Child_DMARD.pdf

8/14/2019 Child_DMARD.pdf

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18th Expert Committee on the Selection and Use of Essential Medicines

(21 to 25 March 2011)

Section 2 Analgesics, antipyretics, NSAIMs, DMARDs

2.4 Disease-modifying agents used in rheumatoid disorders

ReviewofDiseaseModifyingAntiRheumatic

Drugsin

Paediatric

Rheumatic

disease

September2010

Preparedby:

PeterGowdie

RheumatologyandClinicalPharmacologyFellow2009

RoyalChildrensHospital

Melbourne,Australia


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Contents1. Intentofreview2. Identificationofpriorityconditions3. Reviewofpriorityrheumaticdisease

1.

JuvenileIdiopathicarthritis1.Epidemiology2.Diseaseburdenandoutcome3.Clinicalmanifestations4.Complications

macrophageactivationsyndrome uveitis amyloidosis

2. IdiopathicInflammatoryMyopathies(JuvenileDermatomyositis)1.Epidemiology2.

ClinicalManifestations3.Complications

4.CourseandOutcome5.Overviewofmanagement

3. SystemicLupusErythematosus1.Epidemiology2.ClinicalManifestations3.Courseandoutcome4.Overviewofmanagement

4. DMARDs1. Methotrexate

1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritis3.EfficacyinJuvenileDermatomyositis4.Doseandadministration5.Druginteractionandfolatesupplementation6.Safety7.Monitoringandsupervision8.Formulary9.Summaryrecommendations

2. Leflunomide1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritis3.Doseandadministration4.Safety5.Druginteraction6.Monitoringandsupervision7.Formulary8.Summaryrecommendations


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3. Sulphasalazine1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritis3.Doseandadministration4.Safety5.Druginteraction6.Monitoringandsupervision7.Formulary8.Summaryrecommendations

4. Cyclosporin1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritisandMacrophageActivation

Syndrome

3.EfficacyinJuvenileDermatomyositis4.Doseandadministration5.Safety6.Druginteraction7.Monitoringandsupervision8.Formulary9.Summaryrecommendations

5. Azathioprine1.MechanismofactionandPharmacology2.EfficacyinSLE3.EfficacyinJIA4.Doseandadministration5.Safety6.Druginteraction7.Monitoringandsupervision8.Formulary9.Summaryrecommendations

6. Hydroxychloroquine1.MechanismofactionandPharmacology2.EfficacyinSLE3.Doseandadministration4.Safety5.Druginteraction6.Monitoringandsupervision7.Formulary8.Summaryrecommendations


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1. Intentofreview

Toidentifypriorityrheumatologicalconditionsinchildren Tooutlinethetreatmentoptionsfortheseconditions

TooutlinetheroleofDMARDsinthetreatmentofpriorityrheumatologicalconditions

ToreviewtheliteratureandcollatetheevidencefortheefficacyofDMARDsinpriorityconditions

ToreviewthesafetyofDMARDsandoutlinemonitoringandsupervisionrequired TogiverecommendationsfortheinclusionofDMARDsontheWHOEssential

MedicinesList

2. Identificationofpriorityconditions

PaediatricRheumatologyencompassesabroadrangeofinflammatorydisordersinvolvingthejointsandconnectivetissuesinchildren.Juvenileidiopathicarthritisisperhapsthemost

wellrecognisedoftherheumaticdiseasesofchildhoodhoweverthespecialtysscope

includesconditionssuchasacuterheumaticfever,poststreptococcalreactivearthritis,

KawasakidiseaseandLymediseaseaswellaschronicsystemicconditionsincluding

SystemicLupusErythematosus(SLE),JuvenileDermatomyositis(JDM),andthevasculitides.

Themostcommonrheumaticdiseaseaffectingchildrenischronicarthritis.Thefunctional

impactofthisdiseasecanbesignificantandthetimelyadministrationofappropriate

therapy,includingDMARDs,canbeeffectiveinimprovingoutcome.Whilelesscommon,

SLEandJDMarealsoarepotentiallydevastatingconditionsandDMARDtherapyplaysanequallyimportantroleintheirmanagement.

3. Reviewofpriorityconditions

3.1 JuvenileIdiopathicArthritis

Chronicarthritisisacomplexgroupofdisorderscomprisinganumberofclinicalentities

withthecommonfeatureofarthritis. Eachtypeischaracterisedbyadifferentmodeof

presentationanddifferentdiseasecourseandoutcome.Thethreemaingroupsofchronicarthritisare:thoseaffectingfewjoints(oligoarticular);

thoseaffectingmanyjoints(polyarticular);andthosesystemicinonset. Theclassificationof

chronicarthritishasbeenproblematicoverthepastfewdecadesespeciallyintermsof

universallyagreedupondefinitions.This,inpart,largelyreflectsthecomplexand

heterogeneousnatureofthisgroupofconditionsandtheasyetnotclearlydefined

immunogeneticfactorscontributingtotheironset.Itisalsoimportanttorememberthe

population(mostlyCaucasian)inwhicheachofthemajorclassificationcriteriahavebeen

described.Forthepurposesofthispaper,theInternationalLeagueofAssociationfor

Rheumatology(ILAR)criteriaforclassificationofjuvenileidiopathicarthritis(JIA)hasbeen

used.[1]


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3.1.1Epidemiology

JIAremainsanuncommonbutbynomeansrareconditionaffectingchildrenworldwide.[2]

Estimatesofincidenceandprevalencehoweverhavebeendifficulttoascertainformany

reasonsincluding:variationindiagnosticcriteria;differencesinascertainment(community

vsclinicalbasedstudies);differencesinstudydesign;lowfrequencyofdiseaseandsmall

studynumbers.[3]

In2002MannersandBowersummarisedthemostrecentepidemiologicalstudiestothat

pointandfoundareportedprevalenceof0.07to4.01per1000childrenandanannual

incidenceof0.008to0.226per1000children.[3]Thelargedifferenceinreportedprevalence

isconsideredtobelargelyduetovaryingstudycharacteristics.Thehighestprevalencewas

reportedincommunitybasedstudieswherechildrenwereexaminedinclassroomsor

homes.In1993,Meilantsperformedanepidemiologicalstudyusingaquestionnaire

followedbyclinicalexaminationandfoundaprevalenceofdefiniteJIAof1.67per1000.[4]

In1996Mannersetalfoundasignificantlyhigherprevalence(4.01per1000)inanurban

Australiancommunity.[5]Similarly,TayeletalfoundaprevalenceofJIAamongst1015year

oldschoolchildreninAlexandria,Egypt,of3.3per1000.[6]Clinicbasedstudiesontheother

handappeartoreportlowerprevalencerates perhapsreflectingthatmanycliniciansfailto

recogniseJIAandthereforethesechildrendonotmaketheirwaytomedicalcareinlarge

studycentres,thereforeunderestimatingthetrueprevalence.[7]

ThereisverylittlecomparabledataoutliningtheprevalenceofJIAinpopulationsotherthan

thoseofEuropeandescent.Infact,inthemostheavilypopulatedareasoftheworld

epidemiologicaldataisveryscarce.OutsideoftheUS,UKandCanadasomestudiesreveal

verydifferentdata.LowerfrequenciesofJIAhavebeenreportedinchildreninJapan(annual

incidence0.0083per1000)andCostaRica(annualincidence0.068per10000Arguedes1998

and0.054per1000Arguedes1995).In1983Hochbergreportedanannualincidenceof0.066

per1000childrenandaprevalenceof0.26per1000inurbanblackchildrenintheUSA

howeverotherstudiessuggestthatthisisanunderestimate.[8] Manyofthesestudiesare

ultimatelylimitedbythesmallsamplesizeandselectionbias.Oneretrospectivestudy

undertakenbyKuraharaetalin2002demonstratedlowerfrequencyofJIAinHawaiiansof

Filipino,JapaneseandSamoandescentcomparedwithCaucasians.[9]Inasimilarpopulation

KuraharaalsofoundincreasedprevalenceofJIAinruralareascomparedwithurban

areas.[10]

Theextentofjuvenilearthritisinthedevelopingworldandtheepidemiologicalimpactof

ethnicityandgeographyneedsfurtherconsiderationespeciallyinconsideringtheimpact

andburdenofdiseaseofthisgroupofconditions.

3.1.2 BurdenofDiseaseandoutcome

ThediseaseoutcomeandprognosisinJIAisvariableandtosomedegreepredictablebased

onthedifferentdiseasesubtypes.Forexample,seropositivepolyarticularJIAhasa

relativelypooroutcomecomparedwitholigoarticularJIAwhoseoutcomeisgenerallyvery

good.[11,12]However,thelattergrouparealsothemostatriskofdebilitatinguveitisasa

complicationoftheirdisease.ManychildrenwithJIAhaveanexcellentprognosisandforthe


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mostpartremainfreefromsignificantlydebilitatingdisease.However,5070%ofpatients

withsystemicandpolyarticulardiseaseand4050%ofoligoarticulararthritiscontinueinto

adulthoodwithactivedisease[Laxer/Hashkes]. Ithasbeenestimatedthatupto20%of

childrentransitiontoadulthoodwithmoderatetoseverefunctionaldisabilities[13]andan

evenhigherpercentage(3040%)havesignificantlongtermdisabilitiesincluding

unemployment.[14]Majorsurgery,includingjointreplacementisrequiredin2550%.[14]

Delayinreferralandinitiationofacceptabletherapyisassociatedwithpooreroutcome.[2]

TheprognosisinJIAisfrequentlyassessedwiththreemainoutcomemeasures:frequencyof

remission,functionalimpairmentandstructuraldamage.Similartotheoutliningof

epidemiology,outcomestudiesarealsodifficulttodrawconclusionsespeciallygiventhe

prevailinguseofthreedifferentclassificationsystemsandthevariableoutcomemeasures

withoutagreedupondefinitions.Forexample,thereremainsnointernationalagreementon

validatedremissioncriteriaforJIA

Remissionratesvarybetweensubgroupshowever,despitedifferingapproachesand

definitionsacrossstudies,thereisconsistentreportingofhigherremissionratesin

oligoarticulardisease.Intheoligoarticulardiseasethisrangedfrom36%to84%.[15]

Remissionratesforpolyarticulardiseaserangedfrom12.5%to65%whilstsystemicdisease

was0to76%.[15]Thelargerangecanbeexplainedbytherelativeinfrequencyofthese

subtypescomparedwitholigoarticulardiseaseandthereforethesmallsamplesizes

potentiallymoreinfluencedbychance.Similarly,functionaloutcomewasbetterinthe

oligoarticularsubtypeandthefrequencyofseveredisabilitywaslow.Bycontrast,systemic

andpolyarticulardiseasebothhavebeendocumentedtohavesignificantlyworsefunctional

outcome.SystemicJIAinparticularhasalargeproportionofpatientswithseveredisability.

[16]

Whilstestimatesoftheburdenofdiseaseatanindividuallevelhasbeendocumentedto

someextent,thereremainsconsiderabledifficultyinacquiringdatarelatingtoestimatesof

theglobalburdenofthisgroupofdiseases.Theglobalimpactofjuvenilearthritison

disabilityandhandicap,theeducationalandvocationaldisadvantages,lifeexpectancyand

qualityoflifeaswellasthecostofmedicalcareremainstobedefined.

3.1.3 ClinicalManifestationsofJIA

ThecommonfeatureofallthesubtypesofJIAisarthritis.Systemicsymptomstypicallyoccur

insystemicandpolyarticularsubtypesandinclude:fatigue,lossofweight,anaemia,

anorexiaandfever.Jointinflammationresultsinpainanddiscomfortandattimes

considerablemorningstiffness. Largejointsarethemostfrequentlyaffected,howeverany

jointcanbeinvolvedincludingcervicalspine,thoracolumbarspineandtemporo

mandibularjoint.Growthabnormalitiesarenotuncommonandcanresultinshortstatureor

localisedgrowthdisturbancesuchasbonyovergrowth,prematurelyfusedepiphysesand

limblengthdiscrepancies.Otherextraarticularmanifestationsinclude:osteopenia,

rheumatoidnodulesandmuscleatrophy.Cardiopulmonarydiseaseisalsonotuncommon

particularlyinsystemiconsetdisease. Pericarditisoccursinupto9%[17]however

tamponadeisrare.Myocarditisandendocarditishavealsobeendocumentedtohave

occurred.


