarteritis454–455
vasculitis,CHCCnomenclatureof449b
vasculitismanagement,generalprinciplesof450
seealsosmallvesselvasculitis
probenecid685
proptosis240
prostacyclin418,387
prostheticintervertebraldiscreplacement611t
proteinuria213
protozoa527t
proximalmyopathy226
pseudogout47,50
triggeringfactorsof287b
pseudohypoparathyroidism504
psoriasis206
psoriaticarthritis50,308–313
CASPARclassificationcriteria308b
clinicalassessment310–311
clinicalfeatures309–310
comorbidities311
epidemiology308
genetics308
immunopathogenesis309
juvenile318–319,335
NSAIDsandsyntheticDMARDs311–313
pathophysiology308–309
treatment311–313
psychologicaltherapies640
psychology-orientatedrehabilitationprogrammes616t
pulmonaryarteryhypertension
drugs683–684
systemicsclerosis416t,417
pulmonarydisorders/manifestations218–219
airways219
antiphospholipidsyndrome380
arterialhypertension219,720
Behçet’sdisease553
fibrosis219,416t
granulomatosiswithpolyangiitis465
immunoglobulinG4-relateddisease575t
interstitiallungdisease219
nodules/masses218
non-steroidalanti-inflammatorydrugs654t
pleura218
polymyositisanddermatomyositis429,432t
sarcoidosis557t
Sjögren’ssyndrome392t,394
systemiclupuserythematosus349–350
systemicsclerosisandrelateddisorders415–417
vasculature219

pulmonaryhypertrophicosteoarthropathy522
pustules208
PUVA668
pyodermagangrenosum209,562
pyodermagangrenosum,acne,andpyogenicarthritis(PAPA)syndrome547–549
pyrexiaofunknownorigin(PUO)23
Q
quadricepsfemoris(hipflexion/kneeextension)147t
quadricepsphysicalexamination14t
quinine669–670
quininesulphate659
quinolones669–670
R
radialnerve101,126
radiculopathy78–79
radiocarpaljoint696
rareautoinflammatoryandmiscellaneousdiseases541–576
amyloidosis566–567,567t
approachtodiagnosis543
Behçet’sdisease550–554
Blausyndrome549
CANDLEsyndrome549
CARD14-mediatedpsoriasis549
childhoodperiodicfevers545
cutaneousmanifestation543
deficiencyofIL-1receptorantagonist549
eosinophilicfasciitis572
epidemiology542–543
Eurofevertool548t
familialMediterraneanfever546,547
immunoglobulinG4-relateddisease574
mevalonatekinasedeficiency546–547
neonatalandinfantileperiodicfevers545
pathogenesis542
PFAPAsyndrome547
pigmentedvillonodularsynovitis576
polychondritis,relapsing564,565t
presentations543–547
prominentskinmanifestations547–549
pyodermagangrenosum,acne,andpyogenicarthritissyndrome547–549
sarcoidosis556–559
Schnitzler’ssyndrome547
skinconditionsassociatedwitharthritis560–562
spectrum544t
Still’sdisease568–571
synovialchondromatosis576
TNFreceptor-associatedperiodicsyndromes546,547

uncleardiagnosis547
rasburicase686
rash13
childrenandadolescents40
macular207
ulcerating208–209
Raynaud’sdisease116,207,209,392t,402,412
drugs683–684
treatment413t

