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 DrugsinPaediatricRheumaticdisease

September2010 Preparedby: PeterGowdie RheumatologyandClinicalPharmacologyFellow2009 RoyalChildrensHospital Melbourne,Australia

Contents
1. Intentofreview 2. Identificationofpriorityconditions 3. Reviewofpriorityrheumaticdisease 1. JuvenileIdiopathicarthritis 1. Epidemiology 2. Diseaseburdenandoutcome 3. Clinicalmanifestations 4. Complications macrophageactivationsyndrome uveitis amyloidosis 2. IdiopathicInflammatoryMyopathies(JuvenileDermatomyositis) 1. Epidemiology 2. ClinicalManifestations 3. Complications 4. CourseandOutcome 5. Overviewofmanagement 3. SystemicLupusErythematosus 1. Epidemiology 2. ClinicalManifestations 3. Courseandoutcome 4. Overviewofmanagement 4. DMARDs 1. Methotrexate 1. MechanismofactionandPharmacology 2. EfficacyinJuvenileIdiopathicArthritis 3. EfficacyinJuvenileDermatomyositis 4. Doseandadministration 5. Druginteractionandfolatesupplementation 6. Safety 7. Monitoringandsupervision 8. Formulary 9. Summaryrecommendations 2. Leflunomide 1. MechanismofactionandPharmacology 2. EfficacyinJuvenileIdiopathicArthritis 3. Doseandadministration 4. Safety 5. Druginteraction 6. Monitoringandsupervision 7. Formulary 8. Summaryrecommendations 2

3. Sulphasalazine 1. MechanismofactionandPharmacology 2. EfficacyinJuvenileIdiopathicArthritis 3. Doseandadministration 4. Safety 5. Druginteraction 6. Monitoringandsupervision 7. Formulary 8. Summaryrecommendations 4. Cyclosporin 1. MechanismofactionandPharmacology 2. EfficacyinJuvenileIdiopathicArthritisandMacrophageActivation Syndrome 3. EfficacyinJuvenileDermatomyositis 4. Doseandadministration 5. Safety 6. Druginteraction 7. Monitoringandsupervision 8. Formulary 9. Summaryrecommendations 5. Azathioprine 1. MechanismofactionandPharmacology 2. EfficacyinSLE 3. EfficacyinJIA 4. Doseandadministration 5. Safety 6. Druginteraction 7. Monitoringandsupervision 8. Formulary 9. Summaryrecommendations 6. Hydroxychloroquine 1. MechanismofactionandPharmacology 2. EfficacyinSLE 3. Doseandadministration 4. Safety 5. Druginteraction 6. Monitoringandsupervision 7. Formulary 8. Summaryrecommendations

1.Intentofreview
Toidentifypriorityrheumatologicalconditionsinchildren Tooutlinethetreatmentoptionsfortheseconditions TooutlinetheroleofDMARDsinthetreatmentofpriorityrheumatological conditions ToreviewtheliteratureandcollatetheevidencefortheefficacyofDMARDsin priorityconditions ToreviewthesafetyofDMARDsandoutlinemonitoringandsupervisionrequired TogiverecommendationsfortheinclusionofDMARDsontheWHOEssential MedicinesList

2.Identificationofpriorityconditions
PaediatricRheumatologyencompassesabroadrangeofinflammatorydisordersinvolving thejointsandconnectivetissuesinchildren.Juvenileidiopathicarthritisisperhapsthemost wellrecognisedoftherheumaticdiseasesofchildhoodhoweverthespecialtysscope includesconditionssuchasacuterheumaticfever,poststreptococcalreactivearthritis, KawasakidiseaseandLymediseaseaswellaschronicsystemicconditionsincluding SystemicLupusErythematosus(SLE),JuvenileDermatomyositis(JDM),andthevasculitides. Themostcommonrheumaticdiseaseaffectingchildrenischronicarthritis.Thefunctional impactofthisdiseasecanbesignificantandthetimelyadministrationofappropriate therapy,includingDMARDs,canbeeffectiveinimprovingoutcome.Whilelesscommon, SLEandJDMarealsoarepotentiallydevastatingconditionsandDMARDtherapyplaysan equallyimportantroleintheirmanagement.

3.Reviewofpriorityconditions

3.1JuvenileIdiopathicArthritis
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] 4

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 handappeartoreportlowerprevalenceratesperhapsreflectingthatmanycliniciansfailto 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.

3.1.2BurdenofDiseaseandoutcome
ThediseaseoutcomeandprognosisinJIAisvariableandtosomedegreepredictablebased onthedifferentdiseasesubtypes.Forexample,seropositivepolyarticularJIAhasa relativelypooroutcomecomparedwitholigoarticularJIAwhoseoutcomeisgenerallyvery good.[11,12]However,thelattergrouparealsothemostatriskofdebilitatinguveitisasa complicationoftheirdisease.ManychildrenwithJIAhaveanexcellentprognosisandforthe 5

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.

3.1.3ClinicalManifestationsofJIA
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. 6

3.1.4ComplicationsofJIA
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] 7

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<1%andlessthan0.3%inNorthAmerica.[2]

3.2Idiopathicinflammatorymyopathies(JuvenileDermatomyositis andJuvenilePolymyositis)
Idiopathicinflammatorymyopathies(IIM)ofchildhoodarerareconditionsoftenassociated withsignificantdisability.Oftheinflammatorymyopathies,Juveniledermatomyositisisby farthemostcommoninchildrenmakingup85%ofcasesofIIMinchildhood.[23,24] Juvenilepolymyositisaccountsforapproximately28%andoverlapsyndromeswithfeatures ofotherautoimmunediseasesaccountsforapproximately310%.[25]Theothertypesof IIMsarerareinchildrenandmostlydocumentedincasereportsonly. Juveniledermatomyositisisasystemicvasculopathycharacterisedhistologicallyby perivascularBcellpredominantinflammationandcapillaryloss.Thepathogenesisisnot completelyunderstoodbutitisthoughttobeanautoimmuneprocessoccurringina geneticallysusceptiblechildinresponsetoanenvironmentalstimuli.

3.2.1Epidemiology
Juveniledermatomyositisisarareautoimmunemyositisofchildhood.Ithasanestimated incidenceintheUnitedStatesof3.2permillionchildren.[26]Mendezetalcaptureddata overa4yearperiodbetween1995and1998andfoundtheannualincidencerangedbetween 2.5and4.1permillionchildren.Incidenceratesvariedslightlybetweenracialgroups3.4for whiteCaucasian,3.3forAfricanAmericanand2.7forHispanics.[26]Symmonsetal estimatedanincidenceintheUKandIrelandof1.9permillionchildren(95%confidence intervals1.42.6).[27]Theratioofgirlstoboyswasreportedinthesetwostudiestobe2.3:1 byMendezetaland5:1bySymmonsetal.[26,27]Theageofpeakincidenceinboysand girlsissimilar.Pachmanetaldemonstratedabimodalpeakincidenceinbothboys(6and11 years)andgirls(6and12years).[28]

3.2.2ClinicalManifestations
Juveniledermatomyositis(JDM)isamultisysteminflammatoryconditionitcanaffectthe muscle,skin,gastrointestinaltract,heart,lungs,kidneysandeyes.JDMcanmanifestina heterogeneousfashion,however,themaincharacteristicsofthediseaseinclude:symmetrical proximalmuscleweakness,pathognomicskininvolvement(egGottronspapules, heliotropicrash),andraisedmuscleenzymes.ThediagnosisofJDMismadethroughthe applicationofdiagnosticcriteriaestablishedbyBohanandPeterin1975:1)presenceof characteristicrashheliotropicrashwithperiorbitaloedemaandGottronspapules;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

3.2.3Complications
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.

3.2.4CourseandOutcomeofJDM
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.Theuseofcorticosteroidshasdramaticallyimprovedto outlookforpatientswithJDM.Highsuppressivedosesareusedearlyandthentapered graduallyoveronetotwoyears.Thedegreeofsupportivecareisdependentuponthedegree ofdisability.Inpatientswithbulbardysfunctionorsignificantrespiratorymuscleweakness, careneedstobedirectedtopreventionofaspirationandventilatorysupport.Physiotherapy andoccupationaltherapyisadvisedtoavoidlossofmotionandcontracturesinthefirst instanceandthenlatertostrengtheninordertoregainnormalfunction. Otherimmunosuppressiveagentshavenotbeensubjectedtorandomisedcontrolledtrials howevertheyarenowacceptedasanimportantpartofthemanagementofJDM.Four agentshavebeendescribedinthetreatmentofJDMandtheevidencefortheirusewillbe reviewedwithinthisdocument.Theyare:methotrexate,cyclosporine,azathioprineand cyclophosphamide.

3.3SystemicLupusErythematosus
Systemiclupuserythematosus(SLE)isamultisystemautoimmunediseasecharacterisedby inflammationofthebloodvesselsandconnectivetissuesresultingindamagetonumerous organsystemsandassociatedwithantinuclearantibodies.ThediagnosisofSLEisbasedon welldescribedclinicalandlaboratoryfeaturesandissupportedbytheuseoftheAmerican CollegeofRheumatology(ACR)adultSLEclassificationcriteriafirstdevelopedin1982and thenrevisedin1997.However,therearewelldescribeddifferencesintheclinicalfeatures, serologyandoutcomeofpaediatricpatientswithlupuscomparedwithadultpatients[37] 10

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 andphotosensitivitylesscommoninpaediatricSLE.[41]Onestudyreportedmoresevere diseaseonsetinpaediatricpatientscomparedtoadultpatientsandthatrenaland haematologicalfeaturesweremorecommon.[37]Silvermanetalsupportedthisfindingin theirstudycomparingpaediatricwithadultSLE.Theyfoundthatchildrenhadmoreactive diseaseatonsetwithhigherfrequencyofrenaldiseaseandlowerfrequencyof cardiopulmonarydisease.[42] Typicalserologicalfindingsinclude:positiveantinuclearantigen(ANA),positivedouble strandedDNA(dsDNA),antibodiespositivetoextranuclearantigens(ENA),low complementlevelsandpositivelupusanticoagulantandantiphospholipidantibodies.