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3.1.4 ComplicationsofJIA

MacrophageActivationSyndrome

MacrophageActivationSyndrome(MAS)ispotentiallythemostdevastatingsequelaeofJIA.

MASissimilarinmanywaystoreactivehaemophagocyticlymphohistiocytosis(HLH)and

thetermMAShascometorefertoHLHsecondarytorheumaticdisease. MASismostoften

associatedwithsystemiconsetJIA,however,hasbeenrecognisedwithotherrheumatic

diseasessuchas:polyarticularJIA,SLE,JDMandchronicinfantileneurologiccutaneousand

articularsyndrome(CINCA).

MAScontributestoasignificantamountofthemorbidityandmortalityassociatedwith

SoJIA.EstimatesoftheincidenceofMASinSoJIAvary.Sawhneyetalreportanincidenceof

6.7%.[18]However,itisbelievedbymanythatMASisintegraltothepathogenesisofSoJIA

andthatinfactoccultMASiscommoninpatientswithSoJIA.[19]

MASisoftendifficulttodistinguishclinicallyfromSoJIA.Itsfeaturesinclude:fever(often

moresustainedthatSoJIA),hepatosplenomegaly,anaemia,LFTabnormalities,rash,

coagulopathyandcentralnervoussystemdysfunction.Laboratorymarkerssuggestiveof

diagnosisinclude:decreasingwhitecellcountandplatelets,elevatedferritin,

hypertriglyceridemia,hypofibrinogenemiaandevidenceofhaemophaocytosisonbone

marrowaspirate.PreliminaryguidelinesforthediagnosisofMASinassociationwithSoJIA

havebeensuggested.[20]

MASispotentiallyfatalespeciallyinthosepatientswithmultisysteminvolvementorwhen

diagnosisisdelayed.Earlydiagnosisandvigoroustreatmentisnecessary.Corticosteroids

andsupportivecarearethefirstlinetherapies,however,agentssuchascyclosporin,

etoposideandIVIG.TheuseofcyclosporininMASisdiscussedinsection4.4.2.

Uveitis

OneofthemostimportantcomplicationsofJIAisuveitis.Thisisachronicnon

granulomatousinflammationaffectingtheirisandciliarybodytheendresultofwhichcan

bedevastating.Inparticular,bandkeratopathyandcataractsoccurin4258%whilst

glaucomaoccursin1922%.[21]Itsactivitydoesnotcorrelatewiththecourseofthearthritis

anditsowncourseisusuallyinsidiousandoftenasymptomaticmandatingfrequent

ophthalmologicalsurveillance.Ratesofuveitisvarybetweensubtypesofarthritiswiththe

mostfrequentatriskgroupbeingoligoarticularJIA.Uveitishasbeendescribedinmost

racialgroups.

JIAisthemostfrequentnoninfectioussystemicdiseaseassociatedwithuveitisinchildren.

Otherlesscommonnoninfectiouscausesinclude:ulcerativecolitis,tubulointerstitial

nephritissyndrome,Behcetsdiseaseandchronicinfantileneurologiccutaneousand

articularsyndrome(CINCA).Ahighproportionofpaediatricpatientswithuveitisdonot

haveanunderlyingcausefound.Kumpetalfoundnoassociatedsystemicdiseasein58%of

patientswithuveitis.[22]


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Themanagementofuveitisshouldbesupervisedbyanophthalmologistinconjucttionwith

apaediatricianorpediatricrheumatologist.Uveitisisusuallymanagedwithtopical

corticosteroidswithamydriaticagent.Systemicprednisoloneadministeredorallyor

intravenouslymayberequiredinanattempttoachieveshorttermreliefofinflammation.In

childreninwhomuveitisisdifficulttocontrolbythesemeasures,additional

immunosuppressiveagentshavebeenusedincludingincreasinguseofbiologicalagents.

Theefficacyofmethotrexateisdiscussedinsection4.1.4.

Amyloidosis

Amyloidosisisthetissuedepositionoftheproteinamyloidandcanoccurasacomplication

ofJIA.ItisararecomplicationinNorthAmericabutoccursmorefrequentlyinpartsof

Europe.Itmanifestsasproteinuria,nephriticsyndrome,hepatosplenomegalyoranaemia

andcaneventuallyleadtorenalfailure.Amyloidosisandresultantrenalfailureasa

complicationofJIAwas,inthepast,themajorcauseofdeath.Theothermaincauseis

infection.Deathrateshaveimprovedoverrecentdecadesandnowthediseaseassociated

deathrateinEuropeis


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3.2.2 ClinicalManifestations

Juveniledermatomyositis(JDM)isamultisysteminflammatorycondition itcanaffectthe

muscle,skin,gastrointestinaltract,heart,lungs,kidneysandeyes.JDMcanmanifestina

heterogeneousfashion,however,themaincharacteristicsofthediseaseinclude:symmetrical

proximalmuscleweakness,pathognomicskininvolvement(egGottronspapules,

heliotropicrash),andraisedmuscleenzymes.ThediagnosisofJDMismadethroughthe

applicationofdiagnosticcriteriaestablishedbyBohanandPeterin1975:1)presenceof

characteristicrash heliotropicrashwithperiorbitaloedemaandGottronspapules;2)

symmetricalproximalmuscleweakness;3) raisedserummuscleenzymes(atleastoneof

CK,LDH,AST);4)myopathicEMG;5)musclebiopsydemonstratingnecrosisand

inflammation.[29]Patientswitharashandtwootherofthecriteriaareconsideredtohave

possibleJDM,whilerashwiththreeadditionalcriteriaareconsideredtohavedefiniteJDM.

Inpractice,musclebiopsyandEMGareusedlessfrequentlytodaythantheyoncewere.

TheyarebothinvasiveinvestigationsandMRIisnowconsideredasensitivetestfor

myositis.

Theclinicalcourseandprogressionofthediseaseisalsovaried.MostcommonlyJDM

presentswithaninsidiousevolutionoveraperiodof3to6months,howeveritcanpresent

acutely.Ramananetalreviewedtheclinicalfeaturesandoutcomesofalargecaseseriesof

patientstreatedattheHospitalforSickChildreninCanada.[23]Of120patientswithIIM,

105hadJDM.Themostcommonclinicalfeaturesatpresentationwere:Gottronsrash(91%),

heliotroperash(83%),malar/facialrash(42%),nailfoldcapillarychange(80%),

myalgia/arthralgia(25%),dysphoniaordysphagia(24%),anorexia(18%),fever(16%).[23]

Muscleweaknessisprogressiveandfrequentlyresultsintheinabilitytoambulate,sit

uprightorattendtoactivitiesofdailyliving.Weaknessmaybeaccompaniedbysignificant

pain.Thepharyngealandpalatalmusclesmayalsobeinvolvedresultingindifficulty

swallowinganddysphonia.Thisoccurredinupto24%ofpatientsinRamanansseries[23]

andputsthepatientatriskofaspiration

3.2.3 Complications

Calcinosisoccursinupto40%ofpatients[30]andcanresultinsignificantdisability.Deposits

inthesubcutaneoustissuescanbepainfulandleadtoulceration.Earlyandaggressive

controlofinflammationmayminimisethedegreeofcalcinosis.[31]Cutaneousulcerative

diseaseisanotherskincomplicationwhichisnotinfrequentlyseen.Itisthoughttobe

associatedwithmoresevereandprolongedJDM.[32]Lipodystrophyhasalsobeen

describedwithJDM.

Cardiopulmonaryabnormalitiesarealsodescribedhoweverclinicallysignificant

involvementinchildrenwithdermatomyositisisunusual.Themostfrequentcardiac

problemsincludecardiomegalyandnonspecificmurmurs.Moreseriouscardiacinvolvement

isunusualbutpotentiallylifethreatening.Restrictivepulmonarydiseaseduetopoorchest

wallcomplianceandrespiratorymuscleweaknessiscommonandhasbeenreportedinupto

78%patients.[33]Gastrointestinalvasculitisisrarebutisaseverecomplicationwhichcan

leadtodeath.Itmanifestsasabdominalpain,haematemesisandmelaena.


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3.2.4 CourseandOutcomeofJDM

JDMtypicallyfollowsauniphasiccoursealthoughthedurationisquitevariable.Stringeret

alfollowedthecourseof84patientswithJDM.Theyfoundthatthemajority(60%)of

patientshadachronicdiseasecoursedefinedasnoremissionwithin3yearsofdiagnosis.

[34]Theyalsofoundthatasmallpercentageofpatientshadarelapsefollowingremission.

TheoutlookforpatientswithJDMhassignificantlyimprovedoverthepastdecadeswiththe

useofmoreaggressiveimmunosuppressanttherapies.Beforetheuseofcorticosteroids,this

illnesswasdevastating.Manypatientsdiedorsufferedlongtermprogressiveanddisabling

disease.Functionaloutcometodayisusuallyexcellentwith6580%ofpatientsachievinga

goodoutcome[2]Optimaloutcomeseemstobeachievedifdiagnosisismadeshortlyafter

onsetandtreatmentisvigorous.[35]Huberetalfoundthatof65childrenwithJDM,a

favourableoutcomewaspredominant.Eightpercentwereleftwithmoderatetosevere

disabilityandtherewasonedeath.[36]Contracturesandmildatrophyoccurin

approximately25%ofpatients[2]howeverinonestudycohortnoneofthepatientswere

thoughttobeeducationallyorvocationallyimpairedduetotheirillness.[23]Although

deathsarenowlessfrequent,chronicallyactivediseaseoccursinsubstantialnumberof

patientsand,inaddition,sideeffectssuchasgrowthfailurefromprolongedsteroiduseare

notinfrequent.

3.2.5OverviewofManagement

Corticosteroidsandgeneralsupportivecareinamultidisciplinaryteamsettingarethe

mainstaysoftreatmentofJDM.TheuseofcorticosteroidshasdramaticallyimprovedtooutlookforpatientswithJDM.Highsuppressivedosesareusedearlyandthentapered

graduallyoveronetotwoyears.Thedegreeofsupportivecareisdependentuponthedegree

ofdisability.Inpatientswithbulbardysfunctionorsignificantrespiratorymuscleweakness,

careneedstobedirectedtopreventionofaspirationandventilatorysupport.Physiotherapy

andoccupationaltherapyisadvisedtoavoidlossofmotionandcontracturesinthefirst

instanceandthenlatertostrengtheninordertoregainnormalfunction.

Otherimmunosuppressiveagentshavenotbeensubjectedtorandomisedcontrolledtrials

howevertheyarenowacceptedasanimportantpartofthemanagementofJDM.Four

agentshavebeendescribedinthetreatmentofJDMandtheevidencefortheirusewillbereviewedwithinthisdocument.Theyare:methotrexate,cyclosporine,azathioprineand

cyclophosphamide.

3.3SystemicLupusErythematosus

Systemiclupuserythematosus(SLE)isamultisystemautoimmunediseasecharacterisedby

inflammationofthebloodvesselsandconnectivetissuesresultingindamagetonumerous

organsystemsandassociatedwithantinuclearantibodies.ThediagnosisofSLEisbasedon

welldescribedclinicalandlaboratoryfeaturesandissupportedbytheuseoftheAmerican

CollegeofRheumatology(ACR)adultSLEclassificationcriteriafirstdevelopedin1982andthenrevisedin1997. However,therearewelldescribeddifferencesintheclinicalfeatures,

serologyandoutcomeofpaediatricpatientswithlupuscomparedwithadultpatients[37]


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andthereforetheapplicabilityofthesediagnosticcriteriahavebeenquestioned.Therehave

beenfewlargescalevalidationstudiesofthesecriteriainthepaediatricpopulation.Ferrazet

alappliedtheACRcriteriato103paediatricpatientswithlupusanddemonstrateda

sensitivityandspecificityof96%and100%respectively.[38]

TheaetiologyofSLEisunknown.SusceptibilitytothedevelopmentofSLEisconsidered

multifactorialperhapscontributedbytheinteractionofgenetic,acquiredandperhaps

environmentalfactors.ThepathogenesisinvolvesdisorderedimmunitywithautoreactiveT

andBcellsandantibodyandimmunecomplexdeposition.[2]Theclinicalmanifestationsand

courseofSLEareextremelyvariedbutcanbeassociatedwithsignificantmorbidityand

mortality.