reactivearthritis33–34,51,206–207,314–315
clinicalfeatures314
investigation314–315
management315
‘redflags’(backpain)607
referralforfurtherassessment
adults31
childrenandadolescents28–30
referredpain75t,87t
regionalmusculoskeletalconditions71–203
elbowpain98–104
hand112–122
kneepain170–186
lowbackpainanddisordersinadults140–155
lowerlegandfootdisorders188–203
neckpain74–82
pelvic,groin,andthighpain156–169
shoulderpain84–96
thoracicbackandchestpain130–138
upperlimbperipheralnervelesions124–127
wristpain106–110
regionalpainsyndrome106–108
relapsingpolychondritis52,206–207,564,565t
renaldisorders/manifestations220–222
antiphospholipidsyndrome380
Behçet’sdisease554
granulomatosiswithpolyangiitis465
immunoglobulinG4-relateddisease575t
intrinsicrenalfailure–‘activesediment’221
intrinsicrenalfailure–‘blandsediment’221–222
non-steroidalanti-inflammatorydrugs654t
polymyositisanddermatomyositis432t
post-renalazotaemia221
pre-renalazotaemia220
relapsingpolychondritis565t
renalfailureevaluation220
renaltubularacidosis222
sarcoidosis557t
sclerodermarenalcrisis222
Sjögren’ssyndrome392t,394
systemiclupuserythematosus350–351,714–715,717
systemicsclerosisandrelateddisorders417–418
renalosteodystrophy504–505,505t
renaltubularacidosis222,497
repetitivestraininjury72,109
respiratorydisorders/manifestations
non-steroidalanti-inflammatorydrugs654t
relapsingpolychondritis565t
reticulohistiocytosis207,562
rheumaticdiseaseseeinfectionandrheumaticdisease
rheumaticfever52,54,58t,538–540
acute34

rheumatoidarthritis48t,243–263
abatacept258,259b
anti-interleukin-6receptorblocker–tocilizumab258,259b,262b
anti-TNFαtherapy256,259b,260,262b
associatedclinicalmanifestations247
azathioprine254b,255,262b
baselineimaginginvestigations249t
baselinelaboratoryinvestigations248t
B-celldepletion–rituximab256–258,259b,262b
cancerrisk260
classification244,245t
clinicalfeatures246–247
complementarytherapies263
epidemiology244
extra-articularfeatures247
glucocorticoids256,262b
gold254b,255
gutandhepatobiliarymanifestations230t,231t
hydroxychloroquine254b,255,262b
immunopathology244
infectionmanagementwhileonimmunosuppression259–260
investigations248
januskinaseinhibitors–tofacitinib259
jointsandtendons246
leflunomide254b,255,262b
management250–263
methotrexate253,254b,262b
NICEguidance251f
novelmedications259
NSAIDs252,262b
painreliefandanalgesia252
pathogenesis244
pregnancyandbreastfeeding261,262b
sulfasalazine254b,255,262b
surgery261–263
synovialpathology244–245
systemicfeaturesandassessment247
rheumatoidfactor-negativepolyarticularjuvenileidiopathicarthritis334–335
rheumatoidnodules118
rhupus354
Ribbingdisease522
ricketsseeosteomalaciaandrickets
rifampicin673–674
riociguat417,683t
risedronate507–508,682t
rituximab
ANCA-associatedvasculitides467–469
antiphospholipidsyndrome383,387
immunoglobulinG4-relateddisease574
polymyositisanddermatomyositis439,440t
pregnancyandbreastfeeding676t
rheumatoidarthritis256–258,259b,262b,677

Sjögren’ssyndrome398
systemiclupuserythematosus361t,363
systemicsclerosis420
rivaroxaban384
romosozumab492
rosacea206–207
rotatorcufflesions85–87
rotatorcufftear597t
rubefacients659
rubella58t
S
sacralspineanatomy140
sacroiliacjoints145
sacroiliitis51,143,164,229
sailsign101
St.John’swort668
salivaryglands575t
sarcoid
arthropathy54–55
conditions206–207
sarcoidosis556–559
acute(Lofgren’ssyndrome)556
chronic556,557t
clinicalmanifestations557t
diagnosisandinvestigations558–559
early-onset(childhood)556–557
epidemiologyandpathophysiology556
musculoskeletalmanifestations557–558
patternsofdisease556–557
treatment559
scalp206
Scheuermann’sdisease46,143,514,515t
Scheuermann’sosteochondritis132t,134,620
Schnitzler’ssyndrome547
Schöbertest15–16f,144
sciaticnerveentrapment163–164
scleraldisease240
sclerodactyly413
scleroderma230t,412–413
diffusecutaneous209
-likefibrosingdisorders422–423
limitedcutaneous208
linear210t,402,422
renalcrisis222
scleroedema409t,423
scleromyxoedema409t,423
sclerosingbonedisorders522–523
Camurati–Engelmanndisease522
endostealhyperostosis522–523
hepatitisCosteosclerosis523