11

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:avoidanceof excessiveexposuretosunlightandprotectionagainstUVBwithsunscreenandappropriate skincoverwithclothingandheadwear;preventionofinfectionwithimmunisation. CorticosteroidsremainthefirstlinetherapyforthemanagementofpaediatricSLE.NSAIDs arefrequentlyusedtomanagemusculoskeletalcomplaintsandhydroxychloroquineisused asanadjuncttocorticosteroidsinthetreatmentoffatigue,mucucutaneousfeaturesand arthritis.Immunosuppressivetherapyincludingcyclophosphamide,azathioprineand mycophenolatearegenerallyconsideredearlyinthecourseofthediseaseifthereis evidenceofdiffuseproliferativeglomerulonephritis,CNSinvolvementorpulmonary haemorrhage.[45]Otherimmunosuppressantsconsideredincludemethotrexateand cyclosporin.Thechoiceofdrugremainscontroversial.Inotheractiveformsofthedisease thereisnoagreementonthetimingofinitiatingimmunosuppressanttherapy.Manyof thesepatientsareatriskofdevelopingirreversibleorgandamageand,inaddition, potentiallyfacemanyyearsofhighdosecorticosteroidtherapywithitsassociatedtoxic effectsandmaythereforewarranttheadditionofimmunosuppressanttherapy. Mycophenolateinitiallyshowedpromisingresultsinmaintainingdiseasecontrolinadult patientswithresistantorrelapsinglupusnephritis.Ithassincethenbeensubjecttometa analysisandfoundtohavenodifferenceoverazathioprineintermsofresponseratesor developmentofendstagerenaldisease.[46]Itappearstohaveasaferprofilethan azathioprineespeciallyregardstohaematologicalcomplications. Whilstcurrenttherapieshavedramaticallyimprovedsurvival,thereishopethatnewer agentsincludingcytotoxicandbiologictherapiesmayprovidesuperiormanagementand ultimatelyleadtocurativetreatment.[47]

4.DiseaseModifyingAntiRheumaticDrugs(DMARDs)
DMARDsarenotusedforimmediateanalgesicorantiinflammatoryeffectbutratherfor theirlongtermbeneficialeffectsincontrollingdiseaseactivity.Thesemedicationsalsoplay animportantroleinreducingthelongtermexposuretomedicationssuchasprednisolone 12

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

13

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.

14

Table 1. Evidence for the efficacy of Methotrexate in JIA

Author, Year
Giannini, 1992[55]

Popn
US and Soviet Union UK and France

Type of study
Multicentre randomised placebo controlled RCT double blind crossover

Number of patients

Subjects
JIA 3 joints

Duration of study
6 months

Intervention
5mg/m2 vs 10mg/m2 vs placebo 15mg/m2 (up to 30mg/m2) vs placebo

Primary outcomes measured

Joint ROM Swollen joints Pain on joint movement Physician global score Joint ROM Number active joints Physician global score Parent/child global score ESR

Conclusion and comments

63% patients improved on 10mg/m2 32% on 5mg/m2 36% on placebo Significant improvement in 3 out of 5 outcomes: physician global and parent/child global and ESR. Percent overall improved: EOA 48% on MTX vs 18% on placebo; SoJIA 25% MTX vs 16% placebo No difference in frequency of SE After 6 months of treatment, significant improvement in HRQOL Both MTX and Leflunomide resulted in high rates clinical improvement following 16 week phase. 89% MTX vs 68% Leflunomide ACR Pedi 30 response LFT abnormalities noted more frequently with MTX than Leflunomide In screening phase, 72% patients responded to standard dose MTX. 62.5% of patients in intermediate dose group vs 57.5% in higher dose group achieved ACR Pedi 30 response. Plateau of efficacy of MTX at 15mg/m2. No additional therapeutic benefit with doses >15mg/m2/week

Woo, 2000 [54]

38x 10mg/m2 MTX 37x 5mg/m2 MTX 39x placebo 88

Extended oligo JIA (EOA) and SoJIA

12 months

CespedesCruz, 2008[59] Silverman, 2005[60]

Multicentre international

Patients from multi-centre international RCT

521

PolyJIA

12 months

50 item Child Health Questionnaire (CHQ) MTX vs leflunomide ACR Pediatric 30 (30% improvement compared with baseline in 3 of 6 variables included in ACR core set (swollen joints, active joint count, parent global assessment, physician global assessment, CHAQ, ESR) ACR Pedi 30 definition of improvement

RCT Double blind

86 completed 16 weeks, 70 entered extension study

PolyJIA 3-17 yrs old

16 week +/-32 week extension

Ruperto, 2004[53]

Multicentre international

RCT

633 patients screened in phase one. 80 patients deemed to be nonresponders were randomised

Poly JIA

6 months

Standard vs higher parenteral dose of MTX (15 vs 30 mg/m2/week)

15

Table 1. Evidence for the efficacy of Methotrexate in JIA

Ravelli, 1999[57] Italy Retrospective analysis 80 SoJIA 37 polyJIA 20 oligo JIA 23 SoJIA 6 months 6 month clinical response, complete disease control, disease relapse, hepatotoxicity, GI toxicity MTX Range 2.515 mg/week Joint evaluation Fever, rash LAD and splenomegaly Serositis ESR, Hb, WCC and plts Length of time to relapse or continued remission following discontinuation of MTX oligo JIA sybtype was best predictor for short term clinical response and more likely to have relapse after discontinuation 89% improved active joint count and functional class 61% significant improvement in ESR, Hb and plts No withdrawals due to toxicity Relapse in 52% after a mean of 11 months. Of those relapsed patients most (10/13) achieved remission again within 7 months. Optimal time for discontinuing MTX unknown 73% responded 39% achieved remission Prednisolone weaned in 93% 6 patients experienced SE, 1 patient ceased MTX due to LFT abn 33% improved 5% complete remission MTX well tolerated but limited role in refractory JIA 63% responded 37% no response to therapy 11/17 responders had improved carpal length All 6 nonresponders had progressive loss of carpal length Conc: radiological improvement in those responded to MTX 45% remission on MTX

AlSewairy, 1998 [61] Gottleib, 1997[58]

Saudi Arabia

Retrospective analysis

18

Mean 18 months

USA

Retrospective analysis 2 centres

25 patients in remission for a mean duration of 8 months

Poly, pauci and SoJIA

Huang, 1996[62]

Taiwan

Retrospective chart review

26

JIA

Mean follow up of patients post discontinuation was 15 months Mean follow up 3 years Mean duration 15.2 months 6 months therapy Median 2.5 yrs

MTX range 5.2 15.9 mg/m2/dose

Mean weekly dose MTX 10-15 mg/m2 Mean weekly dose MTX 27 mg MTX dose range 7.5-11 mg/m2/week MTX 7.510mg/m2 Disease activity score based on changes in concomitant therapy, labs, physician global, radiological Response defined as 50% reduction in number of joints with active arthritis Assessed radiological progression on serial wrist XR

Reiff, 1995[63] Ravelli, 1994[64] Harel, 1993[65]

USA

Retrospective chart review Retrospective chart review

21 (13/21 SoJIA) 19 23 (5 SoJIA)

Refractory JIA SoJIA 17/23 responders 6/23 non responders PolyJRA (16/49 SoJIA)

Italy USA

Wallace, 1993[66]

USA

49

At least 1 year

MTX 15mg/m2

16

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.

17

Table 2. Evidence for the efficacy of Methotrexate in JDM

Author/ Year Ramanan, 2005[68]

Popn

Typeof study
Prospective cohort study with historical controls

Number of patients

Subjects
31patients prospectively studiedwith22 controls

Durationof study
Control patients followedfor4 years;study patients followedfor average34.6 months Meanduration oftherapywas 23.5months

Groups/Intervention
2groups.Studygroup: MTX1020mg/m2/week (max25mg/week)and prednisolone2mg/kg/d (max75mg)withpred aggressivelytaperedevery 2weeks 2groups:early(<6wks) andlate(572monthspost diagnosis)MTXtherapy.6 patientspergroup

Outcomesmeasured
Timetodiscontinuationof steroids,cumulativesteroid doseandsteroidSE. Diseaseactivity:CHAQ, musclestrength,rash, calcinosis,timetoflare.

Conclusionand comments
UseofMTXand aggressivelytapered steroidsmaybeas effectivetraditional longtermsteroidand decreasesthe cumulativesteroiddose Improvedmuscle weaknessandlackof developmentof calcinosisingroup treatedearly. OnepatientceasedMTX duetoabdominalpain Improvementinall parametersin3patients. 4thpatientinitially improvedthenrelapsed anddiedofbowel perforationandsepsis Allpatientstreatedfor >8monthshadclinical remissionandtherefore concludedthatMTXis usefuladjunctto prednisolone.31% patientsdiscontinued MTXduetoSE.

Single centre, Canad a

53

Al Mayouf, 2000[69]

Saudi Arabia

Prospective cohort study

12newly diagnosed JDM.

Fischer, 1979[31]

US

Caseseries

Patientswith dysphagia, dysphonia,GI bleeding,cutaneous ulcerationorresp muscleinvolvement werestartedMTX early 3patientswihJDM, 1patientwithJPM

Resolutionofclinical indicationsforMTX, decreaseddiseaseactivity (gradedmusclestrengthand enzymelevels)and discontinuationofsteroids

931months

PredplusMTX1mg/kg/wk intravenously

Steroiddosereduction, musclestrength,enzyme levels,EMGchanges

Miller, 1992[70]

US

Retrospectiv echart review

16

16patientswith recalcitrantJDM

6yearfollowup MTXplusprednisolone

Musclestrength,muscle enzymes,prednisolone dosage,medicationtoxicity

18

4.1.4EfficacyofmethotrexateinUveitis
Methotrexatehasbeenusedinchildrenwithuveitisformanyyears.Itsuseissupportedby evidencelargelyfromretrospectivecohortstudies. Aretrospectivechartreviewfoundmethotrexatetobeaneffectiveagentinthetreatmentof uveitis.[71]Twentyfivepatientswithuveitisreceivedmethotrexate(meandoseof 15.6mg/m2)andremissionwasachievedafterameanof4.25months.Sixpatientshad methotrexateceasedafterremissionfor12monthsandofthese4patientswerestillin remissionafter7.5months.Othercaseserieshavedemonstratedtheeffectivenessof methotrexateinuveitisresistanttotopicalcorticosteroids.[72,73]

4.1.4DoseandadministrationinJIAandJDM
Methotrexateisadministeredweekly.Although,aspreviouslymentioned,theserum eliminationhalflifeofmethotrexateis67hoursitsmetabolitescanbemeasured 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]

4.1.5Druginteractionandfolatesupplementation
Anumberofmedicationsincreasethebioavailabilityofmethotrexate.Theseinclude: phenytoin,oralcontraceptivepill,tetracycline,barbituratesandtranquilizers.Co trimoxazoleshouldbeavoidedwithmethotrexateasitcancauseseverebonemarrow suppressionandskinulcerations.Inadditionanumberofmedications,includingpenicillins andcyclosporine,canlowertheeliminationofmethotrexatebydecreasingrenalclearance. Methotrexateiscontraindicatedinrenalfailure. Thereisgoodevidencetosupporttheuseoffolicacidsupplementationtoalleviatethe commongastrointestinalandoralmucosalsideeffectsassociatedwithmethotrexatewithout impactingonthebeneficialantiinflammatoryeffects.[75] TheuseofmethotrexateissafeincombinationwithNSAIDSandcorticosteroids.Thereis someexperienceofcombinedDMARDshowevercontrolledsystematicstudiesarelacking tosupportthisstrategyinthetreatmentofJIA.

19

Table 3. Adverse Effects of Methotrexate Author, Year Ortiz Alvarez, 2004[76]

Typeof study Pro spective study

Duration ofstudy

Subjects and numbers

Drugand monitoring MTX Monthly bloodtests

Hepatotoxicity

Haematological abnormality 26%patientshad abnormalFBE(low granulocyteor lymphocytecountor Hb) 95%ofpatientswith abnhadviralinfection atthetimeofblood test.

