Transcript
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18th Expert Committee on the Selection and Use of Essential Medicines
(21 to 25 March 2011)
Section 2 Analgesics, antipyretics, NSAIMs, DMARDs
2.4 Disease-modifying agents used in rheumatoid disorders
ReviewofDiseaseModifyingAntiRheumatic
Drugsin
Paediatric
Rheumatic
disease
September2010
Preparedby:
PeterGowdie
RheumatologyandClinicalPharmacologyFellow2009
RoyalChildrensHospital
Melbourne,Australia
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Contents1. Intentofreview2. Identificationofpriorityconditions3. Reviewofpriorityrheumaticdisease
1.
JuvenileIdiopathicarthritis1.Epidemiology2.Diseaseburdenandoutcome3.Clinicalmanifestations4.Complications
macrophageactivationsyndrome uveitis amyloidosis
2. IdiopathicInflammatoryMyopathies(JuvenileDermatomyositis)1.Epidemiology2.
ClinicalManifestations3.Complications
4.CourseandOutcome5.Overviewofmanagement
3. SystemicLupusErythematosus1.Epidemiology2.ClinicalManifestations3.Courseandoutcome4.Overviewofmanagement
4. DMARDs1. Methotrexate
1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritis3.EfficacyinJuvenileDermatomyositis4.Doseandadministration5.Druginteractionandfolatesupplementation6.Safety7.Monitoringandsupervision8.Formulary9.Summaryrecommendations
2. Leflunomide1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritis3.Doseandadministration4.Safety5.Druginteraction6.Monitoringandsupervision7.Formulary8.Summaryrecommendations
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3. Sulphasalazine1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritis3.Doseandadministration4.Safety5.Druginteraction6.Monitoringandsupervision7.Formulary8.Summaryrecommendations
4. Cyclosporin1.MechanismofactionandPharmacology2.EfficacyinJuvenileIdiopathicArthritisandMacrophageActivation
Syndrome
3.EfficacyinJuvenileDermatomyositis4.Doseandadministration5.Safety6.Druginteraction7.Monitoringandsupervision8.Formulary9.Summaryrecommendations
5. Azathioprine1.MechanismofactionandPharmacology2.EfficacyinSLE3.EfficacyinJIA4.Doseandadministration5.Safety6.Druginteraction7.Monitoringandsupervision8.Formulary9.Summaryrecommendations
6. Hydroxychloroquine1.MechanismofactionandPharmacology2.EfficacyinSLE3.Doseandadministration4.Safety5.Druginteraction6.Monitoringandsupervision7.Formulary8.Summaryrecommendations
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1. Intentofreview
Toidentifypriorityrheumatologicalconditionsinchildren Tooutlinethetreatmentoptionsfortheseconditions
TooutlinetheroleofDMARDsinthetreatmentofpriorityrheumatologicalconditions
ToreviewtheliteratureandcollatetheevidencefortheefficacyofDMARDsinpriorityconditions
ToreviewthesafetyofDMARDsandoutlinemonitoringandsupervisionrequired TogiverecommendationsfortheinclusionofDMARDsontheWHOEssential
MedicinesList
2. Identificationofpriorityconditions
PaediatricRheumatologyencompassesabroadrangeofinflammatorydisordersinvolvingthejointsandconnectivetissuesinchildren.Juvenileidiopathicarthritisisperhapsthemost
wellrecognisedoftherheumaticdiseasesofchildhoodhoweverthespecialtysscope
includesconditionssuchasacuterheumaticfever,poststreptococcalreactivearthritis,
KawasakidiseaseandLymediseaseaswellaschronicsystemicconditionsincluding
SystemicLupusErythematosus(SLE),JuvenileDermatomyositis(JDM),andthevasculitides.
Themostcommonrheumaticdiseaseaffectingchildrenischronicarthritis.Thefunctional
impactofthisdiseasecanbesignificantandthetimelyadministrationofappropriate
therapy,includingDMARDs,canbeeffectiveinimprovingoutcome.Whilelesscommon,
SLEandJDMarealsoarepotentiallydevastatingconditionsandDMARDtherapyplaysanequallyimportantroleintheirmanagement.