osteopetrosis522
osteopoikilosis523
primaryhypertrophicosteoarthropathy522
pulmonary(secondary)hypertrophicosteoarthropathy522
Ribbingdisease522
spectrum523t
sclerosis149t,227
crises720
lipodermato-210t,409t,561
sclerosteosis522–523
scleroticlesions,localized149t
scoliosis133
congenital620
idiopathic619
measurement619f
neuromuscular620
secukinumab306,313,679
selectiveserotoninreuptakeinhibitors631–632,657
septicarthritis247,528–531,708–711
adults708
antibiotics710t
children708–709
epidemiology528
gonococcal711
immediatemanagementinadults709
investigation528–529
andLymedisease536
management529–530
managementinchildren709–710,710t
non-gonococcal47
pathology528
post-immediatemanagementinadults710–711
post-immediatemanagementinchildren710t
presentation528
septicbursitis530
serotoninandnorepinephrinereuptakeinhibitors657–658
serotoninreuptakeinhibitors657t
serratusanterior92t
sertraline631–632,657
Severdisease515t
shinsplints191
shoulder
acromioclavicularjoint693
glenohumeraljoint692
glucocorticoidinjectiontherapy692–693
physicalexamination14t,17t
subacromialspace693
seealsoshoulderpain
shoulderpain84–96
acromioclavicularjoint90
adults84–95
anatomyofshoulder84

arthrography93–94
bilateralshouldermovements89–90
bloodtests94
bonescan94
causesinadults87t
causesinchildrenandadolescents96t
childrenandadolescents96
electrophysiologicaltests94
examination89–93
glenohumeraljointmovement90
historytaking85–88
isolatedmuscletestingofshouldergirdlemuscles91–92,92t
jointaspiration94
localanaestheticinjection94
magneticresonanceimaging93–94
majorshoulderstructuresandjointcapsule85f
musclesoftheshoulder86f
onsetofpain85–87
painandshoulderlesions84–85
radiographs93
spinalsymptoms88
subacromialimpingement90,91f
supineshoulderexamination92–93
tenderness89
treatment94–95
ultrasound93–94
variationinpain88
visualinspection89
sifalimumab440t
sildenafil417,683t
simvastatin668
Sinding–Larsen–Johanssondisease516
Sipplesyndrome504
Sjögren’ssyndrome389–400
autoimmunediseases,co-existing395
biopsy397
cardiovascularsystem395
classificationcriteria390t,392–395
clinicalmanifestations392–395
endocrinemanifestations226
epidemiologyandpathophysiology390
extraglandulardisease392t
fatigue395
gastrointestinalandhepatobiliarydisease394
glandulardisease392,393t
gutandhepatobiliarymanifestations230t
investigations396–397
joints393
laboratoryfindings396t
lymphoproliferativedisease395
neuromusculardisease394
prognosis400