GItoxicity

other

Conclusion

89JIA

14%patienthadsignificantly elevatedLFTs(>2xULN) 52%hadmildelevatedliver functests

Nodiffnoted intermsof durationand cummulative doseMTXand concurrent meds

Fewsignificantly abnbloodtests beyond2months. Bloodtestsevery4 8weeks unnecessarily frequent

Lahdenne, 2002[77]

Retro spective review. Liverbx correlated withlab findings Retro spective review

Patients onMTX atleast 2.4yrs

34JIA

MTX(20 30mg/m2)for duration>2.4 yrs

Graham, 1992[78]

84296 weeks

62poly JIA

MTX(5 10mg/m2), 3monthly bloodtests, PFTson46 pts

All24ptstreatedwithlow doseMTXhadgradeI Roenigkchanges. Of10patientson>20mg/m2, 4ptsgradeIIhistologyand5 gradeI.Nofibrosisor cirrhosis Transientliverfunctionabn occurredin9/62(14%) 12patientshadliverbiopsy nofibrosisorcirrhosis

AggressiveMTX therapywith concomitantmeds maycontributeto minorreversible liverabn Suggestthatwell tolerated

Macrocyticanaemiain onepatientonco trimoxazole NocasesonTPor neutropenia

Giannini, 1992[55] Woo, 2000[54]

US/Soviet Multi centreRCT DBRCT crossover

6months

89JIA3 joints

MTX5or10 mg/m2

OnepatienthadLFTabn

Nausea occurredin 14/62patients. Pepticulcerin 4/62patients alsoon concomitant NSAID 8patientshad GIupset NauseaandGI upsetoccurred insimilar numbersof patients

NoPFTabn Nostomatitis orrash

12 months

88 15mg/m2(up Total20patientsonMTX EOAJIA to30)vs hadASTabnvs16placebo andSoJIA placebo patients

Bonemarrowfailure didnotoccur

NodifferenceinSE betweenMTXand placebo

20

Table 3. Adverse Effects of Methotrexate Author, Year Hashkes, 1999[79]

Typeof study Liver biopsies compared withRFfor hepatotox Liver biopsies compared withRFfor hepatotox

Duration ofstudy

Subjects and numbers

Drugand monitoring

Hepatotoxicity

Haematological abnormality

GItoxicity

other

Conclusion

25 patients, 33 biopsies 14JIA

Hashkes, 1997[80]

Kugathasan,

1996[81]

Liver biopsies

>3years ofMTX

9JIA

2biopsiesshowedgradeIIIa Roenigkchanges 4showedgradeIIchanges and27gradeI. Nosignificantfibrosis 13/14gradeIRoenigk changes 1/14gradeIIchanges Nobxwithsignificant fibrosis. 13/14LFTabnbutonly5had >3xULN 10mg/m2/wk Noclinicalorbiochemical evidenceofliverinjury Allbiopsieswerenormal

Nosignificant fibrosis. Biochemabn correlatedwith changes Nosignificant clinical consequences despiteminorhisto changes

21

4.1.6Safety

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.

4.1.7Monitoringandsupervision
ChildrenwithJIAonlongtermmethotrexaterequireregularclinicalandlaboratory monitoringbothfortheresponsetothemedicationandforitspotentialtoxicities. HashkesetalexaminedliverbiopsiesinchildrenwithJIAonmethotrexateandfounda relationshipbetweenbiochemicalliverfunctionchangesandhistopathologicalchanges consistentwithmildfibrosis.[79]Whilstthedegreeoffibrosisinthisserieswasnot consideredsignificant,thepotentialhepatotoxiceffectsofmethotrexatehavepromptedthe introductionofguidelinesforthemonitoringoflivertoxicityinpatientstakingmethotrexate. Theseguidelinesweredevelopedin1994andrepresentanexpertconsensusonthe 22

monitoringoflivertoxicitywithmethotrexateuseinadultRheumatoidArthritis.Although developedbasedonadultdata,theseguidelinesformthebasisformonitoringofchildren withJIAonmethotrexate.[87] Itisgenerallyrecommendedthatliverfunction,renalfunctionandfullbloodexaminationbe performedatbaselineforallpatients.MonitoringofLFTs48weeklywasrecommendedby Kremeretalintheinitialguidelinespublishedin1994.[87]Sincethen,OrtizAlvarezetal monitored89patientswithJIAprospectivelyandfoundthatLFTabnormalitieswereusually mildandresolvedspontaneouslyandthatmoresevereabnormalitiessettledrapidlywith discontinuationofmethotrexate.[76]Whentherearenoothercoexistingriskfactors,3 monthlymonitoringfollowinginitialbimonthlyforafewmonthsseemstobeappropriate.

4.1.8Formulary
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

4.1.9Summaryrecommendations
MethotrexatehasbeenshowntobeaneffectiveandsafetherapyinthetreatmentofJIA.Itis associatedwithanumberofpotentiallyseriousadverseeffectsandthereforeitsuserequires monitoringwithbloodtestsandwithcloseclinicalsupervisionfromamedicalspecialist familiarwiththepotentialrisks.Itisnotrecommendedforuseifaccesstothissupervisionis unavailable.ItisrecommendedforinclusionontheWHOcomplementarylistofessential medicines.

4.2Leflunomide
4.2.1MechanismofactionandPharmacology
Leflunomideisanimmunomodulatorymedicationthatinhibitspyrimidinesynthesis throughitsinhibitionoftheenzymedihydroorotatedehydrogensase.Lymphocyte proliferationdependsonpyrimidinesynthesisforproliferationandleflunomidetherefore hasbothantiproliferativeandantiinflammatoryeffects. TheactivemetaboliteisA771726towhichleflunomideisactivelyconvertedviahepatic metabolism.A771726ishighlyproteinboundandhasahalflifeofupto18daysreachinga steadystateafterapproximately20weeks.[88] Thepharmacokineticsofleflunomideanditsactivemetabolitesarenotaffectedbyfood intakeorbygender.Itisexcretedalmostequallyinurineandfaeces.Thepharmacokinetics 23

oforalleflunomidewasstudiedin73paediatricpatientsaged317yearswithpolyarticular JIA.[89]Thisanalysisdemonstratedthatpaediatricpatientswithbodyweights<40kghavea reducedclearancecomparedtoadultsandthereforerequiredoseadjustment(seeDoseand administrationbelow).

4.2.2EfficacyofLeflunomideinJIA
Leflunomidehasbeenshowntobeeffectiveinanumberofstudiesinadultswith RheumatoidArthritis.(Seetable4)TherearefewerstudiesinchildrenwithJIA,however, Slivermanetaldemonstratedinanopenlabelstudyinchildrenwithrefractorypolyarticular diseaseagoodresponsetoleflunomide.[90]Inarandomisedcontrolledtrialof94patients, Silvermancomparedleflunomidewithmethotrexateinpolyarticulardisease.Thistrial concludedthattreatmentwithleflunomidedoesresultinclinicalimprovementbutthatthe rateofimprovementwasnotashighasthatseenwithmethotrexate(89%Leflunomidevs 68%methotrexatemetACRPedi30response).[60] Gaoetal[91]addressedthepotentialforcombiningleflunomidewithmethotrexateby comparingcombinationtherapywithmethotrexatealone.Theyfoundasignificantlyhigher responserateinthosepatientsoncombinedtherapy. Whilsttheredoesappeartobesomeevidencefortheuseofleflunomideinthepaediatric population,theexactroleisyettobedefined.Thereappearstobearoleinpatientswhoare intoleranttomethotrexateorhavefailedtorespondtomethotrexate.

4.2.3Doseandadministration
Adultstudiessuggestthebenefitofloadingdosesof100mg/dayfor3daystorapidlyachieve steadystate.Thisisnotrequiredandmayresultinsignificantsideeffects[2].Intheirstudy, Silvermanetalused100mgloadingdoseforonedayinchildren<20kg,fortwodaysin childrenbetween20and40kg,and100mgforthreedaysinchildren>40kg.Thiswas followedbymaintenancedoseof10mg/dayif<40kgand20mg/dif>40kg.Arecent populationpharmacokineticstudyrecommendedthatleflunomidedosesbeadjustedfor paediatricpatientsasfollows:10mg/dfor1020kg,15mg/dfor2040kg,and20mg/dfor> 40kg.[89]Theuseofaloadingdosemayincreasetoxicityinchildren.(MIMS2009)

4.2.4Safety
Themostcommonlyreportedadverseeffectisgastrointestinalupsetwhichisreportedto occurin17%ofpatients.Thisincludes:abdominalpain,dyspepsia,diarrhoeaandgastritis. Othercommonsideeffectsinclude:headache,rashandalopecia. Liverfunctionabnormalitiesarelessfrequentlyreportedthanwiththeuseofmethotrexate. [60]Thereappearstobeaparticularriskwhenusedincombinationwithmethotrexate.[92] InstudiesofleflunomideinadultswithRheumatoidarthritis,liverfunctionabnormalities arereportedinapproximately5%ofpatients.Thesechangesaremildandreversible.More

24

seriousliverdysfunctionisuncommonandisassociatedwithconcomitantalcohol consumption,viralhepatitisorotherpreexistingliverdisease. Leflunomideisteratogenicandthereforeitisrecommendedthatpatientshaveanegative pregnancytestbeforestartingtreatmentandusereliablecontraceptionduringtherapy.

4.2.5Druginteractions
Theenzymesinvolvedinthemetabolismofleflunomidearenotentirelyknown.Invitro studiesindicatethatleflunomideinhibitscytochromep450andthereforecautionshouldbe takenwhencoadministeredwithotherdrugsinvolvedincytochromep450metabolic pathways.

4.2.6Monitoringandsupervision
Monitoringisrecommendedwithbaselineandmonthlyfullbloodcountandliverfunction for6months,whichcanbereducedto68weeklyifstable.

4.2.7

Formulary

Becausesafetyandefficacyinchildrenhasnotbeenclearlyestablishedwiththeexisting 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 withbloodtestsandcloseclinicalsupervisiontoensurethatthepotentialsideeffectsare minimised.Itisnotrecommendedforuseifaccesstothissupervisionisunavailable.Itis recommendedforinclusionontheWHOcomplementarylistofessentialmedicines.