3. Reviewofpriorityconditions
3.1 JuvenileIdiopathicArthritis
Chronicarthritisisacomplexgroupofdisorderscomprisinganumberofclinicalentities
withthecommonfeatureofarthritis. Eachtypeischaracterisedbyadifferentmodeof
presentationanddifferentdiseasecourseandoutcome.Thethreemaingroupsofchronicarthritisare:thoseaffectingfewjoints(oligoarticular);
thoseaffectingmanyjoints(polyarticular);andthosesystemicinonset. Theclassificationof
chronicarthritishasbeenproblematicoverthepastfewdecadesespeciallyintermsof
universallyagreedupondefinitions.This,inpart,largelyreflectsthecomplexand
heterogeneousnatureofthisgroupofconditionsandtheasyetnotclearlydefined
immunogeneticfactorscontributingtotheironset.Itisalsoimportanttorememberthe
population(mostlyCaucasian)inwhicheachofthemajorclassificationcriteriahavebeen
described.Forthepurposesofthispaper,theInternationalLeagueofAssociationfor
Rheumatology(ILAR)criteriaforclassificationofjuvenileidiopathicarthritis(JIA)hasbeen
used.[1]
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3.1.1Epidemiology
JIAremainsanuncommonbutbynomeansrareconditionaffectingchildrenworldwide.[2]
Estimatesofincidenceandprevalencehoweverhavebeendifficulttoascertainformany
reasonsincluding:variationindiagnosticcriteria;differencesinascertainment(community
vsclinicalbasedstudies);differencesinstudydesign;lowfrequencyofdiseaseandsmall
studynumbers.[3]
In2002MannersandBowersummarisedthemostrecentepidemiologicalstudiestothat
pointandfoundareportedprevalenceof0.07to4.01per1000childrenandanannual
incidenceof0.008to0.226per1000children.[3]Thelargedifferenceinreportedprevalence
isconsideredtobelargelyduetovaryingstudycharacteristics.Thehighestprevalencewas
reportedincommunitybasedstudieswherechildrenwereexaminedinclassroomsor
homes.In1993,Meilantsperformedanepidemiologicalstudyusingaquestionnaire
followedbyclinicalexaminationandfoundaprevalenceofdefiniteJIAof1.67per1000.[4]
In1996Mannersetalfoundasignificantlyhigherprevalence(4.01per1000)inanurban
Australiancommunity.[5]Similarly,TayeletalfoundaprevalenceofJIAamongst1015year
oldschoolchildreninAlexandria,Egypt,of3.3per1000.[6]Clinicbasedstudiesontheother
handappeartoreportlowerprevalencerates perhapsreflectingthatmanycliniciansfailto
recogniseJIAandthereforethesechildrendonotmaketheirwaytomedicalcareinlarge
studycentres,thereforeunderestimatingthetrueprevalence.[7]
ThereisverylittlecomparabledataoutliningtheprevalenceofJIAinpopulationsotherthan
thoseofEuropeandescent.Infact,inthemostheavilypopulatedareasoftheworld
epidemiologicaldataisveryscarce.OutsideoftheUS,UKandCanadasomestudiesreveal
verydifferentdata.LowerfrequenciesofJIAhavebeenreportedinchildreninJapan(annual
incidence0.0083per1000)andCostaRica(annualincidence0.068per10000Arguedes1998
and0.054per1000Arguedes1995).In1983Hochbergreportedanannualincidenceof0.066
per1000childrenandaprevalenceof0.26per1000inurbanblackchildrenintheUSA
howeverotherstudiessuggestthatthisisanunderestimate.[8] Manyofthesestudiesare
ultimatelylimitedbythesmallsamplesizeandselectionbias.Oneretrospectivestudy
undertakenbyKuraharaetalin2002demonstratedlowerfrequencyofJIAinHawaiiansof
Filipino,JapaneseandSamoandescentcomparedwithCaucasians.[9]Inasimilarpopulation
KuraharaalsofoundincreasedprevalenceofJIAinruralareascomparedwithurban
areas.[10]
Theextentofjuvenilearthritisinthedevelopingworldandtheepidemiologicalimpactof
ethnicityandgeographyneedsfurtherconsiderationespeciallyinconsideringtheimpact
andburdenofdiseaseofthisgroupofconditions.