3.3.1Epidemiology

PaediatricSLEisararediseaseandisreportedtohaveanannualincidenceestimatedat

between0.360.9per100,000peryeardependingonthepopulationinwhichitis

studied.[2]Thereisnoaccurateprevalencedata.DatafromRheumatologyclinicsurveys

reportthatSLEaccountsforbetween1%and4.5%ofclinicpopulation.[2]Approximately

15%ofpatientswithSLEhavetherediseaseonsetinchildhood.Onsetisrarebeforetheage

of5anditismorecommoningirlsthanboyswitharatioofapproximately5:1.[39,40]

TherearelimitedpopulationbasedstudiesreportingdataonthedistributionofSLEacross

racialgroups.SLEhasbeenobserveddisproportionatelyinpeopleofAfricanAmerican,

HispanicandAsianbackground.[2]

3.3.2ClinicalandSerologicalManifestations

SLEisamultisysteminflammatoryconditionandcanpresentwithinsidiousonsetorasan

acutelifethreateningillness.Thediseasecanmanifestwithrenal,CNS,cardiac,pulmonary,

musculoskeletal,cutaneous,gastrointestinal,hepaticandhaematologicalfeatures.Onelarge

cohortof256patientswithpaediatricSLEreportedthatthemostcommonclinical

manifestationswere:arthritis(67%),malarrash(66%),nephritis(55%)andCNSdisease

(27%).[40]Constitutionalsymptomssuchasfever,fatigueandweightlossarecommonin

paediatriconsetSLE.[41]Clinicalfeaturessuchasulcers,alopecia,Raynaudsphenomenon

and photosensitivitylesscommoninpaediatricSLE.[41]Onestudyreportedmoreseverediseaseonsetinpaediatricpatientscomparedtoadultpatientsandthatrenaland

haematologicalfeaturesweremorecommon.[37]Silvermanetalsupportedthisfindingin

theirstudycomparingpaediatricwithadultSLE.Theyfoundthatchildrenhadmoreactive

diseaseatonsetwithhigherfrequencyofrenaldiseaseandlowerfrequencyof

cardiopulmonarydisease.[42]

Typicalserologicalfindingsinclude:positiveantinuclearantigen(ANA),positivedouble

strandedDNA(dsDNA),antibodiespositivetoextranuclearantigens(ENA),low

complementlevelsandpositivelupusanticoagulantandantiphospholipidantibodies.


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3.3.3CourseandOutcome

SLEischaracterisedbyachronicrelapsingandremittingcourse.Flarescanoccuratanytime

inthecourseoftheillnessandarefrequentlyprecipitatedbyinfection.Althoughoverall

outcomeformorbidityandmortalityhasimprovedinrecenttimeswithcurrenttherapeutic

options,SLEremainsaseriousandlifethreateningillnesswithanunpredictableprognosis.

In1968,MeislinandRothfieldreporteda5yearsurvivalinpatientswithrenalinvolvement

andwithoutrenalinvolvementof42%and72%respectively.[43]Incontrast,in1998,Yanget

alreporteda5yearsurvivalof91%inpatientswithnephritis.[44]

3.3.4OverviewofManagement

SLEisacomplex,multisystem,chronicdiseasewithpotentialforsignificantmorbidityand

mortalityandisthereforebestmanagedbyamultidisciplinaryteamexperiencedinthe

managementpaediatricSLE.Generalaspectstomanagementinclude:avoidanceofexcessiveexposuretosunlightandprotectionagainstUVBwithsunscreenandappropriate

skincoverwithclothingandheadwear;preventionofinfectionwithimmunisation.

CorticosteroidsremainthefirstlinetherapyforthemanagementofpaediatricSLE.NSAIDs

arefrequentlyusedtomanagemusculoskeletalcomplaintsandhydroxychloroquineisused

asanadjuncttocorticosteroidsinthetreatmentoffatigue,mucucutaneousfeaturesand

arthritis.Immunosuppressivetherapyincludingcyclophosphamide,azathioprineand

mycophenolatearegenerallyconsideredearlyinthecourseofthediseaseifthereis

evidenceofdiffuseproliferativeglomerulonephritis,CNSinvolvementorpulmonary

haemorrhage.[45]Otherimmunosuppressantsconsideredincludemethotrexateandcyclosporin.Thechoiceofdrugremainscontroversial.Inotheractiveformsofthedisease

thereisnoagreementonthetimingofinitiatingimmunosuppressanttherapy.Manyof

thesepatientsareatriskofdevelopingirreversibleorgandamageand,inaddition,

potentiallyfacemanyyearsofhighdosecorticosteroidtherapywithitsassociatedtoxic

effectsandmaythereforewarranttheadditionofimmunosuppressanttherapy.

Mycophenolateinitiallyshowedpromisingresultsinmaintainingdiseasecontrolinadult

patientswithresistantorrelapsinglupusnephritis.Ithassincethenbeensubjecttometa

analysisandfoundtohavenodifferenceoverazathioprineintermsofresponseratesor

developmentofendstagerenaldisease.[46]Itappearstohaveasaferprofilethanazathioprineespeciallyregardstohaematologicalcomplications.

Whilstcurrenttherapieshavedramaticallyimprovedsurvival,thereishopethatnewer

agentsincludingcytotoxicandbiologictherapiesmayprovidesuperiormanagementand

ultimatelyleadtocurativetreatment.[47]

4. DiseaseModifyingAntiRheumaticDrugs(DMARDs)

DMARDsarenotusedforimmediateanalgesicorantiinflammatoryeffectbutratherfor

theirlongtermbeneficialeffectsincontrollingdiseaseactivity.Thesemedicationsalsoplay

animportantroleinreducingthelongtermexposuretomedicationssuchasprednisolone


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andNonSteroidalAntiInflammatoryDrugs(NSAIDs).Historically,DMARDswereused

lateinthecourseofdiseaseprogressionastherewereinitialquestionsregardingtoxicityand

safety.Moreover,theillnessestreatedwerenotoftenconsideredlifethreateningand

thereforeDMARDtherapywasconsiderednotwarranted.Itisnowrecognised,however,

thatnotonlyaremanyofthesemedicationssafeandeffectiveforuseinchildrenbutalso

thattheiruseearlyinthecourseofthediseasemaypreventirreversibledamageand

decreasetheburdenofdisease.

ThereareanumberofDMARDsusedinthetreatmentofrheumaticillnessesinchildren.

Theseinclude:methotrexate,sulfasalazine,azathioprine,leflunomide,hydroxychloroquine

andcyclosporine.Methotrexateisoftenconsideredasthefirstchoiceanditisusedas

treatmentinmanydiseasessuchas:JIA,JDM,SLE,vasculitis,uveitisandlocalised

scleroderma.

4.1Methotrexate

4.1.1MechanismofactionandPharmacology

Methotrexateisafolicacidanalogueandaninhibitorofdihydrofolatereductaseandthereby

interfereswithDNAsynthesisbyreducingthepurineandpyrimidinesupplyinrapidly

dividingcells.Thisantiproliferativeeffectisachievedwithhighdoseregimensandisused

forthetreatmentoftumours.InlowdoseDMARDtherapy,methotrexatealsohasan

immunomodulatoryandantiinflammatoryeffect. Althoughtheexactmechanismofthis

actionremainsunknown,Methotrexateisthoughttoeffectthecellularproductionofa

varietyofcytokinesandtherebyactstoinhibitcellmediatedimmunity.

Thereissignificantvariabilityinthepharmacokineticsofmethotrexatebetweenindividuals

andalsospecificpharmacokineticqualitiesthatimpactonthedosingandrouteof

administration.Methotrexateisabsorbedbythegastrointestinaltractbyasaturableprocess.

Theaverageoralbioavailabilityis0.7butthiscanrangefrom0.25to1.49.[48]Anumberof

factorsarethoughttoimpactonthisincluding:age,sex,dose,creatinineclearance,andfed

vs.fastingstate.[49]Thereisdebateintheliteratureastowhethermealshaveanimpacton

theabsorptionoforalmethotrexate.Absorptionoforallyadministeredmethotrexatehas

beenshowninadultstudiestobereducedatdosesbeyond15mg[50,51]andsomegroups

advocatefortheuseofparenteralmethotrexatefordoseshigherthanthis.

Onceabsorbed,peakserumlevelsarereachedinapproximately1.5hourswiththe

eliminationhalflifebeing7hours.Themajorityofeliminationisthroughrenalexcretionand

circulatinglevelsfallrapidlyasthedrugisdistributedandeliminated.[2]

4.1.2EfficacyofMethotrexateinJuvenileIdiopathicArthritis

MethotrexateisthemostfrequentlyusedsecondlineagentinJuvenileIdiopathicArthritis

andthereisgoodevidenceofitsefficacy.Theevidenceforitsusehasbeendemonstratedin

randomisedplacebocontrolledtrialsaswellasfromalargenumberofretrospectiveand


14/50

14

uncontrolledstudies.Furthermore,thesestudieshaveshownthatMethotrexateissafe.

Table1summarisesstudiesaddressingtheefficacyofmethotrexateinJIA.

Gianninietalpublishedametaanalysisin1993comparingmethotrexatewith

hydroxychloroquine,penicillamineandauranofininJIA.Atotalof520patientswere

enrolledinallthethreestudiesincludedintheanalysisandoutcomemeasuresincluded

physiciansglobalscaleandESR.Onlymethotrexateat10mg/m2showedimprovementin

thesedomains.[52]In2004,PaediatricRheumatologyInternationalTrialsOrganisation

(PRINTO)publishedtheresultsofatrialwhichultimatelycomparedintermediatewith

higherdosemethotrexateinpatientswhohadfailedtorespondinitiallytostandarddoses.

Theinitialscreeningphasedescribesatotalof633patientswithJIAofwhich72%responded

toastandarddoseofmethotrexate(812.5mg/m2/week)after6monthsoftherapy.[53]

TheefficacyofmethotrexateinthetreatmentofJIAhasbeendemonstratedinprospective

controlledtrials. AsystematicCochranereviewin2001setouttoevaluatetheeffectsof

methotrexateonanumberoffunctionaldomains,includingfunctionalability,rangeof

motion,qualityoflife,overallwellbeingandpain.Onlytwostudies[54,55],withatotalof

165patientswithJIA,fulfilledtheinclusioncriteriafortheCochranereviewofplacebo

controlledrandomisedclinicaltrials.BasedonthesestudiesTakkenetalconcludedthat

methotrexatehasaclinicaleffectonpatientcentreddisability.[56]Sincethentherehasnot

beenanyotherpublishedRCTsaddressingtheefficacyofmethotrexatevs.placebo.

Despitetheevidencefortheefficacyofmethotrexatetherearemanyquestionsrelatingtoits

usethatremainunansweredorwithoutsufficientevidencetoenableconcrete

recommendations.Forexample,theresponsetomethotrexatebetweenthevarioussubtypes

ofJIAhasnotbeencomparedinarigorousfashion. Wooetalfoundnodifferencein

responsetomethotrexatebetweenpatientswithextendedoligoarticularandsystemicJIA

althoughoveralltherewasasignificantimprovementofbothgroupscomparedwith

placebo.[54]Incontrast,RavellietalfoundthatwhencomparedtosystemicJIAand

polyarticularJIA, extendedoligoarticularJIAwasthemostlikelytorespondto

methotrexate.[57]

Theoptimaltimingofdiscontinuationofmethotrexatetherapyfollowingremissionisalso

unclear.Asdocumentedintable1,Gottleibetalfoundthatafterameanof8monthsin

completeremission(SD=4months)beforediscontinuationofmethotrexate,relapseoccurred

in52%atameanof11months.[58] Mostpatientsrespondwhenmethotrexateis

restarted.[58]

Insummary,methotrexateisefficaciousinJIAhoweverfurtherstudiesarerequiredto

furtheroutlinethedurationoftherapybeforediscontinuation.