25

Table 4. Evidence for the efficacy of leflunomide in JIA

Author, Year

Popn

Typeof study

Duration Numberof ofstudy patients

16week +/32 week extension

Subjects

Studygroups
MTXvsleflunomide

Primaryoutcomes measured
Percentageofpatientswith ACRPedi30(30% improvementcomparedwith baselinein3of6variables includedinACRcoreset (swollenjoints,activejoint count,parentglobal assessment,physicianglobal assessment,CHAQ,ESR) ACRPedi30

Conclusionandcomments
BothMTXandLeflunomide resultedinhighratesclinical improvementfollowing16week phase. 89%MTXvs68%Leflunomide ACRPedi30response LFTabnormalitiesnotedmore frequentlywithMTXthan Leflunomide 52%metACRPedi30response 44%metACRPedi50and19% metACRpedi70.44%patients respondedasearlyas4weeks. AEreportedin30%ofpatients, ceasedin2patients Significantdifferencein improvementoncombination comparedwithMTXalone. Nosignificantdifferenceinrateof SE. Combinationtherapysafeandwell tolerated

Silverman, Multicentre DBRCT international 2005[60]

86completed Polyarticular 16weeks JIA 70entered 317yrsold extension study

Silverman, 2005[90]

Open label study

26weeks

Gao, 2003[91]

China

26weeks

27patients Only63% patients completed study 40patients

Refractory polyarticular JIA(failed responseor intolerantof Methotrexate) Polyarticular JRA

Leflunomideloadingdose ~100mgfollowedby 10mg/day(+/increaseto 20mg/dat8wks)

Leflunomide(loadingdose of1mg/kg/day)D13then 0.20.4mg/d)plusMTX (0.3mg/kgivevery2wks untilremissionthen 0.2mg/kgweeklyorally)vs MTXalone

Tenderandswollenjoints, parentandphysician evaluationscore,general functionscore,ESR,CRP SEdocumented

26

Table 5. Evidence for the efficacy of Sulfasalazine in JIA

Author , Year Popn Type of study

DBRCT

Duration Number of ofstudy

patients 24weeks 69

Subjects

Studygroups

Outcomes

Conclusionandcomments

Van multicent Rossum, re 1998[93]

Oligoand Polyarthriti s

SSZ50mg/kg/d (max2g/d) Placebo

ACRPediatric30 (withoutfunctional measure) AEs Reductioninactivejoints Activejointcount,patient assessment,ESR AEs Activejointcount,ESR Remissionor improvement(definedas 25%reductioninjoint numberfortwo consecutivevisits) ACRPediatric30

Burgos Vargas, 2002[94] Ansell, 1991[95]

DBRCT

26weeks

33

ERA

multicent re

Pilot study, Un controlle d

52weeks

51

JIA(oligo, polyand SoJIA)

SSZ30 60mg/kg/d(max 2g) Placebo SSZ40mg/kg/d increased incrementally over6weeks. SSZ50mg/kg/d (max2g)

44%improvedinSSZgroupcomparedwith21% placebogroup. MoreAEswithSSZresultinginwithdrawalof10 patientsintotalfromstudy(allfromSSZgroup).All AEsweretransientandreversible.LFTabnn=2, Leukopenian=2,hypoimmunoglobinaemian=3, anorexia/diarrhoea/haematoman=1each. 46%inSSZgroupcomparedwith42%inplacebogroup. Significantdifferencesonlyseeninphysicianand patientassessments 24%goodresponse,16%someresponse,45%no response. 8patientswithdrewduetoAEs

Huang, 1998[96] Single clinic

Retrospe ctive chart review

Mean duration therapy 2.5yrs

36

ERAand JIA

39%patientsinremissionfurther25%improved 11%patientssomeAE.OnepatientceasedSSZ. NodifferencebetweenERAandJIA EffectivesuppressionofdiseaseactivityearlywithSSZ hasbeneficialeffectsthatpersistformanyyears

Van multicent Rossum, re 2007[97]

Pro spective cohort

Median9 years (range7 10)

61

Hoza, 1991[98]

DBRCT

26weeks

39

Oligoand polyarthriti

Patientsinitially managedwith SSZ(32)vs thosemanaged withplacebo (29) SSZ20 30mg/kg/d

Anyimprovementin4 criteria:

48%SSZgroupimprovedcomparedwith28% Chloroquinegroup

27

Table 5. Evidence for the efficacy of Sulfasalazine in JIA

Author , Year

Popn

Type of study

Duration Number of ofstudy

patients

Subjects

Studygroups

Outcomes

Conclusionandcomments

Ozdoga n, 1985[99]

414 months

18

Alltypes JIA

Chloroquine3 4mg/kg/d

Activejoints,pain, morningstiffness,ESR, functionalcapacity ESR Jointtenderness Activejointcount

MoreAEswithSSZ SignificantimprovementinESR,jointtendernessand count

28

4.3Sulfasalazine
4.3.1MechanismofactionandPharmacology
Theexactmechanismofactionofsulfasalazineisnotclearlyunderstood.Itsroleinthe treatmentofJIAispossiblyduetoitsimmunoregulatoryandantiinflammatoryeffect including,amongstotherthings:theinhibitionofprostaglandinsynthesis;inhibitionof bacterialgrowth;inhibitionofleukotrieneformation;modulationofleucocytefunction; inhibitionofDNAsynthesis;impairmentoffolatemetabolismandeffectsoflymphocyte numberandfunction. Sulfasalazineispoorlyabsorbedinthesmallintestine.Inthecolon,sulfasalazineisreduced totwomajoractivemetabolites(5aminosalicylicacidandsulfapyridine)bycolonicflora. Sulfapyridineisrapidlyabsorbedandmetabolisedbyacetylationintheliver.Therateofthis processvariesbetweenindividualsandisgeneticallydetermined. Both5aminosalicylicacidandsulfapyridinehaveanaffinityforcollagenrichtissueand concentrateinthesynovialfluidaswellaspleuralspaces,intestinalwallandperitoneum.

4.3.2EfficacyofSulfasalazineinJIA
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 29

[98]demonstratednosignificantdifferencewhensulfasalazinewascomparedtochloroquine inoligoarticularandpolyarticularJIA. SulfasalazinedoesnothaveconsistentefficacyacrosssubtypesofJIA.Thereisabroad experienceinopen,uncontrolledtrialswhichsuggestthebenefitofsulfasalazineinJIA,and thisissupportedbytheaforementionedblindedcontrolledVanRossumtrial.Someopen labeltrialsfoundanincreaseresponseinolderHLAB27positivechildrenwitholigoarticular disease,howeverthisfindingwasnotconvincinglysupportedinasmallblindedcontrol study.[94]Basedonbestavailableevidence,sulfasalazineismosteffectiveinpolyandoligo articulardiseaseandtheredoesnotappeartobeadifferenceinresponseratesbetweenthese groups.Onthecurrentevidence,sulfasalazineisnoteffectiveinthemanagementofSoJIA and,infact,itsuseispotentiallycomplicatedbyanincreasedriskoftoxicity.

4.3.3Doseandadministration
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,othermorerarebutsevere haematologicalsideeffectssuchasagranulocytosishavebeenreported.Agranulocytosisis 30

saidtooccurin1%ofpatientsandusuallybeginswithin512weeksofonsetoftherapy[103] andispotentiallyfatal. SkinrashisalsoacommonsideeffectandoccurredinhalfofthepatientsintheVanRossum trial[93].Sulfasalazinehasalsobeenassociatedwithotherrarercomplicationssuchasdrug inducedlupuserythematosus.Thismayoccurafterseveralorevenyearsoftherapyand resolvesfollowingwithdrawal.

4.3.5Druginteraction
Sulfasalazineisgenerallywelltoleratedwithothermedications.Sulfasalazinemaydecrease thebioavailabilityofcyclosporin.Therearealsoreportsofpossibleadditivehepatotoxicity whenusedincombinationwithmethotrexate.Careshouldbetakenwhenprescribing sulfasalazineasnumerousotherdruginteractionshavebeenreported.

4.3.6Monitoringandsupervision
FullbloodcountandLiverfunctiontestsshouldbeperformedfrequentlyfollowinginitiation ofsulfasalazine.Productinformationsuggestsbaselineteststhen2weeklyfor3months, monthlyfor3monthsandthenmonthlythereafter.Itisrecommendedthatpatientsbe followedupclinicallyatleast3monthlytoensureongoingtoleranceofsulfasalazine.

4.3.7Formulary
SulfasalazineisFDAapprovedforuseinchildrenforJIApolyarticularcourse.Itisnot licensedforuseintheUK. Australianbrandnames:Pyralin,entericcoatedtablets:500mg;SalazopyrinandSalazopyrin ENtabstablets:500mg UKbrandname:SalazopyrinandSalazopyrinENtabs500mg;Salazopyrinsuspension 250mg/5mlandsuppositories500mg. USbrandnames:Azulfidine,AzulfidineENtabs,SulfazinandSulfazinEC,500mg Canadianbrandnames:AltiSulfasalazineandSalazopyrin

4.3.8Summaryrecommendations
Thecurrentliteraturesuggeststhatsulfasalazinehasaroleasdiseasemodifyingtherapyin thetreatmentofJIAandparticularlyoligoarticularandpolyarticulardisease.Itisnotthe firstDMARDofchoiceespeciallygiventheevidencesupportingmethotrexate.The considerationofsulfasalazineasanalternativeDMARDinJIAshouldbeunderspecialist supervision.Sulfasalazinetherapyalsorequiresspecialistsupervisionparticularlywith respecttothefrequentriskofadverseeffects.Inaddition,regularmonitoringwithblood testsisrecommended.Sulfasalazineisrecommendedforinclusiononthecomplimentary WHOessentialmedicinelistprovidedtheseresourcesareavailable. 31

4.4

CyclosporinA

4.4.1MechanismofactionandPharmacology
CyclosporinA(CyA)isapotentimmunomodulatoryagentusedtoinhibittheadaptive immuneresponseandthereforeeffectiveindiseasesknowntobeofautoimmuneorigin.Itis usedtopreventrejectioninsolidorgantransplant.Theeffectsontheimmunesystemare likelymultifactoral.Calcineurin,animportantproteinintheprocessofTandBcell activation,isboundandinhibitedbyCyA.Thisresultsinimpairedproductionofanumber ofcytokinesimportantintheproliferationofTcells.TheeffectsofCyAontheTcellappear tobespecificandreversible.Cyclosporinmayhaveothereffectsincludingeffectsonantigen presentation. CyAisincompletelyabsorbedformthegastrointestinaltract.Microemulsionpreparations arethoughttoprovideimprovedabsorptionandbioavailability.Ithasmultiplehepatic metabolicpathwaysandismetabolisedtomanymetabolitesbeforeexcretedinthebile.Only asmallpercentageisexcretedintheurine.Thehalflifeisapproximately18hours.

4.4.2EfficacyofCyclosporininJIAandMAS
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]

4.4.3EfficacyofCyclosporininJDM
Thereareanumberofsmallretrospectivestudiesandcaseseriesreportingthebenefitsof CyAinpatientswithJDM.ThesestudiesaresummarisedinTable7.SimilartoJIA,thereare currentlynocontrolledtrialshoweverthereiscurrentlyaninternationalmulticentre 32

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.

4.4.4Doseandadministration
Thegenerallyaccepteddoseforthemanagementofpaediatricrheumaticdiseasesis3 5mg/kg/day[2]orallyandisusuallydividedtwicedaily.Thisissimilartotherecommended dosinginadultpatientswithrheumatoidarthritis.InonestudyofchildrenwithJDM,adose rangingbetween2.5to7.5mg/kg/daywassufficient.[108]

4.4.5Safety
Cyclosporinisassociatedwithpotentiallyconsiderabletoxicityandrequirescareful monitoringandsupervision.Mostsideeffectsaredosedependentandresponsivetodose adjustment.Cyclosporindosesaresignificantlyhigherinthetreatmentofsolidorgan transplantationcomparedtorheumatologicalindicationsandthereforetheratesofside effectsiscomparativelyhigher. Renalfunctionabnormalitiesandhypertensionarethemostconcerningsideeffectsand responsibleforthemajorityofwithdrawalsoftherapy.Risesincreatinineandureaduetoa reducedglomerularfiltrationratehavebeendemonstrated.Theexactmechanismforthisis unclearbutthesechangesareusuallyreversible.Inoneseriesof22patientswithJIAand JDMonCyA,[106]serumcreatininedoubledin6patientsandGFRwasreducedinoneof14 patients.Ostensenstudied14patientsonCyAandfoundmarkedriseinserumcreatininein 5patientsnecessitatingwithdrawal.[109]Thesefindingsnecessitateclosemonitoringof renalfunction.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 33

bonemarroweffectsandthathypertension,gumhyperplasiaandhypertrichosiswerenot observed,suggestingthatinchildrenthesesideeffectsmaybelesscommon.[106]SinceCyA isanimmunosuppressiveagent,childrenadministeredCyAareatincreasedriskofinfection.