pulmonarydisease394
renaldisease394
siccasymptoms,assessmentof396–397
skin212,393–394
treatment398,399t
skeletaldysplasias43
skeletalmanifestationsandpolymyositisanddermatomyositis432t
skier’sthumb115
skinconditionsassociatedwitharthritis560–562
multicentricreticulohistiocytosis562
neutrophilicdermatoses561–562
panniculitis560–561
pyodermagangrenosum562
skindisorders/manifestations206–209
antiphospholipidsyndrome379
Behçet’sdisease550–552
diagnosticissuesinskinthickening209
eruption,typesof207–209
examination,importanceof206
faceandears206–207
granulomatosiswithpolyangiitis465
handsandnails207
immunoglobulinG4-relateddisease575t
Lymedisease537t
macularrashes207
non-steroidalanti-inflammatorydrugs654t
patternrecognitioninskinthickening210t
plaques208
polymyositisanddermatomyositis428–429
pustulesandblisters208
rareautoinflammatorydiseases547–549
regionalabnormalities206–207
relapsingpolychondritis565t
rheumaticfever539
sarcoidosis557t
scalp206
Sjögren’ssyndrome212,393–394
systemiclupuserythematosus206–207,212,348
texturalabnormalities209
ulcersandulceratingrashes208–209
vascularlesions208
widespreadpain63
seealsoskinconditionsassociatedwitharthritis;skinvasculitis
skinvasculitis212–214
diagnosis212
importantconsiderations213
investigations213–214
laboratoryinvestigations214t
precipitantsandassociationsofleucocytoclasticsmallvesselvasculitis212t
skinbiopsy213–214
systemic213
sleep630

slippedepiphysis160t
slippedupperfemoralepiphysis515t
adolescents42–43
slumptest145f
smallvesselvasculitis470–473
allergic(hypersensitivity)471
cryoglobulinaemic472
erythemaelevatumdiutinum472
granulomafaciale472
Henoch–Schönleinpurpura471,476–478
hypergammaglobulinaemicpurpura472
leucocytoclastic470,478
non-leucocytoclastic(lymphocytic)470t,473
urticarial471–472
snaps12
sodiumaurothiomalate669
softtissuelesions75t
soleus147t
spinalcordcompression78,151–152
spinalcordlesions238
spinalcordstimulator616t
spinaldisordersseebackpain
spinalstenosis142–143,151–152,611–612
spinaltumours621,622b
spinealignment,physicalexaminationof14t
spirochaete527t
splinterhaemorrhages207
spondylitis78–79
spondyloarthritis48t,230t
-associatedreactivearthritis314–315
inflammatoryboweldisease-related316–317
juvenile318–320,335
paradigmshift296
spondyloarthropathies132t,134,293–320
axialspondyloarthritisandankylosingspondylitis298–306
classifying296,298–299
inflammatoryboweldisease-relatedspondyloarthritis316–317
juvenilespondyloarthritis318–320
psoriaticarthritis308–313
seealsoankylosing-spondylitis;spondyloarthritis
spondylodiscitis613
spondylolisthesis144,620,621f
spondylolysis620
statins668
stemcelltransplantation364
stenosingtenosynovitis(triggerfinger)117,224–225
steroidinjections182–183,199
Sticklersyndrome206–207,594
stiff-leggedgait38–39
stiffness12
Still’sdisease207,230t,568–571
clinicalfeatures568–569

courseofdiseaseandprognosis571
epidemiologyandpathogenesis568
laboratoryandradiographicfindings569–570
treatment570–571
Yamaguchicriteria569b
stomatitis232
stoopedgait39
straightlegraise(Laseague’stest)146
stressfractures191
stridor219
strontiumranelate491,682t
subacromialbursitis597t
subacromialimpingement84–85,87t,596–597,597t,598f
subacromialspace693
subluxation78–79
subtalarjoints704
sulfasalazine662–663,664,672–673
axialspondyloarthritisandandankylosingspondylitis305
chronicnon-bacterialosteomyelitis511
inflammatoryboweldisease-relatedspondyloarthritis317
juvenileidiopathicarthritis329
juvenilespondyloarthritis320
pregnancyandbreastfeeding665t
psoriaticarthritis311–313
rheumatoidarthritis254b,255,262b
spondyloarthritis-associatedreactivearthritis315
sulfinpyrazone685–686
suprascapularnerve124–125
suprascapularnotchlesion597t
supraspinatus92t
supraspinatus/cufftendonitis597t
Sweet’ssyndrome561–562,562t
swelling12
symphysitis700
syndactyly203
syndesmophytes134
synovialchondromatosis53–54,576
synovialplica185
synovitis108
acne,palmoplantarpustolosis,hyperostosis,asepticosteomyelitis(SAPHO)syndrome52,510–511,
512–513
joint177
oligoarticular47
pigmentedvillonodular576
synoviumdisorders576
systemicconditionsandshoulderpain87t
systemiclupuserythematosus67t,343–373
acuteseesystemiclupuserythematosus,acute
antimalarialdrugs361
andantiphospholipidsyndrome356
assessmentofdiseaseactivity358
atacicept364–365