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15

Author,

Year

Popn Type of

study

Number of

patientsSubjects Duration

of study

Intervention Primary outcomes m

Giannini,

1992[55]

US and

SovietUnion

Multicentre

randomisedplacebocontrolled

38x 10mg/m2

MTX37x 5mg/m2MTX39x placebo

JIA 3

joints

6 months 5mg/m2 vs

10mg/m2 vsplacebo

Joint ROM

Swollen jointsPain on joint movementPhysician global score

Woo,2000 [54]

UK andFrance

RCT doubleblindcrossover

88 Extendedoligo JIA(EOA) and

SoJIA

12 months 15mg/m2 (up to30mg/m2) vsplacebo

Joint ROMNumber active jointsPhysician global score

Parent/child global scoreESR

Cespedes-Cruz,2008[59]

Patients frommulti-centre

internationalRCT

521 PolyJIA 12 months 50 item Child HealthQuestionnaire (CHQ)

Silverman,

2005[60]

Multicentre

internationalRCT

Double blind

86 completed

16 weeks,70 entered

extensionstudy

PolyJIA

3-17 yrsold

16 week

+/-32 weekextension

MTX vs

leflunomide

ACR Pediatric 30 (30%

improvement compared wbaseline in 3 of 6 variab

included in ACR core set(swollen joints, active joiparent global assessmentphysician global assessmCHAQ, ESR)

Ruperto,

2004[53]

Multicentre

international

RCT 633 patients

screened inphase one.80 patients

deemed to benonresponders

wererandomised

Poly JIA 6 months Standard vs

higher parenteraldose of MTX (15vs 30mg/m2/week)

ACR Pedi 30 definition o

improvement

Table 1. Evidence for the efficacy of Methotrexate in JIA


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16

Ravelli,1999[57]

Italy Retrospectiveanalysis

80 SoJIA 37polyJIA 20oligo JIA

23

6 months 6 month clinical responsecomplete disease control,relapse, hepatotoxicity, G

toxicityAl-Sewairy,1998 [61]

SaudiArabia

Retrospectiveanalysis

18 SoJIA Mean 18months

MTX Range 2.5-15 mg/week

Joint evaluationFever, rashLAD and splenomegalySerositisESR, Hb, WCC and plts

Gottleib,1997[58]

USA Retrospectiveanalysis2 centres

25 patients inremission for amean durationof 8 months

Poly, pauciand SoJIA

Meanfollow upof patientspost

discontinu-ation was

15 months

MTX range 5.2 15.9 mg/m2/dose

Length of time to relapsecontinued remission follodiscontinuation of MTX

Huang,1996[62]

Taiwan Retrospectivechart review

26 JIA Meanfollow up3 years

Mean weeklydose MTX 10-15mg/m2

Reiff,1995[63]

USA Retrospectivechart review

21 (13/21SoJIA)

RefractoryJIA

Meanduration15.2

months

Mean weeklydose MTX 27 mg

Disease activity score baschanges in concomitant thlabs, physician global,

radiological

Ravelli,1994[64]

Italy Retrospectivechart review

19 SoJIA 6 monthstherapy

MTX dose range7.5-11

mg/m2/week

Response defined as 50reduction in number of jo

active arthritis

Harel,1993[65] USA 23 (5 SoJIA) 17/23responders6/23 nonresponders

Median 2.5yrs MTX 7.5-10mg/m2 Assessed radiological proon serial wrist XR

Wallace,1993[66]

USA 49 PolyJRA(16/49SoJIA)

At least 1year

MTX 15mg/m2

Table 1. Evidence for the efficacy of Methotrexate in JIA


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17

4.1.3EfficacyofmethotrexateinJuvenileDermatomyositis

Methotrexateisthemostfrequentlyusedoftheimmunosuppressiveagentsdescribedinthe

treatmentofJDM.ArecentsurveyofPaediatricRheumatologistsdemonstratedconsiderable

variationinthemanagementofJDM.[34]Thisvariancereflectsthelackofdataavailableon

whichtobasetreatment.Morerecentlythreeconsensusprotocolsweredevelopedata

consensusmeetinginTorontoinvolving12PaediatricRheumatologists.Eachofthese

protocolsinvolvedtheuseofcorticosteroidsandmethotrexate.[67]

Methotrexatehasnotbeensubjectedtoaprospectiverandomisedcontrolledtrialand

thereforeevidenceforitsuseisderivedfromobservationalstudiesonly.In2005Ramananet

aldemonstratedinaninceptioncohortstudytheeffectivenessofmethotrexate.Thirtyone

patientswithJDMwerecommencedmethotrexateasfirstlinetherapyatameandoseof

15mg/m2andtheirsteroidsaggressivelytapered.Thesepatientswerecomparedto22

historicalcontrolstreatedwithprednisolonealone.Patientsinthestudygroupwerefound

tohaveashortertimetodiscontinuationofcorticosteroidsandalsoreducedcumulative

dose.[68]However,thisstudyfailedtodemonstratewhetheraggressivetaperofsteroids

alonewithouttheadditionofmethotrexatehadasimilaroutcome.Improvedoutcomewith

theearlyinitiationofprednisoloneandmethotrexatewasalsodemonstratedbyAlMayoub

etalinasmallseriesofpatientswithJDMandassociatedcutaneousulcerationand/or

dysphagia.[69]Inaretrospectivechartreview,initiationofmethotrexateinpatientswho

hadfailedtorespondtosteroidtherapywithin6weekswasthoughttobebeneficialin

reducingtheoverallriskoflongtermcomplicationsincludingcalcinosis.[31]

Thereiscurrentlyaninternationalmulticentreprospectivelyrandomisedtrialcoordinated

byPRINTO(PaediatricRheumatologyInternationalTrialsOrganisation)whichis

comparingprednisolonealonewithprednisolone/methotrexatecombinationand

prednisolone/cyclosporinecombinationinpatientsnewlydiagnosedwithJDM.Theresults

ofthistrialareeagerlyawaitedinordertoguidethemanagementofJDM.


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18

Author/

Year

Popn Typeof

study

Number

of

patients

Subjects Durationof

study

Groups/Intervention O

Ramanan,2005[68]

Singlecentre,

Canad

a

Prospectivecohort

study

with

historical

controls

53 31patientsprospectively

studiedwith22

controls

Controlpatients

followedfor4

years;study

patients

followedfor

average34.6

months

2groups.Studygroup:MTX1020mg/m2/week

(max25mg/week)and

prednisolone2mg/kg/d

(max75mg)withpred

aggressivelytaperedevery

2weeks

Timstero

dose

Dise

mus

calc

Al

Mayouf,

2000[69]

Saudi

Arabia

Prospective

cohort

study

12newly

diagnosed

JDM.

Patientswith

dysphagia,

dysphonia,GI

bleeding,cutaneousulcerationorresp

muscleinvolvement

werestartedMTX

early

Meanduration

oftherapywas

23.5months

2groups:early(


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19

4.1.4EfficacyofmethotrexateinUveitis

Methotrexatehasbeenusedinchildrenwithuveitisformanyyears.Itsuseissupportedby

evidencelargelyfromretrospectivecohortstudies.

Aretrospectivechartreviewfoundmethotrexatetobeaneffectiveagentinthetreatmentof

uveitis.[71]Twentyfivepatientswithuveitisreceivedmethotrexate(meandoseof

15.6mg/m2)andremissionwasachievedafterameanof4.25months.Sixpatientshad

methotrexateceasedafterremissionfor12months andofthese4patientswerestillin

remissionafter7.5months.Othercaseserieshavedemonstratedtheeffectivenessof

methotrexateinuveitisresistanttotopicalcorticosteroids.[72,73]

4.1.4 DoseandadministrationinJIAandJDM

Methotrexateisadministeredweekly.Although,aspreviouslymentioned,theserumeliminationhalflifeofmethotrexateis67hoursitsmetabolitescanbemeasured

intracellularlyover1week.Methotrexatecanbeadministeredorallyorparenterally.The

standardguidelineformethotrexateuseisaninitialdoseof10mg/m2/weekgradingupto

15mg/m2/week.[2]Oralmethotrexateshouldbegivenonanemptystomachasfood

decreasesitsbioavailability.Rupertoetaldemonstratedthattherewasnoadditionalbenefit

ofparenteraldosesabove15mg/m2.[53]Parenteraladministrationisrecommendedfor

doses>15mg/m2/weekbecauseofbetterbioavailabilityandgastrointestinaltolerability.

Parenteraldosingshouldalsobeconsideredinthosechildrenwhohaveapoorresponseto

oralmethotrexateorwherepoorcomplianceimpactsondiseasecontrol.[2]Thereisno

differenceinthebioavailabilityofsubcutaneousandintramusculartherapy.[74]

4.1.5 Druginteractionandfolatesupplementation

Anumberofmedicationsincreasethebioavailabilityofmethotrexate.Theseinclude:

phenytoin,oralcontraceptivepill,tetracycline,barbituratesandtranquilizers.Co

trimoxazoleshouldbeavoidedwithmethotrexateasitcancauseseverebonemarrow

suppressionandskinulcerations.Inadditionanumberofmedications,includingpenicillins

andcyclosporine,canlowertheeliminationofmethotrexatebydecreasingrenalclearance.

Methotrexateiscontraindicatedinrenalfailure.

Thereisgoodevidencetosupporttheuseoffolicacidsupplementationtoalleviatethe

commongastrointestinalandoralmucosalsideeffectsassociatedwithmethotrexatewithout

impactingonthebeneficialantiinflammatoryeffects.[75]

TheuseofmethotrexateissafeincombinationwithNSAIDSandcorticosteroids.Thereis

someexperienceofcombinedDMARDshowevercontrolledsystematicstudiesarelacking

tosupportthisstrategyinthetreatmentofJIA.


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20

Author,

Year

Typeof

studyDuration

ofstudy

Subjects

and

numbers

Drugand

monitoring

Hepatotoxicity Haematological

abnormality

G

Ortiz

Alvarez,

2004[76]

Pro

spective

study

89JIA MTX

Monthly

bloodtests

14%patienthadsignificantly

elevatedLFTs(>2xULN)

52%hadmildelevatedliver

functests

26%patientshad

abnormalFBE(low

granulocyteor

lymphocytecountor

Hb)

95%ofpatientswith

abnhadviralinfection

atthetimeofblood

test.

Lahdenne,

2002[77]

Retro

spective

review.

Liverbx

correlated

withlab

findings

Patients

onMTX

atleast

2.4yrs

34JIA MTX(20

30mg/m2)for

duration>2.4

yrs

All24ptstreatedwithlow

doseMTXhadgradeI

Roenigkchanges.

Of10patientson>20mg/m2,

4ptsgradeIIhistologyand5

gradeI.Nofibrosisor

cirrhosis

Graham,

1992[78]

Retro

spective

review

84296

weeks

62poly

JIA

MTX(5

10mg/m2),

3monthly

bloodtests,

PFTson46

pts

Transientliverfunctionabn

occurredin9/62(14%)

12patientshadliverbiopsy

nofibrosisorcirrhosis

Macrocyticanaemiain

onepatientonco

trimoxazole

NocasesonTPor

neutropenia

Nau

occ

14/6

Pep

4/62

also

con

NSA

Giannini,

1992[55]

US/Soviet

Multi

centreRCT

6months 89JIA3

joints

MTX5or10

mg/m2

OnepatienthadLFTabn 8pa

GIu

Woo,

2000[54]

DBRCT

crossover12

months

88

EOAJIA

andSoJIA

15mg/m2(up

to30)vs

placebo

Total20patientsonMTX

hadASTabnvs16placebo

patients

Bonemarrowfailure

didnotoccur

Nau

ups

ins

num

pat

Table 3. Adverse Effects of Methotrexate


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21

Author,

Year

Typeof

studyDuration

ofstudy

Subjects

and

numbers

Drugand

monitoring

Hepatotoxicity Haematological

abnormality

G

Hashkes,

1999[79]

Liver

biopsies

compared

withRFfor

hepatotox

25

patients,

33

biopsies

2biopsiesshowedgradeIIIa

Roenigkchanges

4showedgradeIIchanges

and27gradeI.