4.4.6Druginteraction
Cyclosporinshouldbeusedwithcautionwhenadministeredincombinationwithother potentiallynephrotoxicmedications.Inparticular,NSAIDsarefrequentlyusedinpaediatric rheumaticdiseaseandmayexacerbatethetoxiceffectsofCyA.Inthissituationclose monitoringofrenalfunctionisrecommended.ThebioavailabilityofCyAincreaseswhenthe drugistakenwithgrapefruitjuice.

4.4.7Monitoringandsupervision
Itisrecommendedthatbloodpressurebemonitoredatleastweeklyforthefirstmonthof therapyandthenmonthlythereafter.[2]Inaddition,laboratorymonitoringisrequired monthlyparticularlyscreeningforrenal,bonemarroworhepaticeffects.Doseadjustmentis recommendedifserumcreatinineincreasesby>30%. TheneedformonitoringofCyAlevelsinnontransplantpatientsisunclear.Itisgenerally recommendedthatwholebloodtroughlevelsbemaintainedbetween125and175g/ml.[2] Monitoringmaybeparticularlyimportantinpatientswithunexpectedtoxicity.

4.4.8

Formulary

AustralianBrandnames: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

4.4.9Summaryrecommendations
Cyclosporinhasaroleinthemanagementofpaediatricrheumaticdisease.Several observationalstudiesprovideevidenceforitsefficacyintreatingJIAandinparticularSoJIA andassociatedMASandalsointhetreatmentofJDM.Cyclosporinisapotent immunosuppressiveagentandisassociatedwithanumberofpotentiallyseriousadverse effects.Theadministrationofcyclosporinshouldbeunderspecialistsupervisionwiththe facilitytofrequentlymonitorwithbloodtests.ItisrecommendedfortheWHOessential medicinescomplimentarylist.

34


Table 6. Evidence for the efficacy of Cyclosporin in JIA

Author, Year
Gerloni, 2001[104]

Popn

Typeof study
Open prospective trial

Number of patients

Subjects
34patientswith SoJIAand7 patientswithJIA andchronic anterioruveitis
18SoJIA,2polyJIA, 2lupus,2 unclassified inflammatory disorders

Durationof study
Avgduration therapy1.4yr (max7.2yr)

Intervention
AllpatientsreceivedCyA 35mg/kg/d

Outcomesmeasured
Improvedfever;improved arthritis(50%decreasein numberofactivejoints);Hb; ESR;physicianglobal SEofCyA. Clinicalandbiological measuresofRHS

Conclusionandcomments
CyAhasbenefitsincontroloffeverand reducingsteroidexposureinpatients withSoJIA.CyAislesseffectivein controlofarthritis. SEfreqbutusuallymildandreversible. 26%patientswithdrewduetoSE. CyAconsistentlyandrapidlyeffective inpatientswhenusedasfirstline therapyandwhensteroidshadfailed CyAmaybeeffectiveintreatmentof refractoryJRAandJDM. ConcomitantMTXappearssafe

Italy

41

Stephan, 2001[105]

Multi Retrospectiv centre e French observationa

lstudy

24 with RHS 22

Patients accumulated over10yrs Meanperiod 16months(6 42months)

various

Reiff, 1997[106]

US

Retrospectiv e observationa l

17JRA,5JDM

Pistoia, 1993[112]

Italy

Caseseries

12

Mouy, 1996[107]

Caseseries

9patientswith CyAgivenfor JCA(7SoJIA,2 948months poly);3patients withJDM 5patientswith MAS(4SoJIAand 1polyJIA)

AllpatientsreceivedCyA meandose3.2mg/kg/d. Mostpatientsreceived concomitantCSand 16/22patientsreceived concomitantMTX. AllpatientsreceivedCyA atmeandose5mg/kg/day afterfailureofCStherapy 3patientsfailingto respondtoCStherapy hadCyAaddedand2 patientswithlesssevere manifestationstreated withCyAalone

Labvariables;jointcount; jointswelling;morning stiffnessinpatientswithJRA. Muscleweaknessand enzymelevelsinJDM. Clinicalandlaboratory measuresofdiseaseactivity

CyAwassatisfactoryoveralland thoughttobeapromisingagentin treatmentofJIAandJDM. Rapidimprovementinallpatients. Apyrexiainallpatientswithin48 hours. Biologicalabnormalitiesimproved moreslowly.

Clinicalandbiological markersofMAS

35


Table 7. Evidence for the efficacy of Cyclosporin in JDM

Author/ Year Reiff, 1997[106]

Popn

Typeof study
Retrospectiv e observationa l

Number of patients

Subjects
17JRA,5JDM

Durationof study
Meanperiod 16months(6 42months)

Intervention
AllpatientsreceivedCyA meandose3.2mg/kg/d. Mostpatientsreceived concomitantCSand 16/22patientsreceived concomitantMTX. AllpatientsreceivedCyA atmeandose5mg/kg/day afterfailureofCStherapy CyAstartingat2.5 mg/kg/ddividedbdand increasedaccordingto clinicalresponse.Max 12mg/kg/d

Outcomesmeasured
Labvariables;jointcount; jointswelling;morning stiffnessinpatientswithJRA. Muscleweaknessand enzymelevelsinJDM. Clinicalandlaboratory measuresofdiseaseactivity

Conclusionandcomments
CyAmaybeeffectiveintreatmentof refractoryJRAandJDM. ConcomitantMTXappearssafe

US

22

Pistoia, 1993[112]

Italy

Caseseries

12

Heckmatt,

UK

Caseseries

14

1989[108]

Zeller, 1996[113]

Retrospectiv ecasereview

9patientswith JCA(7SoJIA,2 poly);3patients withJDM 14patientswith JDMnot respondedfully toCSandother immuno suppressantswith chronicallyactive diseaseavg3yrs Patientswith refractoryJDM

CyAgivenfor 948months

CyAwassatisfactoryoveralland thoughttobeapromisingagentin treatmentofJIAandJDM. AllpatientsimprovedonCyA. Recoveryofmusclestrength,resolution ofcomplicationsandreductionor cessationofsteroids. NoseriousSEobserved.HTeasily controlledwithdosereduction.

Average12 months therapyto timeof publication(5 28months)

Muscleweakness,extentof rash,serumCK, MonitoringofSEicluding BP,serumcreatinine,CyA levels.

Meanfollow up51.5 months

CyA

Clinicalmarkersofdisease. MedicationSE,Steroiddoses

CyAseemseffectiveandshouldbe consideredinrefractorycases.SE rare/minor

36

4.5Azathioprine 4.5.1MechanismofactionandPharmacology
Azathioprineisapurineanaloguemetabolisedinthelivertoitsactivemetabolite6 mercaptopurine(6MP).6MPisthenfurthermetabolisedviathreemajorpathways,the metabolitesofwhichinhibitDNAsynthesisthroughthesuppressionofguanineandadenine synthesis.AzathioprineinhibitscellmediatedimmunitythroughinhibitionofTcellgrowth andresultsinreducedantibodyproduction. Thebioavailabilityofazathioprineisapproximately50%.[114]Itisrapidlymetabolisedin theliveranditsmetabolite,6MP,hasahalflifeof0.73hours.Smallamountsare eliminatedasunchangeddrugandmetabolitesarepredominantlyrenallyexcreted.

4.5.2EfficacyofAzathioprineinSLE
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]

37

4.5.3EfficacyofAzathioprineinJIA
Theevidencefortheefficacyofazathioprineisbasedoncaseseries,casereportsand uncontrolledtrials.Todatethereisonlyonerandomiseddoubleblindplacebocontrolled trialaddressingtheefficacyofazathioprineinthetreatmentof32JIA[118]Statistically significantimprovementwasonlyseenintwodiseaseactivitymeasurementsanditis thereforenotconsideredtohavegreaterefficacythanplacebo.Itisnotusedroutinelyinthe treatmentofJIA.Seetable8fordetailsofstudies. Anuncontrolledprospectivetrialinvolving129patientswithrefractoryJCAdemonstrated improvementinbothclinicalandlaboratoryoutcomeswithacceptablesideeffectprofile. [119]Afurtherretrospectivestudyof24patientsdemonstratedclinicalimprovementin 62.5%ofpatientsandremissionin37.5%.[120]Whilstthestrengthofthisevidenceisnotas compellingasthatofotherDMARDsusedinthetreatmentofJIA,thesestudiessuggestthat theremaybearoleofazathioprineinJIA.

4.5.4Doseandadministration
Azathioprineshouldbestartedat11.5mg/kg/dayincreasingtoamaximumdoseof2 2.5mg/kg/day.Itisgenerallyconsideredthataminimumof12weeksisrequiredtoachieve adequatetherapeuticresponse.Azathioprineshouldbeadministeredwithfoodtoreduce gastrointestinaldisturbance.

4.5.5Safety
Gastrointestinalsideeffectsmanifestingasnausea,vomiting,diarrhoeaandepigastricpain arecommonwithazathioprine.Thesesideeffectscanbediminishedifthedosedividedorif administeredwithmeals.Upto12%ofpatientsexperiencethesesymptomsandinone study10%ofadultpatientswithrheumatoidarthritiswithdrewfromtherapydueto gastrointestinalintolerance.[121] Otherlessfrequentlyobservedsideeffectsinclude:pancreatitis,livertoxicity(abnormalliver functiontests),interstitialpneumonitisandrash.Itisdifficulttoestimatetheincidenceof thesesideeffectsinthepaediatricrheumaticdiseasepopulationasstudiesoftheuseand safetyofazathioprinearefrequentlyintheadultpopulationandinconditionsotherthan rheumaticdiseases. Dosedependenteffectsonthebonemarrowhavealsobeenwelldescribedinassociation withazathioprinecausinggranulocytearrestandleukopeniaand,lessfrequently,anaemia andthrombocytopenia.Thisisthoughttobeduetoreducedactivityofthiopurine methyltransferase(TPMT).TMPTactivityisloworabsentin0.3%ofthepopulationand causesthesehaematologicaleffectsshortlyafterinitiationoftherapy.LowerTMPTactivity hasbeenobservedinAfricanAmericanindividualscomparedtoCaucasianAmericans. [122]DistinctTMPTmutationshavebeenidentifiedandaredetectableonPCRbased technique.

38

4.5.6Druginteraction
Anumberofmedications,usedconcomitantly,havebeenreportedtoenhancethe myelosuppressiveeffectofazathioprineincludingtrimethoprim.5ASAderivativesmay decreasethemetabolismofthiopurineanalogs.Thetoxiceffectsofleflunomidemayalsobe enhancedwhenusedwithazathioprineandrequiremorestringentmonitoringofbone marrowtoxicity.Azathioprinemayalsodecreaseplasmacyclosporinlevels.