autoantibodies355t
azathioprine363
belimumab364
cardiovasculardisease349,360
classification344,345t
clinicalfeatures348–352,352t
cyclophosphamide363
drug-inducedlupuserythematosus(DILE)359
eculizumab364–365
environmentalfactors346
epidemiology344
epratuzumab364–365
gastrointestinalclinicalfeatures352t
genetics346
glucocorticoids360
gutandhepatobiliarymanifestations230t,231t
haematologicalfeatures351
immunologicalclinicalfeatures352t
immunosuppression360–365,362f
investigations354
juvenile368–370
malignancy352
management360–365
methotrexate363
mucocutaneousmanifestations348
musculoskeletalclinicalfeatures348
mycophenolatemofetil(MMF)363
neonatallupussyndrome372–373
neurologicaldisease351–352
ocularclinicalfeatures352t
osteoporosisandosteopenia352
pathophysiology346
plasmaexchange364
pooledimmunoglobulin(IVIG)365
andpregnancy357
prognosisandsurvival366
pulmonarydisease349–350
recommendationsfordruguse361t
renaldisease350–351
rituximab363
serologyandimmunecomplexes346
skin206–207,212,348
stemcelltransplantation364
tacrolimus364–365
tocilizumab364–365
vascularclinicalfeatures352t
vitaminDdeficiency352
systemiclupuserythematosus,acute714–717
cardiorespiratory715,716t
diagnosis714
haematologicalmanifestations716–717
paediatric–haematologicalmanifestations717

paediatric–renalmanifestations717
renal714–715,715f
systemic-onsetjuvenileidiopathicarthritis326t,335–336
conditionsandinvestigationstoconsider326t
diagnosis336
treatment336
systemicpolyarteritisnodosa479–480
systemicsclerosisandrelateddisorders210t,401–423
ACR/EULARclassificationcriteria402t
cardiacdisease415–417,416t
characteristicfindings410t
classificationanddiseasepatterns406
clinicalfeatures412–418
diagnosis408
differentialdiagnosis408,409t
diffusecutaneous406,407t,410t
earlysystemicsclerosis407t
environmentalfactors405
eosinophilicfasciitis422
epidemiology404
essentialinitialinvestigations408
fibrosis405
gastrointestinaltract414–415
genetics/epigenetics404
genitalia418t
immunecellactivationandcytokines404
inflammation405
limitedcutaneous406,407t,410t
linearscleroderma422
liver418t
morphoea422
nephrogenicsystemicfibrosis422–423
nervoussystem418t
pathophysiology404–405
prognosis420
pulmonaryarteryhypertension417
pulmonarydisease415–417,416t
Raynaud’sdisease412,413t
renaldisease417–418
scleroderma-likefibrosingdisorders422–423
scleroedema423
scleromyxoedema423
sinescleroderma407t
skin412–413
thyroidgland418t
treatment420
vasculopathy405
systemicsclerosiscrises720
pulmonaryhypertension720
renalcrisis720
systemicvasculitis448t,718–719