Nosignificantfibrosis

Hashkes,

1997[80]

Liver

biopsies

compared

withRFfor

hepatotox

14JIA 13/14gradeIRoenigk

changes

1/14gradeIIchanges

Nobxwithsignificant

fibrosis.

13/14LFTabnbutonly5had

>3xULN

Kugathasan,

1996[81]

Liver

biopsies>3years

ofMTX

9JIA 10mg/m2/wk Noclinicalorbiochemical

evidenceofliverinjury

Allbiopsieswerenormal

Table 3. Adverse Effects of Methotrexate


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22

4.1.6 Safety

Methotrexateisgenerallywelltoleratedinchildren,however,ithasanumberofpotentially

seriousadverseeffects.Themostcommonsideeffectisnauseaandvomitingforwhichfolic

acidhasbeenreportedtobebeneficial.[75]Mostoftheothersideeffectsaremildand

reversible.Oralulceration,alopecia,moodchanges,rash,pepticulcerandheadachehave

beenreportedtooccur.Table3summarisesreportedadverseeffectsofmethotrexate.

Hepatictoxicityisoneofthemainpotentiallyseriousadversereactionswithmethotrexate

use.Theexactmechanismisnotclearlyunderstood.[82]Childrenarethoughttohavea

reducedriskofmethotrexateassociatedhepatotoxicitycomparedwithadultsasthey

generallyhavefewercoexistingdiseasesandfewerenvironmentalexposuressuchas

alcohol.Acutemildliverfunctionabnormalitiesoccurinapproximately9%ofchildrenon

lowdosetherapy.[83]Thesechangesareusuallytransientandimprovewithaperiodof

cessation.Itisdifficulttoassessthetrueeffectofmethotrexateasitisoftenusedin

combinationwithNSAIDswhichmaycontributetoatransaminaserise.

Thepotentialforlongtermliverdamagewithfibrosisandcirrhosishasraisedconcernsin

thepasthoweverthereareonlyafewreportsoffibrosisinchildrenandnoreportsof

cirrhosissecondarytomethotrexate.Refertotable2forsummaryofseriesaddressingliver

fibrosisandcirrhosis.

Haematologicalabnormalitiesarerarewiththeuseofmethotrexate.Themaintoxiceffects

describedinclude:macrocyticanaemia,leukopenia,thrombocytopeniaandpancytopenia.[2]

OnlycasereportsofchildrenwithhaematologicalsideeffectsofMTXexist,however,the

adultliteraturereportsafrequencyof13%.[84]Inpatientswithmildbonemarrow

suppression,spontaneousrecoveryisusualwithin2weeks.[2] Malignancydueto

methotrexateremainsanareaofcontroversy.Therehavebeenafewcasesdescribedin

childrenwithJIAonmethotrexateofHodgkinsandNonHodgkinslymphoma.[85,86]

Methotrexatehasbeenreportedtohavecausedfoetaldeathandcongenitalabnormalities

andthereforeitsuseisnotrecommendedforuseinpregnancy.Itissuggestedthat

pregnancyisavoidedforaminimumof3monthsaftercompletionoftherapyinmale

patientsandforatleastoneovulatorycycleinfemalepatients.

4.1.7Monitoring

and

supervision

ChildrenwithJIAonlongtermmethotrexaterequireregularclinicalandlaboratory

monitoringbothfortheresponsetothemedicationandforitspotentialtoxicities.

HashkesetalexaminedliverbiopsiesinchildrenwithJIAonmethotrexateandfounda

relationshipbetweenbiochemicalliverfunctionchangesandhistopathologicalchanges

consistentwithmildfibrosis.[79]Whilstthedegreeoffibrosisinthisserieswasnot

consideredsignificant,thepotentialhepatotoxiceffectsofmethotrexatehavepromptedthe

introductionofguidelinesforthemonitoringoflivertoxicityinpatientstakingmethotrexate.

Theseguidelinesweredevelopedin1994andrepresentanexpertconsensusonthe


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23

monitoringoflivertoxicitywithmethotrexateuseinadultRheumatoidArthritis.Although

developedbasedonadultdata,theseguidelinesformthebasisformonitoringofchildren

withJIAonmethotrexate.[87]

Itisgenerallyrecommendedthatliverfunction,renalfunctionandfullbloodexaminationbe

performedatbaselineforallpatients.MonitoringofLFTs48weeklywasrecommendedby

Kremeretalintheinitialguidelinespublishedin1994.[87]Sincethen,OrtizAlvarezetal

monitored89patientswithJIAprospectivelyandfoundthatLFTabnormalitieswereusually

mildandresolvedspontaneouslyandthatmoresevereabnormalitiessettledrapidlywith

discontinuationofmethotrexate.[76]Whentherearenoothercoexistingriskfactors,3

monthlymonitoringfollowinginitialbimonthlyforafewmonthsseemstobeappropriate.

4.1.8 Formulary

Australianbrandname:Methoblastin:Tablets:yellowanduncoated,2.5mg(round),10mg(capsuleshaped);Injection:25mg/ml,1000mg/10ml

UKbrandname:Maxtrex:2.5mg,10mgtablets;Metoject:prefilledsyringe10mg/ml(7.5mg,

10mg,15mg,20mg,25mg)

USbrandnames:Rheumatrex:2.5mg;Trexall:tablets2.5mg,5mg,7.5mg,10mg,15mg

Canadianbrandnames:ApoMethotrexate;RatioMethotrexate

4.1.9 Summaryrecommendations

MethotrexatehasbeenshowntobeaneffectiveandsafetherapyinthetreatmentofJIA.Itis

associatedwithanumberofpotentiallyseriousadverseeffectsandthereforeitsuserequiresmonitoringwithbloodtestsandwithcloseclinicalsupervisionfromamedicalspecialist

familiarwiththepotentialrisks.Itisnotrecommendedforuseifaccesstothissupervisionis

unavailable.ItisrecommendedforinclusionontheWHOcomplementarylistofessential

medicines.

4.2Leflunomide


Leflunomideisanimmunomodulatorymedicationthatinhibitspyrimidinesynthesis

throughitsinhibitionoftheenzymedihydroorotatedehydrogensase.Lymphocyte

proliferationdependsonpyrimidinesynthesisforproliferationandleflunomidetherefore

hasbothantiproliferativeandantiinflammatoryeffects.

TheactivemetaboliteisA771726towhichleflunomideisactivelyconvertedviahepatic

metabolism.A771726ishighlyproteinboundandhasahalflifeofupto18daysreachinga

steadystateafterapproximately20weeks.[88]

Thepharmacokineticsofleflunomideanditsactivemetabolitesarenotaffectedbyfoodintakeorbygender.Itisexcretedalmostequallyinurineandfaeces.Thepharmacokinetics


24/50

24

oforalleflunomidewasstudiedin73paediatricpatientsaged317yearswithpolyarticular

JIA.[89]Thisanalysisdemonstratedthatpaediatricpatientswithbodyweights

40kg.[89]Theuseofaloadingdosemayincreasetoxicityinchildren.(MIMS2009)

4.2.4 Safety

Themostcommonlyreportedadverseeffectisgastrointestinalupsetwhichisreportedto

occurin17%ofpatients.Thisincludes:abdominalpain,dyspepsia,diarrhoeaandgastritis.

Othercommonsideeffectsinclude:headache,rashandalopecia.

Liverfunctionabnormalitiesarelessfrequentlyreportedthanwiththeuseofmethotrexate.

[60]Thereappearstobeaparticularriskwhenusedincombinationwithmethotrexate.[92]

InstudiesofleflunomideinadultswithRheumatoidarthritis,liverfunctionabnormalities

arereportedinapproximately5%ofpatients.Thesechangesaremildandreversible.More


25/50

25

seriousliverdysfunctionisuncommonandisassociatedwithconcomitantalcohol

consumption,viralhepatitisorotherpreexistingliverdisease.

Leflunomideisteratogenicandthereforeitisrecommendedthatpatientshaveanegative

pregnancytestbeforestartingtreatmentandusereliablecontraceptionduringtherapy.

4.2.5 Druginteractions

Theenzymesinvolvedinthemetabolismofleflunomidearenotentirelyknown.Invitro

studiesindicatethatleflunomideinhibitscytochromep450andthereforecautionshouldbe

takenwhencoadministeredwithotherdrugsinvolvedincytochromep450metabolic

pathways.

4.2.6 Monitoringandsupervision

Monitoringisrecommendedwithbaselineandmonthlyfullbloodcountandliverfunctionfor6months,whichcanbereducedto68weeklyifstable.

4.2.7 FormularyBecausesafetyandefficacyinchildrenhasnotbeenclearlyestablishedwiththeexisting

evidence,mostmanufacturersdonotlistleflunomidewithpaediatricadvice.

Australianbrandnames:Arava(tablets10mg,20mg,100mg);Arabloc(tablets:10mg,

20mg)

USbrandnames:

Canadianbrandnames:

4.2.8Summaryrecommendations

Insummary,despitelimitedstudiesinthepaediatricpopulation,leflunomidehasbeen

showntobeeffectiveforthetreatmentofJIAbothasamonotherapy[60]andincombination

withmethotrexate[91].Itsuseinthetreatmentofrheumaticdiseaserequiresmonitoring

withbloodtestsandcloseclinicalsupervisiontoensurethatthepotentialsideeffectsareminimised.Itisnotrecommendedforuseifaccesstothissupervisionisunavailable.Itis

recommendedforinclusionontheWHOcomplementarylistofessentialmedicines.


26/50

26

Author,

Year

Popn Typeof

study

Duration

ofstudy

Numberof

patients

Subjects Studygroups Primaryo

measu

Silverman,2005[60]

Multicentreinternational

DBRCT 16week+/32

week

extension

86completed16weeks

70entered

extension

study

PolyarticularJIA

317yrsold

MTXvsleflunomide PercentageofpaACRPedi30(3

improvementco

baselinein3of

includedinACR

(swollenjoints,a

count,parentglo

assessment,phy

assessment,CHA

Silverman,

2005[90]

Open

labelstudy

26weeks 27patients

Only63%patients

completed

study

Refractory

polyarticularJIA(failed

responseor

intolerantof

Methotrexate)

Leflunomideloadingdose

~100mgfollowedby10mg/day(+/ increaseto

20mg/dat8wks)

ACRPedi30

Gao,

2003[91]

China 26weeks 40patients Polyarticular

JRA

Leflunomide(loadingdose

of1mg/kg/day)D13then

0.20.4mg/d)plusMTX

(0.3mg/kgivevery2wks

untilremissionthen

0.2mg/kgweeklyorally)vs

MTXalone

Tenderandswo

parentandphys

evaluationscore

functionscore,E

SEdocumented

Table 4. Evidence for the efficacy of leflunomide in JIA


27/50

27

Author

,

Year

Popn Type

of

study

Duration

ofstudy

Number

of

patients

Subjects Studygroups Outcomes

Van

Rossum,

1998[93]

multicent

re

DBRCT 24weeks 69 Oligoand

Polyarthriti

s

SSZ50mg/kg/d

(max2g/d)

Placebo

ACRPediatric30

(withoutfunctional

measure)

AEs

44%imp

placebo

MoreAEpatients

AEswer

Leukope

anorexia

Burgos

Vargas,

2002[94]

DBRCT 26weeks 33 ERA SSZ30

60mg/kg/d(max

2g)

Placebo

Reductioninactivejoints 46%inS

Significa

patienta

Ansell,

1991[95]

multicent

re

Pilot

study,

Uncontrolle

d

52weeks 51 JIA(oligo,

polyand

SoJIA)

SSZ40mg/kg/d

increased

incrementally

over6weeks.