4.5.7Monitoringandsupervision
Toxicitymonitoringshouldoccurthroughouttreatment.Itisgenerallyrecommendedthat clinicalevaluationoccurat12monthsthen3monthlythereafterorearlierifdiseaseseverity warrants.Laboratorymonitoringshouldinclude:weeklyFBEwithdifferentialuntilstable thenmonthlythereafterandmonthlyLFTsandUEC.[2]AnalysisofTMPTgenotypeshould beconsideredforpatientswhodevelopsevereleukopeniaonazathioprine. Azathioprineshouldbeceasedifthereissignificantleukopenia,thrombocytopeniaor elevatedliverenzymes.

4.5.8Formulary
Australianbrandname:Imuran(tablets25mg,50mg,powderforreconstitution50mg) UKbrandnames:Imuran(tablets25mg,50mg,powderforreconstitution50mg) USbrandnames:Imuran(tablets25mg,50mg,powderforreconstitution50mg);Azasan Canadianbrandnames:AltiAzathioprine;ApoAzathioprine;GenAzathioprine; Imuran;MylanAzathioprine;NovoAzathioprine

4.5.9Summaryrecommendations
AzathioprineappearstohavearoleinthemanagementofbothpaediatricSLEandJIA althoughconclusivestrongevidencewithRCTsislacking.Azathioprineisassociatedwith potentiallyserioussideeffectsinparticularrelatingtobonemarrowsuppression. Administrationofazathioprineshouldbeunderthesupervisionofspecialistcarewithaccess toappropriateclinicalandlaboratorymonitoring.Azathioprineisrecommendedfor inclusiononthecomplementaryWHOessentialmedicineslist.

39

 Table 8. Evidence for the efficacy of Azathioprine in JIA

Author/ Year Kvien, 1986[118]

Typeof study
RDBPCT

Number of patients

Subjects
JIAalltypes

Durationof study
16weeks

Intervention
AZA22.5mg/kg/d Vsplacebo

Outcomesmeasured
Laboratory(ESR,FBE) Numberofclinicalmeasures includingactivejointcount, functionalcapacity, physiciansoverall assessment

Conclusionandcomments
Significantimprovementonlyin patientssubjectivefunctionalcapacity andsubjectivetotalassessment. Trendinfavourofazathioprinebutnot conclusiveevidenceofefficacy 15%remission.14%temporary remission(stillontherapy). SustainedeffectwithacceptableSE 14%discontinuedduetoSE 62.5%showedclinicalimprovement. 37.5%clinicalremission Welltolerated. Steroidsparingagent

32

Savolaine Uncontrolled n 1997[119] Lin, 2000[120]

Retrospectiv echart review

129

RefractoryJCA

Median treatment13 months, Meanduration treatment13 months,mean followup45 months

24

JRAtreated previouslywith azathioprine

AZA(avgmaxdose 1.9mg/kg/d) 12patientsreceived DMARDspriortostartof AZA

40

4.6Hydroxychloroquine 4.6.1MechanismofactionandPharmacology
Hydroxychloroquineisanantimalarialagentusedinthetreatmentofrheumaticdisease. HydroxychloroquineinhibitsthesynthesisofDNA,RNAandproteinbyinteractingwith nucleicacid.Itsimmunosuppressiveeffectisviaanumberofmechanismsincluding: alterationinlysosomalpHandinterferenceinantigenprocessing;stabilizationoflysosomal membranes;inhibitionofantigenantibodyreactions;suppressionoflymphocyteresponse andinhibitionofneutrophilchemotaxis.[2] Hydroxychloroquineisrapidlyabsorbedfromtheintestinewithanoralbioavailabilityof 74%.[123]Thehalflifeis40days,steadystateisreachedin2to6monthsanditisprimarily renallyexcreted.[123]

4.6.2EfficacyofHydroxychloroquineinJIA
HydroxychloroquinehasnotbeenconvincinglyshowntobeeffectiveinthetreatmentofJIA. Thereisoneplacebocontrolledtrialaddressingtheefficacyofhydroxychloroquineinthe treatmentofJIA.[124]Thisrandomiseddoubleblindedtrialof162patientswith polyarticularJIAcomparedhydroxychloroquinewithpenicillamineorplacebo.Therewas nosignificantdifferencebetweengroups. Kvienetaldemonstratedinanopenrandomisedtrial(notplacebocontrolled)of72patients witholigoandpolyarticularJIA,thathydroxychloroquinewasnotmoreefficaciousthan goldorpenicillamine.[125]Interestingly,ametaanalysisin2000ofallRCTsandCCTs comparinghydroxychloroquinetoplaceboinadultpatientswithrheumatoidarthritis revealedanoverallmoderateeffectandwithalowtoxicityprofile.[126]

4.6.3EfficacyofHydroxychloroquineinpaediatricSLE
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. 41

4.6.4Doseandadministration
Theusualdoseofhydroxychloroquineinchildrenis35mg/kgkg/daydivided12timesper daywithamaximumof400mgperday.Itshouldbeadministeredwithfoodtoreducethe occurrenceofgastrointestinalintolerance.

4.6.5Safety
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.

4.6.6Druginteraction
HydroxychloroquinelevelsmaybedecreasedbyEchinacea.Inadditionthereareanumber ofmedicationsthatshouldbeavoidedormonitoredcarefullyorincreasedordecreased effectwhenusedconcomitantlywithhydroxychloroquine.Theseinclude:betablockers,anti psychoticsandothers.

4.6.7Monitoringandsupervision
Whilsthydroxychloroquineisasafemedication,itdoesneedregularmonitoring.Fullblood examinationissuggestedonaregularbasisandophthalmologyexaminationshouldoccurat leastyearly.

4.6.8Formulary
HydroxychloroquineisnotFDAapprovedfortheuseinpaediatricSLE.IntheUK hydroxychloroquineislicensedforuseinJIA,SLEanddiscoidLEandotherdermatological conditionscausedbyoraggravatedbythesun. Australianbrandnames:Plaquenil(200mgtablets) UKbrandnames:Plaquenil(200mgtablets) USbrandnames:Plaquenil 42

Canadianbrandnames:ApoHydroxyquine;GenHydroxychloroquine;Plaquenil;Pro Hydroxyquine

4.6.9Summaryrecommendations
Hydroxychloroquineappearstobeasafeandeffectivetreatmentinthemanagementof juvenileSLE.IthasnoprovenroleinthemanagementofJIA.Hydroxychloroquineis recommendedfortheuseinjuvenileSLEprovidedpatientshaveaccesstospecialistcare includingophthalmologicalandlaboratoryassessments.Itisrecommendedforinclusionon theWHOessentialmedicinescomplementarylist.

43

 BIBLIOGRAPHY
1. 2. 3. 4. 5. 6. 7. 8. 9. Petty,R.E.,etal.,InternationalLeagueofAssociationsforRheumatologyclassificationofjuvenileidiopathic arthritis:secondrevision,Edmonton,2001.JRheumatol,2004.31(2):p.3902. CassidyJ.T.,P.,R.E.,LaxerR.M.,LindsleyC.B,TextbookofPediatricRheumatology.5thed.2005:Elsevier Saunders. Manners,P.J.andC.Bower,Worldwideprevalenceofjuvenilearthritiswhydoesitvarysomuch?JRheumatol, 2002.29(7):p.152030. Mielants,H.,etal.,Prevalenceofinflammatoryrheumaticdiseasesinanadolescenturbanstudentpopulation,age 12to18,inBelgium.ClinExpRheumatol,1993.11(5):p.5637. Manners,P.J.andD.A.Diepeveen,Prevalenceofjuvenilechronicarthritisinapopulationof12yearold childreninurbanAustralia.Pediatrics,1996.98(1):p.8490. Tayel,M.Y.andK.Y.Tayel,Prevalenceofjuvenilechronicarthritisinschoolchildrenaged10to15yearsin Alexandria.JEgyptPublicHealthAssoc,1999.74(56):p.52946. Petty,R.E.,Frequencyofuncommondiseases:isjuvenileidiopathicarthritisunderrecognized?JRheumatol, 2002.29(7):p.13567. Hochberg,M.C.,M.S.Linet,andE.M.Sills,Theprevalenceandincidenceofjuvenilerheumatoidarthritisinan urbanBlackpopulation.AmJPublicHealth,1983.73(10):p.12023. Kurahara,D.,etal.,Ethnicdifferencesinriskforpediatricrheumaticillnessinaculturallydiversepopulation.J Rheumatol,2002.29(2):p.37983.

10. Kurahara,D.K.,etal.,Visitingconsultantclinicstostudyprevalenceratesofjuvenilerheumatoidarthritisand childhoodsystemiclupuserythematosusacrossdispersedgeographicareas.JRheumatol,2007.34(2):p.4259. 11. Cassidy,J.T.,etal.,Astudyofclassificationcriteriaforadiagnosisofjuvenilerheumatoidarthritis.Arthritis Rheum,1986.29(2):p.27481. 12. Oen,K.,etal.,Earlypredictorsoflongtermoutcomeinpatientswithjuvenilerheumatoidarthritis:subsetspecific correlations.JRheumatol,2003.30(3):p.58593. 13. Zak,M.andF.K.Pedersen,Juvenilechronicarthritisintoadulthood:alongtermfollowupstudy. Rheumatology(Oxford),2000.39(2):p.198204. 14. Hashkes,P.J.andR.M.Laxer,Medicaltreatmentofjuvenileidiopathicarthritis.JAMA,2005.294(13):p.1671 84. 15. Adib,N.,A.Silman,andW.Thomson,Outcomefollowingonsetofjuvenileidiopathicinflammatoryarthritis:I. frequencyofdifferentoutcomes.Rheumatology(Oxford),2005.44(8):p.9951001. 16. Packham,J.C.andM.A.Hall,Longtermfollowupof246adultswithjuvenileidiopathicarthritis:functional outcome.Rheumatology(Oxford),2002.41(12):p.142835. 17. Goldenberg,J.,etal.,Symptomaticcardiacinvolvementinjuvenilerheumatoidarthritis.IntJCardiol,1992. 34(1):p.5762. 18. Sawhney,S.,P.Woo,andK.J.Murray,Macrophageactivationsyndrome:apotentiallyfatalcomplicationof rheumaticdisorders.ArchDisChild,2001.85(5):p.4216. 19. Behrens,E.M.,etal.,Occultmacrophageactivationsyndromeinpatientswithsystemicjuvenileidiopathic arthritis.JRheumatol,2007.34(5):p.11338.