T
tacrolimus
dermatomyositis440–441
juvenileidiopathicarthritis329
polymyositisanddermatomyositis439
Still’sdisease570–571
systemiclupuserythematosus361t,364–365
tadalafil417,683t
Takayasuarteritis454–455
epidemiology454
investigation454
presentation454
treatment455
talipesequinovarus(clubfoot)202
talusosteochondritis515t
tarsalcoalitions202
tarsaltunnel704
tearsofmenisci174
telangiectasia208
temporomandibularjointdysfunction637
tendonitis
acutecalcificsupraspinatus89–90
anserine173–174
supraspinatus/cuff597t
tendonsandrheumatoidarthritis246
tenniselbowseelateralepicondylitis
tenosynovitis47,117,119
teriparatide491,581,682t
thenareminencemuscles113t,114f
theophylline660,684
thighpainseepelvic,groin,andthighpain
thiopurinemethyltransferase(TPMT)deficiency667
Thomastest162,169t
thoracicbackandchestpain130–138
adults130–135
bonescintigraphy135
cardiachistoryandexamination137
causesinchildrenandadolescents136t
characteristicsfromnon-neurologicalandnon-musculoskeletalpathology131t
childrenandadolescents136–138
examination133–134,136–138
historytaking130–133,136–138
magneticresonanceimaging135
musculoskeletalfeatures137
painfulneurologicalandmusculoskeletalconditions132t
palpation133
pulmonarydiseasefeatures137
qualityofpain132
radiographs134
symptoms,other,andriskfactors132–133
thoracicspinalinvolvement134
visualinspection133

thoracicconditions87t
thoracicnerves74f,124
thoracicspine,physicalexaminationof17t
thoracicvertebraldisease132t
throatandgranulomatosiswithpolyangiitis465
thrombocytopenia378t,380
thrombosis378
thyroidacropachy226
thyroiddisease54
thyroidgland418t
thyroiditis,lymphocytic226
thyrotoxicosis226
tibialtorsion186
tibialisanterior(ankledorsiflexion)147t
tibialisposterior(ankleinversionanddorsiflexion)147t
Tinel’ssign127,195
tizanidine659
tocilizumab
giantcellarteritis460
juvenileidiopathicarthritis329
polymyositisanddermatomyositis440t
pregnancyandbreastfeeding676t
rheumatoidarthritis258,259b,262b,678–679
Sjögren’ssyndrome398
Still’sdisease571
systemiclupuserythematosus364–365
systemic-onsetjuvenileidiopathicarthritis336
systemicsclerosis420
Takayasuarteritis455
toeanomalies203
toewalking32t,39
tofacitinib259,306,673–674
tolbutamide670
topicalagents659
torticollis77
Toxoplasmagondii58t
tramadol610,631–632,652,658
transaminitis232
transcutaneouselectricnervestimulation252,615t,636
Trendelenburglimp/gait38–39
Trendelenburgtest169t
triamcinolone660
trichorhinophalangealsyndrome46
tricyclicantidepressants631–632,636,641,657
trigeminalneuralgia637
triggerfinger117,224–225
trimethoprim667,672
trimethoprim-sulfamethoxazole468,469
trochantericbursitis/enthesitis158–159,700
T-score488–489
tuberculosis260,713
tubularnecrosis,acute221–222