Activejointcount,patient

assessment,ESR

AEs

24%goo

response

8patien

Huang,

1998[96]

Single

clinic

Retrospe

ctive

chart

review

Mean

duration

therapy

2.5yrs

36 ERAand

JIA

SSZ50mg/kg/d

(max2g)

Activejointcount, ESR

Remissionor

improvement(definedas

25%reductioninjoint

numberfortwo

consecutivevisits)

39%pat

11%pat

Nodiffe

Van

Rossum,2007[97]

multicent

re

Pro

spectivecohort

Median9

years(range7

10)

61 Patientsinitially

managedwithSSZ(32)vs

thosemanaged

withplacebo

(29)

ACRPediatric30 Effective

hasbene

Hoza,

1991[98]

DBRCT 26weeks 39 Oligoand

polyarthriti

SSZ20

30mg/kg/d

Anyimprovementin4

criteria:

48%SSZ

Chloroq

Table 5. Evidence for the efficacy of Sulfasalazine in JIA


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28

Author

,

Year

Popn Type

of

study

Duration

ofstudy

Number

of

patients

Subjects Studygroups Outcomes

s

Chloroquine3

4mg/kg/d

Activejoints,pain,

morningstiffness,ESR,

functionalcapacity

MoreAE

Ozdoga

n,1985[99]

414

months

18 Alltypes

JIA

ESR

JointtendernessActivejointcount

Significa

count

Table 5. Evidence for the efficacy of Sulfasalazine in JIA


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29

4.3Sulfasalazine


Theexactmechanismofactionofsulfasalazineisnotclearlyunderstood.ItsroleinthetreatmentofJIAispossiblyduetoitsimmunoregulatoryandantiinflammatoryeffect

including,amongstotherthings:theinhibitionofprostaglandinsynthesis;inhibitionof

bacterialgrowth;inhibitionofleukotrieneformation;modulationofleucocytefunction;

inhibitionofDNAsynthesis;impairmentoffolatemetabolismandeffectsoflymphocyte

numberandfunction.

Sulfasalazineispoorlyabsorbedinthesmallintestine.Inthecolon,sulfasalazineisreduced

totwomajoractivemetabolites(5aminosalicylicacidandsulfapyridine)bycolonicflora.

Sulfapyridineisrapidlyabsorbedandmetabolisedbyacetylationintheliver.Therateofthis

processvariesbetweenindividualsandisgeneticallydetermined.

Both5aminosalicylicacidandsulfapyridinehaveanaffinityforcollagenrichtissueand

concentrateinthesynovialfluidaswellaspleuralspaces,intestinalwallandperitoneum.

4.3.2 EfficacyofSulfasalazineinJIA

TheuseofsulfasalazineinthetreatmentofJIAwasfirstreportedin1986[99],althoughit

hadbeenusedformanyyearspriortothisforthetreatmentofadultRheumatoidarthritis.

Table4summarisesthestudiesaddressingefficacyofsulfasalazineinJIAandasis

illustratedinthetable,whilsttherearefewcontrolledstudies,thereissomeevidenceto

supportitsuseinJIA.

Inarandomiseddoubleblindedplacebocontrolledtrialof69patients,VanRossumetal

foundthatsulfasalazinereducedtheoverallarticularseverityscore,globalassessmentsand

laboratoryparameters.[ref]Adverseeventsweremorefrequenthoweverthesewerefound

tobetransientandreversible.

Ozdogansstudyin1986[99]wasasmalluncontrolledtrial(n=18)whichdemonstrated

benefitsofSSZ.Elevenpatientshadanexcellentresponsewithonly3patientsshowingno

response.SimilarlyinanotheropenlabelstudybyJoosetal[100],21of41patientsachieved

remissionandsignificantimprovementwasseenin12.Inthisstudy,nochangewasseenin

onepatientandtheconditionworsenedinthree.ImundoandJacobs[100,101]observedthat

thebestresponseratewasANApositiveyounggirlswitholigoarticularJIA,andthatthe

worseresponse(indicatedbyahighfailurerate)wasinsystemicJIA.Only28%had

completeremission.Otheropenlabelstudieshaveshownthatsulfasalazineismosteffective

inboysolderthan9andadolescentswitholigoarticularJIA,raisingthequestionofitsusein

enthesitisrelatedarthritis(ERA).

Theothercontrolledstudiesincludeaplacebocontrolledrandomisedblindedstudyof

patients(n=33)withERA.[94]Burgosdemonstratednosignificantdifferenceinresponse

ratehoweversomeimprovementinphysicianandpatientglobalassessments.Hozaetalalso


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30

[98]demonstratednosignificantdifferencewhensulfasalazinewascomparedtochloroquine

inoligoarticularandpolyarticularJIA.

SulfasalazinedoesnothaveconsistentefficacyacrosssubtypesofJIA.Thereisabroad

experienceinopen,uncontrolledtrialswhichsuggestthebenefitofsulfasalazineinJIA,and

thisissupportedbytheaforementionedblindedcontrolledVanRossumtrial.Someopen

labeltrialsfoundanincreaseresponseinolderHLAB27positivechildrenwitholigoarticular

disease,howeverthisfindingwasnotconvincinglysupportedinasmallblindedcontrol

study.[94]Basedonbestavailableevidence,sulfasalazineismosteffectiveinpolyandoligo

articulardiseaseandtheredoesnotappeartobeadifferenceinresponseratesbetweenthese

groups.Onthecurrentevidence,sulfasalazineisnoteffectiveinthemanagementofSoJIA

and,infact,itsuseispotentiallycomplicatedbyanincreasedriskoftoxicity.

4.3.3 Doseandadministration

SulfasalazineisadministeredorallyinchildrenwithJIA.Initiationoftherapyshouldbegin

withasmalldosefollowedbyagradingupatweeklyintervals. Therecommendedstarting

doseis5mg/kgtwicedailyforoneweek,then10mg/kgtwicedailyforoneweek,then

20mg/kgtwicedailyforoneweek,thenamaintenancedoseof2025mg/kgtwicedaily.The

maximumrecommendeddoseinchildrenis2g/day.

Sulfasalazineshouldbeadministeredaftermealsorwithfoodandshouldnotbe

concurrentlytakenwithantacids.

4.3.4Safety

Intoleranceandadverseeventsarefrequentlyassociatedwithsulfasalazineadministration.

Adversereactionsfrequentlyreportedinclude:rash,gastrointestinalsymptomsand

haematologicalabnormalities.Onestudy[93]reportsadiscontinuationrateof

approximately30%.Theyfoundthat86%ofpatientsonsulfasalazinereportedatleastone

adverseeventandthisresultedin10patients(28.5%)requiringwithdrawalfromthestudy.

Onepatientwasconsideredashavingaseriousadverseeventbuttheauthorsnotedthatall

oftheadverseeventswerereversiblewithdiscontinuationoftherapy.[93]

Gastrointestinalintoleranceisthemostfrequentlyreportedsideeffect.Symptomsinclude:anorexia,nausea,abdominaldiscomfortanddiarrhoea.Liverfunctionabnormalitiesalso

occurcommonlyestimatedtooccurinapprox4%patients.Moresevere(andpotentially

fatal)hepatotoxicityhasbeenreportedinassociationwithDRESSsyndrome(DrugReaction

withEosinophiliaandSystemicSymptoms)ahypersensitivityreactionthoughtduetothe

sulfapyridinemetabolite.Featuresinclude:fever,rash,raisedliverfunctiontests,

eosinophiliaandlymphadenopathy.Corticosteroidtherapyisfrequentlyrequiredtotreat

DRESSsyndrome.

Haematologicalsideeffectssuchasleucopeniahaveanincidenceacrosstheliteratureof3%

[102].Whilstleucopeniaisreversiblewithcessationofthedrug,othermorerarebutseverehaematologicalsideeffectssuchasagranulocytosishavebeenreported.Agranulocytosisis


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saidtooccurin1%ofpatientsandusuallybeginswithin512weeksofonsetoftherapy[103]

andispotentiallyfatal.

SkinrashisalsoacommonsideeffectandoccurredinhalfofthepatientsintheVanRossum

trial[93].Sulfasalazinehasalsobeenassociatedwithotherrarercomplicationssuchasdrug

inducedlupuserythematosus.Thismayoccurafterseveralorevenyearsoftherapyand

resolvesfollowingwithdrawal.

4.3.5 Druginteraction

Sulfasalazineisgenerallywelltoleratedwithothermedications.Sulfasalazinemaydecrease

thebioavailabilityofcyclosporin.Therearealsoreportsofpossibleadditivehepatotoxicity

whenusedincombinationwithmethotrexate.Careshouldbetakenwhenprescribing

sulfasalazineasnumerousotherdruginteractionshavebeenreported.


FullbloodcountandLiverfunctiontestsshouldbeperformedfrequentlyfollowinginitiation

ofsulfasalazine.Productinformationsuggestsbaselineteststhen2weeklyfor3months,

monthlyfor3monthsandthenmonthlythereafter.Itisrecommendedthatpatientsbe

followedupclinicallyatleast3monthlytoensureongoingtoleranceofsulfasalazine.

4.3.7 Formulary

SulfasalazineisFDAapprovedforuseinchildrenforJIApolyarticularcourse.ItisnotlicensedforuseintheUK.

Australianbrandnames:Pyralin,entericcoatedtablets:500mg;SalazopyrinandSalazopyrin

ENtabstablets:500mg

UKbrandname:SalazopyrinandSalazopyrinENtabs500mg;Salazopyrinsuspension

250mg/5mlandsuppositories500mg.

USbrandnames:Azulfidine, AzulfidineENtabs,SulfazinandSulfazinEC,500mg

Canadianbrandnames:AltiSulfasalazineandSalazopyrin


Thecurrentliteraturesuggeststhatsulfasalazinehasaroleasdiseasemodifyingtherapyin

thetreatmentofJIAandparticularlyoligoarticularandpolyarticulardisease.Itisnotthe

firstDMARDofchoiceespeciallygiventheevidencesupportingmethotrexate.The

considerationofsulfasalazineasanalternativeDMARDinJIAshouldbeunderspecialist

supervision.Sulfasalazinetherapyalsorequiresspecialistsupervisionparticularlywith

respecttothefrequentriskofadverseeffects.Inaddition,regularmonitoringwithblood

testsisrecommended.SulfasalazineisrecommendedforinclusiononthecomplimentaryWHOessentialmedicinelistprovidedtheseresourcesareavailable.


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4.4 CyclosporinA4.4.1 MechanismofactionandPharmacology

CyclosporinA(CyA)isapotentimmunomodulatoryagentusedtoinhibittheadaptiveimmuneresponseandthereforeeffectiveindiseasesknowntobeofautoimmuneorigin.Itis

usedtopreventrejectioninsolidorgantransplant. Theeffectsontheimmunesystemare

likelymultifactoral.Calcineurin,animportantproteinintheprocessofTandBcell

activation,isboundandinhibitedbyCyA. Thisresultsinimpairedproductionofanumber

ofcytokinesimportantintheproliferationofTcells.TheeffectsofCyAontheTcellappear

tobespecificandreversible.Cyclosporinmayhaveothereffectsincludingeffectsonantigen

presentation.

CyAisincompletelyabsorbedformthegastrointestinaltract.Microemulsionpreparations

arethoughttoprovideimprovedabsorptionandbioavailability.Ithasmultiplehepaticmetabolicpathwaysandismetabolisedtomanymetabolitesbeforeexcretedinthebile.Only

asmallpercentageisexcretedintheurine.Thehalflifeisapproximately18hours.

4.4.2 EfficacyofCyclosporininJIAandMAS

TheroleofcyclosporininthetreatmentofJIAhasnotbeenclearlydefined.Itmaybe

particularlyimportantinthetreatmentofSoJIAespeciallyinassociationwithMAS.As

illustratedinTable6,thereislittlestrongevidencesupportingitsefficacyandthereareno

controlledtrials.Evidenceincludesobservationalstudiesandcaseseries.