44

20. Ravelli,A.,etal.,Preliminarydiagnosticguidelinesformacrophageactivationsyndromecomplicatingsystemic juvenileidiopathicarthritis.JPediatr,2005.146(5):p.598604. 21. Kanski,J.J.andG.A.ShunShin,Systemicuveitissyndromesinchildhood:ananalysisof340cases. Ophthalmology,1984.91(10):p.124752. 22. Kump,L.I.,etal.,Analysisofpediatricuveitiscasesatatertiaryreferralcenter.Ophthalmology,2005.112(7): p.128792. 23. Ramanan,A.V.andB.M.Feldman,Clinicalfeaturesandoutcomesofjuveniledermatomyositisandother childhoodonsetmyositissyndromes.RheumDisClinNorthAm,2002.28(4):p.83357. 24. McCann,L.J.,etal.,TheJuvenileDermatomyositisNationalRegistryandRepository(UKandIreland)clinical characteristicsofchildrenrecruitedwithinthefirst5yr.Rheumatology(Oxford),2006.45(10):p.125560. 25. Feldman,B.M.,etal.,Juveniledermatomyositisandotheridiopathicinflammatorymyopathiesofchildhood. Lancet,2008.371(9631):p.220112. 26. Mendez,E.P.,etal.,USincidenceofjuveniledermatomyositis,19951998:resultsfromtheNationalInstituteof ArthritisandMusculoskeletalandSkinDiseasesRegistry.ArthritisRheum,2003.49(3):p.3005. 27. Symmons,D.P.,J.A.Sills,andS.M.Davis,Theincidenceofjuveniledermatomyositis:resultsfromanationwide study.BrJRheumatol,1995.34(8):p.7326. 28. Pachman,L.M.,etal.,Juveniledermatomyositisatdiagnosis:clinicalcharacteristicsof79children.JRheumatol, 1998.25(6):p.1198204. 29. Bohan,A.andJ.B.Peter,Polymyositisanddermatomyositis(firstoftwoparts).NEnglJMed,1975.292(7):p. 3447. 30. Blane,C.E.,etal.,Patternsofcalcificationinchildhooddermatomyositis.AJRAmJRoentgenol,1984.142(2):p. 397400. 31. Fisler,R.E.,etal.,Aggressivemanagementofjuveniledermatomyositisresultsinimprovedoutcomeanddecreased incidenceofcalcinosis.JAmAcadDermatol,2002.47(4):p.50511. 32. Crowe,W.E.,etal.,Clinicalandpathogeneticimplicationsofhistopathologyinchildhoodpolydermatomyositis. ArthritisRheum,1982.25(2):p.12639. 33. Pachman,L.M.andN.Cooke,Juveniledermatomyositis:aclinicalandimmunologicstudy.JPediatr,1980. 96(2):p.22634. 34. Stringer,E.,D.SinghGrewal,andB.M.Feldman,Predictingthecourseofjuveniledermatomyositis: significanceofearlyclinicalandlaboratoryfeatures.ArthritisRheum,2008.58(11):p.358592. 35. Laxer,R.M.,L.D.Stein,andR.E.Petty,Intravenouspulsemethylprednisolonetreatmentofjuvenile dermatomyositis.ArthritisRheum,1987.30(3):p.32834. 36. Huber,A.M.,etal.,Mediumandlongtermfunctionaloutcomesinamulticentercohortofchildrenwithjuvenile dermatomyositis.ArthritisRheum,2000.43(3):p.5419. 37. Tucker,L.B.,etal.,Adultandchildhoodonsetsystemiclupuserythematosus:acomparisonofonset,clinical features,serology,andoutcome.BrJRheumatol,1995.34(9):p.86672. 38. Ferraz,M.B.,etal.,Evaluationofthe1982ARAlupuscriteriadatasetinpediatricpatients.Committeesof PediatricRheumatologyoftheBrazilianSocietyofPediatricsandtheBrazilianSocietyofRheumatology.ClinExp Rheumatol,1994.12(1):p.837.

45

39. Norris,D.G.,A.R.Colon,andG.B.Stickler,Systemiclupuserythematosusinchildren:thecomplexproblemsof diagnosisandtreatmentencounteredin101suchpatientsattheMayoClinic.ClinPediatr(Phila),1977.16(9):p. 7748. 40. Hiraki,L.T.,etal.,Clinicalandlaboratorycharacteristicsandlongtermoutcomeofpediatricsystemiclupus erythematosus:alongitudinalstudy.JPediatr,2008.152(4):p.5506. 41. Tucker,L.B.,Makingthediagnosisofsystemiclupuserythematosusinchildrenandadolescents.Lupus,2007. 16(8):p.5469. 42. Brunner,H.I.,etal.,Differenceindiseasefeaturesbetweenchildhoodonsetandadultonsetsystemiclupus erythematosus.ArthritisRheum,2008.58(2):p.55662. 43. Meislin,A.G.andN.Rothfield,Systemiclupuserythematosusinchildhood.Analysisof42cases,with comparativedataon200adultcasesfollowedconcurrently.Pediatrics,1968.42(1):p.3749. 44. Yang,L.Y.,W.P.Chen,andC.Y.Lin,Lupusnephritisinchildrenareviewof167patients.Pediatrics,1994. 94(3):p.33540. 45. Tucker,L.B.,Controversiesandadvancesinthemanagementofsystemiclupuserythematosusinchildrenand adolescents.BestPractResClinRheumatol,2002.16(3):p.47180. 46. Lee,Y.,etal.,Inductionandmaintenancetherapyforlupusnephritis:asystematicreviewandmetaanalysis. Lupus. 47. Macdermott,E.J.,A.Adams,andT.J.Lehman,Systemiclupuserythematosusinchildren:currentand emergingtherapies.Lupus,2007.16(8):p.67783. 48. Ravelli,A.,etal.,Plasmalevelsafteroralmethotrexateinchildrenwithjuvenilerheumatoidarthritis.J Rheumatol,1993.20(9):p.15737. 49. Godfrey,C.,etal.,Thepopulationpharmacokineticsoflongtermmethotrexateinrheumatoidarthritis.BrJClin Pharmacol,1998.46(4):p.36976. 50. Hoekstra,M.,etal.,Bioavailabilityofhigherdosemethotrexatecomparingoralandsubcutaneousadministration inpatientswithrheumatoidarthritis.JRheumatol,2004.31(4):p.6458. 51. Hamilton,R.A.andJ.M.Kremer,Whyintramuscularmethotrexatemaybemoreefficaciousthanoraldosingin patientswithrheumatoidarthritis.BrJRheumatol,1997.36(1):p.8690. 52. Giannini,E.H.,etal.,Comparativeefficacyandsafetyofadvanceddrugtherapyinchildrenwithjuvenile rheumatoidarthritis.SeminArthritisRheum,1993.23(1):p.3446. 53. Ruperto,N.,etal.,Arandomizedtrialofparenteralmethotrexatecomparinganintermediatedosewithahigher doseinchildrenwithjuvenileidiopathicarthritiswhofailedtorespondtostandarddosesofmethotrexate.Arthritis Rheum,2004.50(7):p.2191201. 54. Woo,P.,etal.,Randomized,placebocontrolled,crossovertrialoflowdoseoralmethotrexateinchildrenwith extendedoligoarticularorsystemicarthritis.ArthritisRheum,2000.43(8):p.184957. 55. Giannini,E.H.,etal.,Methotrexateinresistantjuvenilerheumatoidarthritis.ResultsoftheU.S.A.U.S.S.R. doubleblind,placebocontrolledtrial.ThePediatricRheumatologyCollaborativeStudyGroupandTheCooperative ChildrensStudyGroup.NEnglJMed,1992.326(16):p.10439. 56. Takken,T.,J.VanDerNet,andP.J.Helders,Methotrexatefortreatingjuvenileidiopathicarthritis.Cochrane DatabaseSystRev,2001(4):p.CD003129. 57. Ravelli,A.,etal.,Theextendedoligoarticularsubtypeisthebestpredictorofmethotrexateefficacyinjuvenile idiopathicarthritis.JPediatr,1999.135(3):p.31620.

46

58. Gottlieb,B.S.,etal.,Discontinuationofmethotrexatetreatmentinjuvenilerheumatoidarthritis.Pediatrics,1997. 100(6):p.9947. 59. CespedesCruz,A.,etal.,Methotrexateimprovesthehealthrelatedqualityoflifeofchildrenwithjuvenile idiopathicarthritis.AnnRheumDis,2008.67(3):p.30914. 60. Silverman,E.,etal.,Leflunomideormethotrexateforjuvenilerheumatoidarthritis.NEnglJMed,2005.352(16): p.165566. 61. alSewairy,W.,etal.,MethotrexatetherapyinsystemiconsetjuvenilerheumatoidarthritisinSaudiArabia:a retrospectiveanalysis.ClinRheumatol,1998.17(1):p.527. 62. Huang,J.L.,Methotrexateinthetreatmentofchildrenwithchronicarthritislongtermobservationsofefficacy andsafety.BrJClinPract,1996.50(6):p.3114. 63. Reiff,A.,etal.,Highdosemethotrexateinthetreatmentofrefractoryjuvenilerheumatoidarthritis.ClinExp Rheumatol,1995.13(1):p.1138. 64. Ravelli,A.,etal.,Factorsassociatedwithresponsetomethotrexateinsystemiconsetjuvenilechronicarthritis. ActaPaediatr,1994.83(4):p.42832. 65. Harel,L.,etal.,Effectsofmethotrexateonradiologicprogressioninjuvenilerheumatoidarthritis.Arthritis Rheum,1993.36(10):p.13704. 66. Wallace,C.A.,etal.,Predictingremissioninjuvenilerheumatoidarthritiswithmethotrexatetreatment.J Rheumatol,1993.20(1):p.11822. 67. Huber,A.M.,etal.,Protocolsfortheinitialtreatmentofmoderatelyseverejuveniledermatomyositis:resultsofa ChildrensArthritisandRheumatologyResearchAllianceConsensusConference.ArthritisCareRes(Hoboken). 62(2):p.21925. 68. Ramanan,A.V.,etal.,Theeffectivenessoftreatingjuveniledermatomyositiswithmethotrexateandaggressively taperedcorticosteroids.ArthritisRheum,2005.52(11):p.35708. 69. AlMayouf,S.,A.AlMazyed,andS.Bahabri,Efficacyofearlytreatmentofseverejuveniledermatomyositis withintravenousmethylprednisoloneandmethotrexate.ClinRheumatol,2000.19(2):p.13841. 70. Miller,L.C.,etal.,Methotrexatetreatmentofrecalcitrantchildhooddermatomyositis.ArthritisRheum,1992. 35(10):p.11439. 71. Foeldvari,I.andA.Wierk,Methotrexateisaneffectivetreatmentforchronicuveitisassociatedwithjuvenile idiopathicarthritis.JRheumatol,2005.32(2):p.3625. 72. Weiss,A.H.,C.A.Wallace,andD.D.Sherry,Methotrexateforresistantchronicuveitisinchildrenwithjuvenile rheumatoidarthritis.JPediatr,1998.133(2):p.2668. 73. Malik,A.R.andC.Pavesio,Theuseoflowdosemethotrexateinchildrenwithchronicanteriorandintermediate uveitis.BrJOphthalmol,2005.89(7):p.8068. 74. Jundt,J.W.,etal.,Acomparisonoflowdosemethotrexatebioavailability:oralsolution,oraltablet,subcutaneous andintramusculardosing.JRheumatol,1993.20(11):p.18459. 75. Ortiz,Z.,etal.,Theefficacyoffolicacidandfolinicacidinreducingmethotrexategastrointestinaltoxicityin rheumatoidarthritis.Ametaanalysisofrandomizedcontrolledtrials.JRheumatol,1998.25(1):p.3643. 76. OrtizAlvarez,O.,etal.,Guidelinesforbloodtestmonitoringofmethotrexatetoxicityinjuvenileidiopathic arthritis.JRheumatol,2004.31(12):p.25016. 77. Lahdenne,P.,etal.,Hepatotoxicityinpatientswithjuvenileidiopathicarthritisreceivinglongtermmethotrexate therapy.JRheumatol,2002.29(11):p.24425.