3.1.2 BurdenofDiseaseandoutcome
ThediseaseoutcomeandprognosisinJIAisvariableandtosomedegreepredictablebased
onthedifferentdiseasesubtypes.Forexample,seropositivepolyarticularJIAhasa
relativelypooroutcomecomparedwitholigoarticularJIAwhoseoutcomeisgenerallyvery
good.[11,12]However,thelattergrouparealsothemostatriskofdebilitatinguveitisasa
complicationoftheirdisease.ManychildrenwithJIAhaveanexcellentprognosisandforthe
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mostpartremainfreefromsignificantlydebilitatingdisease.However,5070%ofpatients
withsystemicandpolyarticulardiseaseand4050%ofoligoarticulararthritiscontinueinto
adulthoodwithactivedisease[Laxer/Hashkes]. Ithasbeenestimatedthatupto20%of
childrentransitiontoadulthoodwithmoderatetoseverefunctionaldisabilities[13]andan
evenhigherpercentage(3040%)havesignificantlongtermdisabilitiesincluding
unemployment.[14]Majorsurgery,includingjointreplacementisrequiredin2550%.[14]
Delayinreferralandinitiationofacceptabletherapyisassociatedwithpooreroutcome.[2]
TheprognosisinJIAisfrequentlyassessedwiththreemainoutcomemeasures:frequencyof
remission,functionalimpairmentandstructuraldamage.Similartotheoutliningof
epidemiology,outcomestudiesarealsodifficulttodrawconclusionsespeciallygiventhe
prevailinguseofthreedifferentclassificationsystemsandthevariableoutcomemeasures
withoutagreedupondefinitions.Forexample,thereremainsnointernationalagreementon
validatedremissioncriteriaforJIA
Remissionratesvarybetweensubgroupshowever,despitedifferingapproachesand
definitionsacrossstudies,thereisconsistentreportingofhigherremissionratesin
oligoarticulardisease.Intheoligoarticulardiseasethisrangedfrom36%to84%.[15]
Remissionratesforpolyarticulardiseaserangedfrom12.5%to65%whilstsystemicdisease
was0to76%.[15]Thelargerangecanbeexplainedbytherelativeinfrequencyofthese
subtypescomparedwitholigoarticulardiseaseandthereforethesmallsamplesizes
potentiallymoreinfluencedbychance.Similarly,functionaloutcomewasbetterinthe
oligoarticularsubtypeandthefrequencyofseveredisabilitywaslow.Bycontrast,systemic
andpolyarticulardiseasebothhavebeendocumentedtohavesignificantlyworsefunctional
outcome.SystemicJIAinparticularhasalargeproportionofpatientswithseveredisability.
[16]
Whilstestimatesoftheburdenofdiseaseatanindividuallevelhasbeendocumentedto
someextent,thereremainsconsiderabledifficultyinacquiringdatarelatingtoestimatesof
theglobalburdenofthisgroupofdiseases.Theglobalimpactofjuvenilearthritison
disabilityandhandicap,theeducationalandvocationaldisadvantages,lifeexpectancyand
qualityoflifeaswellasthecostofmedicalcareremainstobedefined.
3.1.3 ClinicalManifestationsofJIA
ThecommonfeatureofallthesubtypesofJIAisarthritis.Systemicsymptomstypicallyoccur
insystemicandpolyarticularsubtypesandinclude:fatigue,lossofweight,anaemia,
anorexiaandfever.Jointinflammationresultsinpainanddiscomfortandattimes
considerablemorningstiffness. Largejointsarethemostfrequentlyaffected,howeverany
jointcanbeinvolvedincludingcervicalspine,thoracolumbarspineandtemporo
mandibularjoint.Growthabnormalitiesarenotuncommonandcanresultinshortstatureor
localisedgrowthdisturbancesuchasbonyovergrowth,prematurelyfusedepiphysesand
limblengthdiscrepancies.Otherextraarticularmanifestationsinclude:osteopenia,
rheumatoidnodulesandmuscleatrophy.Cardiopulmonarydiseaseisalsonotuncommon
particularlyinsystemiconsetdisease. Pericarditisoccursinupto9%[17]however
tamponadeisrare.Myocarditisandendocarditishavealsobeendocumentedtohave
occurred.