Gerlonietaldescribedagroupof34patientswithSoJIAinaprospectiveopentrial[104]in

whomtherewasbenefitincontroloffeverandinreducingsteroidexposure.Twentysix

percentofpatientswithdrewfromCyAtreatmentthoughduetoadverseevents.Inaddition,

50%withdrewduetolackofefficacyorflareofdisease.Stephanetalreportedthe

effectivenessofCyAin12patientswithreactivehaemophagocyticsyndrome.Infivepatients

CyAwasusedasfirstlinetherapyandinsevenpatientsitwasusedwhensteroidshad

failed.[105]Reiffetaldescribed22patients(17withJIAofwhich14/17hadSoJIA)and

concludedthatCyAresultedinimprovementinthemajorityofpatients.[106]Jointcount

improvedin70%patientsandinpatientswithSoJIA,feverresolvedin91%,anaemia

improvedin33%andconcomitantprednisolonetherapywasreducedin77%ofpatients,[106]supportingthehypothesisthatCyAismorebeneficialinthetreatmentofsystemic

symptoms(suchasfeverandanaemia)thanthecontrolofarthritis.Mouyetallookedata

smallgroupofpatientswithMAStreatedwithCyAanddemonstratedrapidimprovement

inallpatients.[107]

4.4.3 EfficacyofCyclosporininJDM

Thereareanumberofsmallretrospectivestudiesandcaseseriesreportingthebenefitsof

CyAinpatientswithJDM.ThesestudiesaresummarisedinTable7. SimilartoJIA,thereare

currentlynocontrolledtrialshoweverthereiscurrentlyaninternationalmulticentre


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prospectivelyrandomisedtrialcoordinatedbyPRINTO(PediatricRheumatology

InternationalTrialsOrganisation)whichiscomparingprednisolonealonewith

prednisolone/methotrexatecombinationandprednisolone/cyclosporinecombinationin

patientsnewlydiagnosedwithJDM.Theresultsofthistrialareeagerlyawaitedinorderto

guidethemanagementofJDM.

Heckmattetalstudied14patientswithJDMwhohadnotfullyrespondedtocorticosteroids

orotherimmunosuppressants(methotrexate,azathioprineorcyclophosphamide)andhada

chronicallyactivecourseaveragingthreeyears.[108]Manyofthesepatientshadserious

complicationsofthediseaseoroftheirprevioustreatment.Mostpatientsweretreatedwith

2.57.5mg/kg/d(dividedtwicedaily)andallpatientswerefoundtohaveimprovedmuscle

strengthandsteroiddosereductions.


Thegenerallyaccepteddoseforthemanagementofpaediatricrheumaticdiseasesis3

5mg/kg/day[2]orallyandisusuallydividedtwicedaily.Thisissimilartotherecommended

dosinginadultpatientswithrheumatoidarthritis.InonestudyofchildrenwithJDM,adose

rangingbetween2.5to7.5mg/kg/daywassufficient.[108]

4.4.5 Safety

Cyclosporinisassociatedwithpotentiallyconsiderabletoxicityandrequirescareful

monitoringandsupervision.Mostsideeffectsaredosedependentandresponsivetodose

adjustment.Cyclosporindosesaresignificantlyhigherinthetreatmentofsolidorgantransplantationcomparedtorheumatologicalindicationsandthereforetheratesofside

effectsiscomparativelyhigher.

Renalfunctionabnormalitiesandhypertensionarethemostconcerningsideeffectsand

responsibleforthemajorityofwithdrawalsoftherapy. Risesincreatinineandureaduetoa

reducedglomerularfiltrationratehavebeendemonstrated.Theexactmechanismforthisis

unclearbutthesechangesareusuallyreversible.Inoneseriesof22patientswithJIAand

JDMonCyA,[106]serumcreatininedoubledin6patientsandGFRwasreducedinoneof14

patients. Ostensenstudied14patientsonCyAandfoundmarkedriseinserumcreatininein

5patientsnecessitatingwithdrawal.[109]Thesefindingsnecessitateclosemonitoringofrenalfunction.Interstitialfibrosisandtubulardamagemayalsooccur[110]andmaybe

irreversible.Cyclosporininducedhypertensionisalsofrequentlyseeninchildrenandin

adultshasbeenestimatedtocausehypertensioninapproximately10%ofadultstreated.A

recentCochranereviewdemonstratedstatisticallysignificantincreasesinbloodpressure

withCyAinadoserelatedfashion.Theyconcludedthatprescribersshouldfindthelowest

effectivedoseinthosepatientsrequiringlongtermuse.[111]

Otherencounteredsideeffectsinclude:hypertrichosis,gingivalhyperplasia,gastrointestinal

disturbance,tremorandparesthesias,hepaticdysfunctionandbonemarrowsuppression.

Theseadverseeffectsaremostlyreversiblewithreductionorcessationoftherapy. Inone

seriesof22patients,doseslessthen3.5mg/kg/dwereunlikelytocausehepatotoxicityand


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bonemarroweffectsandthathypertension,gumhyperplasiaandhypertrichosiswerenot

observed,suggestingthatinchildrenthesesideeffectsmaybelesscommon.[106]SinceCyA

isanimmunosuppressiveagent,childrenadministeredCyAareatincreasedriskofinfection.


Cyclosporinshouldbeusedwithcautionwhenadministeredincombinationwithother

potentiallynephrotoxicmedications.Inparticular,NSAIDsarefrequentlyusedinpaediatric

rheumaticdiseaseandmayexacerbatethetoxiceffectsofCyA.Inthissituationclose

monitoringofrenalfunctionisrecommended.ThebioavailabilityofCyAincreaseswhenthe

drugistakenwithgrapefruitjuice.


Itisrecommendedthatbloodpressurebemonitoredatleastweeklyforthefirstmonthoftherapyandthenmonthlythereafter.[2]Inaddition,laboratorymonitoringisrequired

monthlyparticularlyscreeningforrenal,bonemarroworhepaticeffects.Doseadjustmentis

recommendedifserumcreatinineincreasesby>30%.

TheneedformonitoringofCyAlevelsinnontransplantpatientsisunclear.Itisgenerally

recommendedthatwholebloodtroughlevelsbemaintainedbetween125and175g/ml.[2]

Monitoringmaybeparticularlyimportantinpatientswithunexpectedtoxicity.

4.4.8 FormularyAustralianBrandnames:Neoral(caps10,25,50and100mg,solution100mg/ml),

Sandimmun;Cicloral(caps25,50and100mg)

U.S.BrandNames:Gengraf(caps25and100mg,solution100mg/ml);Neoralcaps25and

100mg,solution100mg/ml);Sandimmunecaps25and100mg,solution100mg/ml)

CanadianBrandNames:ApoCyclosporine;Neoral;Rhoxalcyclosporine;Sandimmune

I.V.;SandozCyclosporine

4.4.9Summary

recommendations

Cyclosporinhasaroleinthemanagementofpaediatricrheumaticdisease.Several

observationalstudiesprovideevidenceforitsefficacyintreatingJIAandinparticularSoJIA

andassociatedMASandalsointhetreatmentofJDM.Cyclosporinisapotent

immunosuppressiveagentandisassociatedwithanumberofpotentiallyseriousadverse

effects.Theadministrationofcyclosporinshouldbeunderspecialistsupervisionwiththe

facilitytofrequentlymonitorwithbloodtests.ItisrecommendedfortheWHOessential

medicinescomplimentarylist.


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36

Author/

Year

Popn Typeof

study

Number

of

patients

Subjects Durationof

study

Intervention Outcomesme

Reiff,

1997[106]

US Retrospectiv

eobservationa

l

22 17JRA,5JDM Meanperiod

16months(642months)

AllpatientsreceivedCyA

meandose3.2mg/kg/d.Mostpatientsreceived

concomitantCSand

16/22patientsreceived

concomitantMTX.

Labvariables;joint

jointswelling;morstiffnessinpatients

Muscleweaknessa

enzymelevelsinJD

Pistoia,

1993[112]

Italy Caseseries 12 9patientswith

JCA(7SoJIA,2

poly);3patients

withJDM

CyAgivenfor

948months

AllpatientsreceivedCyA

atmeandose5mg/kg/day

afterfailureofCStherapy

Clinicalandlabora

measuresofdiseas

Heckmatt,

1989[108]

UK Caseseries 14 14patientswithJDMnot

respondedfullytoCSandother

immuno

suppressantswith

chronicallyactive

diseaseavg3yrs

Average12

months

therapytotimeof

publication(5

28months)

CyAstartingat2.5

mg/kg/ddividedbdand

increasedaccordingtoclinicalresponse.Max

12mg/kg/d

Muscleweakness,

rash,serumCK,

MonitoringofSEicBP,serumcreatinin

levels.

Zeller,

1996[113]

Retrospectiv

ecasereview6 Patientswith

refractoryJDM

Meanfollow

up51.5

months

CyA Clinicalmarkersof

MedicationSE,Ste

Table 7. Evidence for the efficacy of Cyclosporin in JDM


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4.5 Azathioprine

4.5.1 MechanismofactionandPharmacology

Azathioprineisapurineanaloguemetabolisedinthelivertoitsactivemetabolite6mercaptopurine(6MP).6MPisthenfurthermetabolisedviathreemajorpathways,the

metabolitesofwhichinhibitDNAsynthesisthroughthesuppressionofguanineandadenine

synthesis.AzathioprineinhibitscellmediatedimmunitythroughinhibitionofTcellgrowth

andresultsinreducedantibodyproduction.

Thebioavailabilityofazathioprineisapproximately50%.[114]Itisrapidlymetabolisedin

theliveranditsmetabolite,6MP,hasahalflifeof0.73hours.Smallamountsare

eliminatedasunchangeddrugandmetabolitesarepredominantlyrenallyexcreted.

4.5.2Efficacy

of

Azathioprine

in

SLE

AzathioprinehasbeenusedforthemanagementofSLEinchildrenfordecades.Despitethis

longexperience,therearenocontrolledtrialsaddressingitsefficacyinpaediatriclupusand

thereforeitsuseremainscontroversial.

AzathioprineisusedinavarietyofclinicalcircumstancesinSLEbutmostfrequentlyin

combinationwithcorticosteroids.Theadditionofazathioprineassecondlinetherapymay

beindicatedtopermitsteroiddosereductioninpatientsrequiringunacceptablyhighdoses

ofcorticosteroids.[2]Inadultpatientsthiswasfoundtobeassociatedwithfewer

hospitalisations.[115]

Theroleofazathioprineinthemanagementofpaediatriclupuscomplicatedbynephritisis

evenlesswelldefined.Thereisconflictingevidenceintheadultliteratureaboutitsusein

thiscontext.Somestudiesareinfavourofitsuse.Aretrospectivecohortstudyof26adult

patientswithSLEandassociatedproliferativelupusnephritisweremanagedlongtermwith

prednisoloneandazathioprine.[116]Thisstudyconcludedthatazathioprinewaswell

toleratedandthat510yearsurvivalratesweresimilartothoseofcyclophosphamidebased

therapies.[116]Oneoutcomestudyofchildrenwithlupusnephritisconcludedthatlong

termoutcomewasexcellentwith94%survivalatmeanfollowupof11years.Inthisgroupof

patients,azathioprinewasthemostfrequentlyprescribedagent.[117]

AlthoughthereislimitedevidencefortheefficacyofazathioprineinSLEandinparticular

paediatricSLE,manyrheumatologistsacknowledgethatitdoeshavearoleintherapy.In

particular,itisusedtocontrolserologicdiseaseflares,allowreductionofsteroiddosesand

maintaindiseasecourseafterparenteralcyclophosphamide.[45]


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4.5.3 EfficacyofAzathioprineinJIA

Theevidencefortheefficacyofazathioprineisbasedoncaseseries,casereportsand

uncontrolledtrials.Todatethereisonlyonerandomiseddoubleblindplacebocontrolled

trialaddressing

the

efficacy

of

azathioprine

in

the

treatment

of

32

JIA

[118]

Statistically

significantimprovementwasonlyseenintwodiseaseactivitymeasurementsanditis

thereforenotconsideredtohavegreaterefficacythanplacebo.Itisnotusedroutinelyinthe

treatmentofJIA.Seetable8fordetailsofstudies.

Anuncontrolledprospectivetrialinvolving129patientswithrefractoryJCAdemonstrated

improvementinbothclinicalandlaboratoryoutcomeswithacceptablesideeffectprofile.