47

78. Graham,L.D.,etal.,Morbidityassociatedwithlongtermmethotrexatetherapyinjuvenilerheumatoidarthritis.J Pediatr,1992.120(3):p.46873. 79. Hashkes,P.J.,etal.,Therelationshipofhepatotoxicriskfactorsandliverhistologyinmethotrexatetherapyfor juvenilerheumatoidarthritis.JPediatr,1999.134(1):p.4752. 80. Hashkes,P.J.,etal.,Thelongtermeffectofmethotrexatetherapyontheliverinpatientswithjuvenilerheumatoid arthritis.ArthritisRheum,1997.40(12):p.222634. 81. Kugathasan,S.,etal.,Liverbiopsyfindingsinpatientswithjuvenilerheumatoidarthritisreceivinglongterm, weeklymethotrexatetherapy.JPediatr,1996.128(1):p.14951. 82. West,S.G.,Methotrexatehepatotoxicity.RheumDisClinNorthAm,1997.23(4):p.883915. 83. Singsen,B.H.andR.GoldbachMansky,Methotrexateinthetreatmentofjuvenilerheumatoidarthritisand otherpediatricrheumatoidandnonrheumaticdisorders.RheumDisClinNorthAm,1997.23(4):p.81140. 84. Niehues,T.andP.Lankisch,Recommendationsfortheuseofmethotrexateinjuvenileidiopathicarthritis. PaediatrDrugs,2006.8(6):p.34756. 85. Padeh,S.,etal.,Hodgkinslymphomainsystemiconsetjuvenilerheumatoidarthritisaftertreatmentwithlow dosemethotrexate.JRheumatol,1997.24(10):p.20357. 86. Londino,A.V.,Jr.,J.Blatt,andA.S.Knisely,Hodgkinsdiseaseinapatientwithjuvenilerheumatoidarthritis takingweeklylowdosemethotrexate.JRheumatol,1998.25(6):p.12456. 87. Kremer,J.M.,etal.,Methotrexateforrheumatoidarthritis.Suggestedguidelinesformonitoringlivertoxicity. AmericanCollegeofRheumatology.ArthritisRheum,1994.37(3):p.31628. 88. Rozman,B.,Clinicalpharmacokineticsofleflunomide.ClinPharmacokinet,2002.41(6):p.42130. 89. Shi,J.,etal.,Populationpharmacokineticsoftheactivemetaboliteofleflunomideinpediatricsubjectswith polyarticularcoursejuvenilerheumatoidarthritis.JPharmacokinetPharmacodyn,2005.32(34):p.41939. 90. Silverman,E.,etal.,Longtermopenlabelpreliminarystudyofthesafetyandefficacyofleflunomideinpatients withpolyarticularcoursejuvenilerheumatoidarthritis.ArthritisRheum,2005.52(2):p.55462. 91. Gao,J.S.,H.Wu,andJ.Tian,[Treatmentofpatientswithjuvenilerheumatoidarthritiswithcombinationof leflunomideandmethotrexate].ZhonghuaErKeZaZhi,2003.41(6):p.4358. 92. Cannon,G.W.andJ.M.Kremer,Leflunomide.RheumDisClinNorthAm,2004.30(2):p.295309,vi. 93. vanRossum,M.A.,etal.,Sulfasalazineinthetreatmentofjuvenilechronicarthritis:arandomized,doubleblind, placebocontrolled,multicenterstudy.DutchJuvenileChronicArthritisStudyGroup.ArthritisRheum,1998. 41(5):p.80816. 94. BurgosVargas,R.,etal.,A26weekrandomised,doubleblind,placebocontrolledexploratorystudyof sulfasalazineinjuvenileonsetspondyloarthropathies.AnnRheumDis,2002.61(10):p.9412. 95. Ansell,B.M.,etal.,Amulticentrepilotstudyofsulphasalazineinjuvenilechronicarthritis.ClinExp Rheumatol,1991.9(2):p.2013. 96. Huang,J.L.andL.C.Chen,Sulphasalazineinthetreatmentofchildrenwithchronicarthritis.ClinRheumatol, 1998.17(5):p.35963. 97. vanRossum,M.A.,etal.,Longtermoutcomeofjuvenileidiopathicarthritisfollowingaplacebocontrolledtrial: sustainedbenefitsofearlysulfasalazinetreatment.AnnRheumDis,2007.66(11):p.151824. 98. Hoza,J.,etal.,SulphasalazineandDelagilacomparativestudyinpatientswithjuvenilechronicarthritis.Acta UnivCarolMed(Praha),1991.37(12):p.803.

48

99. Ozdogan,H.,etal.,Sulphasalazineinthetreatmentofjuvenilerheumatoidarthritis:apreliminaryopentrial.J Rheumatol,1986.13(1):p.1245. 100. Joos,R.,etal.,Sulfasalazinetreatmentinjuvenilechronicarthritis:anopenstudy.JRheumatol,1991.18(6):p. 8804. 101. Imundo,L.F.andJ.C.Jacobs,Sulfasalazinetherapyforjuvenilerheumatoidarthritis.JRheumatol,1996.23(2): p.3606. 102. Brooks,C.D.,Sulfasalazineforthemanagementofjuvenilerheumatoidarthritis.JRheumatol,2001.28(4):p. 84553. 103. Marouf,E.S.andI.M.Morris,Neutropeniainpatientswithrheumatoidarthritis,treatedwithsulphasalazine.Br JRheumatol,1990.29(5):p.4079. 104. Gerloni,V.,etal.,EfficacyandsafetyprofileofcyclosporinAinthetreatmentofjuvenilechronic(idiopathic) arthritis.Resultsofa10yearprospectivestudy.Rheumatology(Oxford),2001.40(8):p.90713. 105. Stephan,J.L.,etal.,Reactivehaemophagocyticsyndromeinchildrenwithinflammatorydisorders.Aretrospective studyof24patients.Rheumatology(Oxford),2001.40(11):p.128592. 106. Reiff,A.,etal.,PreliminaryevidenceforcyclosporinAasanalternativeinthetreatmentofrecalcitrantjuvenile rheumatoidarthritisandjuveniledermatomyositis.JRheumatol,1997.24(12):p.243643. 107. Mouy,R.,etal.,EfficacyofcyclosporineAinthetreatmentofmacrophageactivationsyndromeinjuvenile arthritis:reportoffivecases.JPediatr,1996.129(5):p.7504. 108. Heckmatt,J.,etal.,Cyclosporininjuveniledermatomyositis.Lancet,1989.1(8646):p.10636. 109. Ostensen,M.,H.M.Hoyeraal,andE.Kass,ToleranceofcyclosporineAinchildrenwithrefractoryjuvenile rheumatoidarthritis.JRheumatol,1988.15(10):p.15368. 110. Palestine,A.G.,etal.,Renalhistopathologicalterationsinpatientstreatedwithcyclosporineforuveitis.NEnglJ Med,1986.314(20):p.12938. 111. Robert,N.,G.W.Wong,andJ.M.Wright,Effectofcyclosporineonbloodpressure.CochraneDatabaseSyst Rev,(1):p.CD007893. 112. Pistoia,V.,etal.,CyclosporinAinthetreatmentofjuvenilechronicarthritisandchildhoodpolymyositis dermatomyositis.Resultsofapreliminarystudy.ClinExpRheumatol,1993.11(2):p.2038. 113. Zeller,V.,etal.,Cyclosporinatherapyinrefractoryjuveniledermatomyositis.Experienceandlongtermfollowup of6cases.JRheumatol,1996.23(8):p.14247. 114. Sandborn,W.J.,Azathioprine:stateoftheartininflammatoryboweldisease.ScandJGastroenterolSuppl,1998. 225:p.929. 115. Ginzler,E.,etal.,Longtermmaintenancetherapywithazathioprineinsystemiclupuserythematosus.Arthritis Rheum,1975.18(1):p.2734. 116. Nossent,H.C.andW.Koldingsnes,Longtermefficacyofazathioprinetreatmentforproliferativelupus nephritis.Rheumatology(Oxford),2000.39(9):p.96974. 117. Hagelberg,S.,etal.,Longtermfollowupofchildhoodlupusnephritis.JRheumatol,2002.29(12):p.263542. 118. Kvien,T.K.,H.M.Hoyeraal,andB.Sandstad,Azathioprineversusplaceboinpatientswithjuvenilerheumatoid arthritis:asinglecenterdoubleblindcomparativestudy.JRheumatol,1986.13(1):p.11823. 119. Savolainen,H.A.,etal.,Azathioprineinpatientswithjuvenilechronicarthritis:alongtermfollowupstudy.J Rheumatol,1997.24(12):p.244450.

49

120. Lin,Y.T.,etal.,Longtermeffectsofazathioprinetherapyforjuvenilerheumatoidarthritis.JFormosMedAssoc, 2000.99(4):p.3305. 121. Singh,G.,etal.,Toxicityprofilesofdiseasemodifyingantirheumaticdrugsinrheumatoidarthritis.JRheumatol, 1991.18(2):p.18894. 122. McLeod,H.L.andC.Siva,ThethiopurineSmethyltransferasegenelocusimplicationsforclinical pharmacogenomics.Pharmacogenomics,2002.3(1):p.8998. 123. Tett,S.E.,etal.,Bioavailabilityofhydroxychloroquinetabletsinhealthyvolunteers.BrJClinPharmacol,1989. 27(6):p.7719. 124. Brewer,E.J.,etal.,Penicillamineandhydroxychloroquineinthetreatmentofseverejuvenilerheumatoidarthritis. ResultsoftheU.S.A.U.S.S.R.doubleblindplacebocontrolledtrial.NEnglJMed,1986.314(20):p.126976. 125. Kvien,T.K.,H.M.Hoyeraal,andB.Sandstad,Slowactingantirheumaticdrugsinpatientswithjuvenile rheumatoidarthritisevaluatedinarandomized,parallel50weekclinicaltrial.JRheumatol,1985.12(3):p.533 9. 126. SuarezAlmazor,M.E.,etal.,Antimalarialsfortreatingrheumatoidarthritis.CochraneDatabaseSystRev, 2000(4):p.CD000959. 127. Arandomizedstudyoftheeffectofwithdrawinghydroxychloroquinesulfateinsystemiclupuserythematosus.The CanadianHydroxychloroquineStudyGroup.NEnglJMed,1991.324(3):p.1504. 128. RuizIrastorza,G.,etal.,Clinicalefficacyandsideeffectsofantimalarialsinsystemiclupuserythematosus:a systematicreview.AnnRheumDis.69(1):p.208. 129. Easterbrook,M.,Currentconceptsinmonitoringpatientsonantimalarials.AustNZJOphthalmol,1998. 26(2):p.1013.

50