tumour-inducedosteomalacia498
tumournecrosisfactor(TNF)receptor-associatedperiodicsyndrome(TRAPS)546
late-onset547
tumours
bone524
Brown’s227
spinal621,622b
U
ulcerativecolitis228t
spondyloarthritis316–317
ulcersandulceratingrashes208–209
ulnarnerve125,125–126,128f
unexplainedacute-phaseresponse23
upperlimbmusculoskeletallesions595–603
adhesivecapsulitis600
lateralhumeralepicondylitis(tenniselbow)602–603,603f
subacromialimpingement345t,596–597,598f
upperlimbperipheralnervelesions124–127
carpaltunnelsyndrome127
dermatomesofanteriorandposterioraspects128f
mediannerve126–127
radialnerve126
suprascapularnerve124–125
thoracicnerve,long124
ulnarnerve125–126
urethritis51
urgentrheumatologicalassessment30
urothelialtoxicity668–669
urticarialvasculitis471–472
ustekinumab306,312–313,679
uveitis51,240
differentialdiagnosisofcauses340t
juvenileidiopathicarthritis340–341
management341
surveillance(screening)programmes340–341,341t
V
valvulardisease217
VanBuchemdisease522–523
vancomycin530
varicellainfections713
vasculardisorders/manifestations
immunoglobulinG4-relateddisease575t
systemiclupuserythematosus352t
vascularlesions208
vasculature219
vasculitis117
allergic(hypersensitivity)471

CHCCnomenclatureof449b
cutaneous392t
large-vessel452
leucocytoclastic470,478
livedoid473
management450
nodular473
non-leucocytoclastic(lymphocytic)470t,473
withpanniculitis561
‘severe’718–719
skindisorders208
systemic448t,718–719
urticarial471–472
seealsoskinvasculitis;smallvesselvasculitis
vasculopathy405
venlafaxine631–632
vertebralend-plateosteophytes,marginal149t
vertebroplasty492–493
Vilanova’sdisease560
viralenteritis228t
viruses527t,712t
visceralcausesofbackpaininchildren618t
vitaminDdeficiency494–498
clinicalandlaboratoryfindings495–496
management496
systemiclupuserythematosus352
vitaminD-dependentrickets496
W
waddlinggait38–39
warfarin660,667,670,684
antiphospholipidsyndrome381–384,382t
Weber–Christiandisease560–561
Wegener’sgranulomatosisseegranulomatosiswithpolyangiitis
Whipple’sdisease228t
widespreadpain55–63
abnormality,patternsof64–65
affectedjoints57
age,gender,andracialbackground56
antinuclearantibodies67t
bonepathology60–61
categoriesofconditions55t
chestpain,dyspnoea,palpitations,cough,andhaemoptysis62
commoninfectionswithacutepolyarthritisandraisedacutephaseresponse58t
drughistory62
dysphagia,abdominalpain,anddiarrhoea63
electrophysiologyandimaging69
examination63–70
familyhistory62
fibromyalgia,sitesoftendernessin65f
historyofpainatdifferentsites56

historytaking56
initialimpressions55
investigations67
ischaemicpains60
jointexamination63
jointhypermobilitysyndrome64t
jointpainatrest,afterrest,orwithjointuse57
laboratorytests68–69
malignancy,investigationsfor69–70
musclebiopsy69
musclepain58,69
myalgiasandweakness59t,60,65–67
myopathies59t,66f
pastmedicalhistory61
patternofjointsymptomsovertime57–58
patternofmusclepainsovertime60
polyarthropathy,basictestsin68
previousdiagnoses56
psychosocialandsexualhistory61
skinandnailsexamination63
travel61
Williams’syndrome502t
Wilson’sdisease228t,229
work-relateddisorder(WRD)72
wrist
glucocorticoidinjectiontherapy696–698
physicalexaminationof17t
seealsowristpain
wristpain106–110
adults106–110
bonescintigraphy119
childrenandadolescents122
dorsumexamination110
examination109–110
flexion/extensionrangetests109
flexorandextensortendonsheaths107f
functionalanatomy106
historytaking106–109
job/leisureactivities109
locationofpain106
magneticresonanceimaging119
painfulconditionsanddiagnoses108t
qualityof108
radiographs119,120t
synovitis108
tendonintegritytesting110
traumahistory106–108
treatment110,121
ultrasound119
visualinspection109

X
xerophthalmia240
X-linkedhypophosphataemicrickets497
Y
yeasts712t
‘yellowflags’(backpain)607
Z
zoledronicacid305,460,507–508,581
zoledronicacid682t
Z-score488–489