[119]Afurtherretrospectivestudyof24patientsdemonstratedclinicalimprovementin

62.5%ofpatientsandremissionin37.5%.[120]Whilstthestrengthofthisevidenceisnotas

compellingasthatofotherDMARDsusedinthetreatmentofJIA,thesestudiessuggestthat

theremaybearoleofazathioprineinJIA.


Azathioprineshouldbestartedat11.5mg/kg/dayincreasingtoamaximumdoseof2

2.5mg/kg/day.Itisgenerallyconsideredthataminimumof12weeksisrequiredtoachieve

adequatetherapeuticresponse.Azathioprineshouldbeadministeredwithfoodtoreduce

gastrointestinaldisturbance.

4.5.5 Safety

Gastrointestinalsideeffectsmanifestingasnausea,vomiting,diarrhoeaandepigastricpain

arecommonwithazathioprine.Thesesideeffectscanbediminishedifthedosedividedorif

administeredwithmeals.Upto12%ofpatientsexperiencethesesymptomsandinone

study10%ofadultpatientswithrheumatoidarthritiswithdrewfromtherapydueto

gastrointestinalintolerance.[121]

Otherlessfrequentlyobservedsideeffectsinclude:pancreatitis,livertoxicity(abnormalliver

functiontests),interstitialpneumonitisandrash.Itisdifficulttoestimatetheincidenceof

thesesideeffectsinthepaediatricrheumaticdiseasepopulationasstudiesoftheuseand

safetyofazathioprinearefrequentlyintheadultpopulationandinconditionsotherthanrheumaticdiseases.

Dosedependenteffectsonthebonemarrowhavealsobeenwelldescribedinassociation

withazathioprinecausinggranulocytearrestandleukopeniaand,lessfrequently,anaemia

andthrombocytopenia.Thisisthoughttobeduetoreducedactivityofthiopurine

methyltransferase(TPMT).TMPTactivityisloworabsentin0.3%ofthepopulationand

causesthesehaematologicaleffectsshortlyafterinitiationoftherapy.LowerTMPTactivity

hasbeenobservedinAfricanAmericanindividualscomparedtoCaucasianAmericans.

[122]DistinctTMPTmutationshavebeenidentifiedandaredetectableonPCRbased

technique.


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Anumberofmedications,usedconcomitantly,havebeenreportedtoenhancethe

myelosuppressiveeffectofazathioprineincludingtrimethoprim. 5ASAderivativesmay

decreasethe

metabolism

of

thiopurine

analogs.

The

toxic

effects

of

leflunomide

may

also

be

enhancedwhenusedwithazathioprineandrequiremorestringentmonitoringofbone

marrowtoxicity.Azathioprinemayalsodecreaseplasmacyclosporinlevels.


Toxicitymonitoringshouldoccurthroughouttreatment. Itisgenerallyrecommendedthat

clinicalevaluationoccurat12monthsthen3monthlythereafterorearlierifdiseaseseverity

warrants.Laboratorymonitoringshouldinclude:weeklyFBEwithdifferentialuntilstable

thenmonthlythereafterandmonthlyLFTsandUEC.[2]AnalysisofTMPTgenotypeshould

beconsideredforpatientswhodevelopsevereleukopeniaonazathioprine.

Azathioprineshouldbeceasedifthereissignificantleukopenia,thrombocytopeniaor

elevatedliverenzymes.

4.5.8 Formulary

Australianbrandname:Imuran(tablets25mg,50mg,powderforreconstitution50mg)

UKbrandnames:Imuran(tablets25mg,50mg,powderforreconstitution50mg)

USbrandnames:Imuran(tablets25mg,50mg,powderforreconstitution50mg);Azasan

Canadianbrandnames:AltiAzathioprine;ApoAzathioprine;GenAzathioprine;Imuran;MylanAzathioprine;NovoAzathioprine


AzathioprineappearstohavearoleinthemanagementofbothpaediatricSLEandJIA

althoughconclusivestrongevidencewithRCTsislacking.Azathioprineisassociatedwith

potentiallyserioussideeffectsinparticularrelatingtobonemarrowsuppression.

Administrationofazathioprineshouldbeunderthesupervisionofspecialistcarewithaccess

toappropriateclinicalandlaboratorymonitoring.Azathioprineisrecommendedfor

inclusiononthecomplementaryWHOessentialmedicineslist.


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Author/

Year

Typeof

study

Number

of

patients

Subjects Durationof

study

Intervention Outcomesmeasu

Kvien,

1986[118]

RDBPCT 32 JIAalltypes 16weeks AZA22.5mg/kg/d

Vsplacebo

Laboratory(ESR,FBE)

Numberofclinicalmeaincludingactivejointc

functionalcapacity,

physiciansoverall

assessment

Savolaine

n

1997[119]

Uncontrolled 129 RefractoryJCA Median

treatment13

months,

Lin,

2000[120]

Retrospectiv

echart

review

24 JRAtreatedpreviouslywith

azathioprine

Meanduration

treatment13

months,meanfollowup45

months

AZA(avgmaxdose

1.9mg/kg/d)

12patientsreceivedDMARDspriortostartof

AZA

Table 8. Evidence for the efficacy of Azathioprine in JIA


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4.6 Hydroxychloroquine

4.6.1 MechanismofactionandPharmacology

Hydroxychloroquineisanantimalarialagentusedinthetreatmentofrheumaticdisease.HydroxychloroquineinhibitsthesynthesisofDNA,RNAandproteinbyinteractingwith

nucleicacid.Itsimmunosuppressiveeffectisviaanumberofmechanismsincluding:

alterationinlysosomalpHandinterferenceinantigenprocessing; stabilizationoflysosomal

membranes;inhibitionofantigenantibodyreactions;suppressionoflymphocyteresponse

andinhibitionofneutrophilchemotaxis.[2]

Hydroxychloroquineisrapidlyabsorbedfromtheintestinewithanoralbioavailabilityof

74%.[123]Thehalflifeis40days,steadystateisreachedin2to6monthsanditisprimarily

renallyexcreted.[123]

4.6.2 EfficacyofHydroxychloroquineinJIA

HydroxychloroquinehasnotbeenconvincinglyshowntobeeffectiveinthetreatmentofJIA.

Thereisoneplacebocontrolledtrialaddressingtheefficacyofhydroxychloroquineinthe

treatmentofJIA.[124]Thisrandomiseddoubleblindedtrialof162patientswith

polyarticularJIAcomparedhydroxychloroquinewithpenicillamineorplacebo.Therewas

nosignificantdifferencebetweengroups.

Kvienetaldemonstratedinanopenrandomisedtrial(notplacebocontrolled)of72patients

witholigoandpolyarticularJIA,thathydroxychloroquinewasnotmoreefficaciousthangoldorpenicillamine.[125]Interestingly,ametaanalysisin2000ofallRCTsandCCTs

comparinghydroxychloroquinetoplaceboinadultpatientswithrheumatoidarthritis

revealedanoverallmoderateeffectandwithalowtoxicityprofile.[126]

4.6.3 EfficacyofHydroxychloroquineinpaediatricSLE

Hydroxychloroquineisfrequentlyusedasanadjuncttosteroidtherapyattheonsetof

treatmentofjuvenileSLE.However,therearenotrialsaddressingtheeffectivenessof

hydroxychloroquineinthepaediatricpopulation.Evidenceforitsefficacywasdemonstrated

inarandomised,doubleblinded,placebocontrolledwithdrawaltrialbytheCanadian

HydroxychloroquineStudyGroup.[127]Patientsassignedtotheplacebogrouphada

significantlyhigherrelativeriskofflareandthatthetimetoflarewasshortercomparedto

thosepatientswhocontinuedHCQ.

TherehavesincebeenmanyotherstudiessupportingitsuseinSLE.Recentsystematic

reviewdemonstratedhighlevelsofevidencethathydroxychloroquinepreventsSLEflaresan

increaseslongtermsurvival.[128]Therewasmoderateevidenceofprotectionagainst

irreversibleorgandamage,thrombosisandbonemassloss.[128] Recommendationsarethat

hydroxychloroquineshouldbecommencedinmostpatientsandcontinuedthroughoutthe

courseofthedisease.


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Theusualdoseofhydroxychloroquineinchildrenis35mg/kgkg/daydivided12timesper

daywithamaximumof400mgperday.Itshouldbeadministeredwithfoodtoreducethe

occurrenceof

gastrointestinal

intolerance.

4.6.5 Safety

Hydroxychloroquineisgenerallyconsideredtobeaverysafemedication.Thefrequencyand

severityofadverseeffectsislowevenafterprolongeduse.Thereisalargeamountof

supportingevidenceforthisintheadultliterature.[128]

Gastrointestinaldisturbanceoccursinapproximately10%ofadultpatients.Itisconsidered

lesscommoninchildren.Centralnervoussystemsideeffectsarecommonandinclude:

headache,lightheadedness,insomnia,nervousness,nightmaresandconfusion.

Themostconcerningsideeffectisoculartoxicity.Thisoccursrarelybutcancauseblindness.

Retinaltoxicityisthoughtnottooccurinadultsifthedoseremainslessthan

6.5mg/kg/day.[129]Protocolsandpracticesvaryworldwide,howeveritisgenerally

recommendedthatophthalmologicalexaminationsareperformedyearly.Localprotocols

shouldbeestablishedbetweentheprescribingphysicianandthetreatingophthalmologist.

Retinalabnormalitiesshouldpromptimmediatecessationofthemedication.

Hydroxychloroquineisconsideredsafeinpregnancyandbreastfeeding.


HydroxychloroquinelevelsmaybedecreasedbyEchinacea.Inadditionthereareanumber

ofmedicationsthatshouldbeavoidedormonitoredcarefullyorincreasedordecreased

effectwhenusedconcomitantlywithhydroxychloroquine.Theseinclude:betablockers,anti

psychoticsandothers.


Whilsthydroxychloroquineisasafemedication,itdoesneedregularmonitoring.Fullblood

examinationissuggestedonaregularbasisandophthalmologyexaminationshouldoccuratleastyearly.

4.6.8 Formulary

HydroxychloroquineisnotFDAapprovedfortheuseinpaediatricSLE.IntheUK

hydroxychloroquineislicensedforuseinJIA,SLEanddiscoidLEandotherdermatological

conditionscausedbyoraggravatedbythesun.

Australianbrandnames:Plaquenil(200mgtablets)

UKbrandnames:Plaquenil(200mgtablets)

USbrandnames: Plaquenil


43/5043

Canadianbrandnames:ApoHydroxyquine;GenHydroxychloroquine;Plaquenil;Pro

Hydroxyquine


Hydroxychloroquineappearstobeasafeandeffectivetreatmentinthemanagementof

juvenileSLE.IthasnoprovenroleinthemanagementofJIA.Hydroxychloroquineis

recommendedfortheuseinjuvenileSLEprovidedpatientshaveaccesstospecialistcare

includingophthalmologicalandlaboratoryassessments.Itisrecommendedforinclusionon

theWHOessentialmedicinescomplementarylist.


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arthritis:secondrevision,Edmonton,2001.JRheumatol,2004.31(2):p.3902.

2. CassidyJ.T.,P.,R.E.,LaxerR.M.,LindsleyC.B,Textbookof

Pediatric

Rheumatology.5thed.2005:ElsevierSaunders.

3. Manners,P.J.andC.Bower,Worldwideprevalenceofjuvenilearthritiswhydoesitvarysomuch?JRheumatol,

2002.29(7):p.152030.

4. Mielants,H.,etal.,Prevalenceofinflammatoryrheumaticdiseasesinanadolescenturbanstudentpopulation,age

12to18,inBelgium.ClinExpRheumatol,1993.11(5):p.5637.

5. Manners,P.J.andD.A.Diepeveen,Prevalenceofjuvenilechronicarthritisinapopulationof12yearold

childreninurbanAustralia.Pediatrics,1996.98(1):p.8490.

6. Tayel,M.Y.andK.Y.Tayel,Prevalenceofjuvenilechronicarthritisinschoolchildrenaged10to1

Child_DMARD.pdf

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