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3.1.4 ComplicationsofJIA
MacrophageActivationSyndrome
MacrophageActivationSyndrome(MAS)ispotentiallythemostdevastatingsequelaeofJIA.
MASissimilarinmanywaystoreactivehaemophagocyticlymphohistiocytosis(HLH)and
thetermMAShascometorefertoHLHsecondarytorheumaticdisease. MASismostoften
associatedwithsystemiconsetJIA,however,hasbeenrecognisedwithotherrheumatic
diseasessuchas:polyarticularJIA,SLE,JDMandchronicinfantileneurologiccutaneousand
articularsyndrome(CINCA).
MAScontributestoasignificantamountofthemorbidityandmortalityassociatedwith
SoJIA.EstimatesoftheincidenceofMASinSoJIAvary.Sawhneyetalreportanincidenceof
6.7%.[18]However,itisbelievedbymanythatMASisintegraltothepathogenesisofSoJIA
andthatinfactoccultMASiscommoninpatientswithSoJIA.[19]
MASisoftendifficulttodistinguishclinicallyfromSoJIA.Itsfeaturesinclude:fever(often
moresustainedthatSoJIA),hepatosplenomegaly,anaemia,LFTabnormalities,rash,
coagulopathyandcentralnervoussystemdysfunction.Laboratorymarkerssuggestiveof
diagnosisinclude:decreasingwhitecellcountandplatelets,elevatedferritin,
hypertriglyceridemia,hypofibrinogenemiaandevidenceofhaemophaocytosisonbone
marrowaspirate.PreliminaryguidelinesforthediagnosisofMASinassociationwithSoJIA
havebeensuggested.[20]
MASispotentiallyfatalespeciallyinthosepatientswithmultisysteminvolvementorwhen
diagnosisisdelayed.Earlydiagnosisandvigoroustreatmentisnecessary.Corticosteroids
andsupportivecarearethefirstlinetherapies,however,agentssuchascyclosporin,
etoposideandIVIG.TheuseofcyclosporininMASisdiscussedinsection4.4.2.
Uveitis
OneofthemostimportantcomplicationsofJIAisuveitis.Thisisachronicnon
granulomatousinflammationaffectingtheirisandciliarybodytheendresultofwhichcan
bedevastating.Inparticular,bandkeratopathyandcataractsoccurin4258%whilst
glaucomaoccursin1922%.[21]Itsactivitydoesnotcorrelatewiththecourseofthearthritis
anditsowncourseisusuallyinsidiousandoftenasymptomaticmandatingfrequent
ophthalmologicalsurveillance.Ratesofuveitisvarybetweensubtypesofarthritiswiththe
mostfrequentatriskgroupbeingoligoarticularJIA.Uveitishasbeendescribedinmost
racialgroups.
JIAisthemostfrequentnoninfectioussystemicdiseaseassociatedwithuveitisinchildren.
Otherlesscommonnoninfectiouscausesinclude:ulcerativecolitis,tubulointerstitial
nephritissyndrome,Behcetsdiseaseandchronicinfantileneurologiccutaneousand
articularsyndrome(CINCA).Ahighproportionofpaediatricpatientswithuveitisdonot
haveanunderlyingcausefound.Kumpetalfoundnoassociatedsystemicdiseasein58%of
patientswithuveitis.[22]
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Themanagementofuveitisshouldbesupervisedbyanophthalmologistinconjucttionwith
apaediatricianorpediatricrheumatologist.Uveitisisusuallymanagedwithtopical
corticosteroidswithamydriaticagent.Systemicprednisoloneadministeredorallyor
intravenouslymayberequiredinanattempttoachieveshorttermreliefofinflammation.In
childreninwhomuveitisisdifficulttocontrolbythesemeasures,additional
immunosuppressiveagentshavebeenusedincludingincreasinguseofbiologicalagents.
Theefficacyofmethotrexateisdiscussedinsection4.1.4.
Amyloidosis
Amyloidosisisthetissuedepositionoftheproteinamyloidandcanoccurasacomplication
ofJIA.ItisararecomplicationinNorthAmericabutoccursmorefrequentlyinpartsof
Europe.Itmanifestsasproteinuria,nephriticsyndrome,hepatosplenomegalyoranaemia
andcaneventuallyleadtorenalfailure.Amyloidosisandresultantrenalfailureasa
complicationofJIAwas,inthepast,themajorcauseofdeath.Theothermaincauseis
infection.Deathrateshaveimprovedoverrecentdecadesandnowthediseaseassociated
deathrateinEuropeis
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3.2.2 ClinicalManifestations
Juveniledermatomyositis(JDM)isamultisysteminflammatorycondition itcanaffectthe
muscle,skin,gastrointestinaltract,heart,lungs,kidneysandeyes.JDMcanmanifestina
heterogeneousfashion,however,themaincharacteristicsofthediseaseinclude:symmetrical
proximalmuscleweakness,pathognomicskininvolvement(egGottronspapules,
heliotropicrash),andraisedmuscleenzymes.ThediagnosisofJDMismadethroughthe
applicationofdiagnosticcriteriaestablishedbyBohanandPeterin1975:1)presenceof
characteristicrash heliotropicrashwithperiorbitaloedemaandGottronspapules;2)
symmetricalproximalmuscleweakness;3) raisedserummuscleenzymes(atleastoneof
CK,LDH,AST);4)myopathicEMG;5)musclebiopsydemonstratingnecrosisand
inflammation.[29]Patientswitharashandtwootherofthecriteriaareconsideredtohave
possibleJDM,whilerashwiththreeadditionalcriteriaareconsideredtohavedefiniteJDM.
Inpractice,musclebiopsyandEMGareusedlessfrequentlytodaythantheyoncewere.
TheyarebothinvasiveinvestigationsandMRIisnowconsideredasensitivetestfor
myositis.
Theclinicalcourseandprogressionofthediseaseisalsovaried.MostcommonlyJDM
presentswithaninsidiousevolutionoveraperiodof3to6months,howeveritcanpresent
acutely.Ramananetalreviewedtheclinicalfeaturesandoutcomesofalargecaseseriesof
patientstreatedattheHospitalforSickChildreninCanada.[23]Of120patientswithIIM,
105hadJDM.Themostcommonclinicalfeaturesatpresentationwere:Gottronsrash(91%),
heliotroperash(83%),malar/facialrash(42%),nailfoldcapillarychange(80%),
myalgia/arthralgia(25%),dysphoniaordysphagia(24%),anorexia(18%),fever(16%).[23]
Muscleweaknessisprogressiveandfrequentlyresultsintheinabilitytoambulate,sit
uprightorattendtoactivitiesofdailyliving.Weaknessmaybeaccompaniedbysignificant
pain.Thepharyngealandpalatalmusclesmayalsobeinvolvedresultingindifficulty
swallowinganddysphonia.Thisoccurredinupto24%ofpatientsinRamanansseries[23]
andputsthepatientatriskofaspiration
3.2.3 Complications
Calcinosisoccursinupto40%ofpatients[30]andcanresultinsignificantdisability.Deposits
inthesubcutaneoustissuescanbepainfulandleadtoulceration.Earlyandaggressive
controlofinflammationmayminimisethedegreeofcalcinosis.[31]Cutaneousulcerative
diseaseisanotherskincomplicationwhichisnotinfrequentlyseen.Itisthoughttobe
associatedwithmoresevereandprolongedJDM.[32]Lipodystrophyhasalsobeen
describedwithJDM.
Cardiopulmonaryabnormalitiesarealsodescribedhoweverclinicallysignificant
involvementinchildrenwithdermatomyositisisunusual.Themostfrequentcardiac
problemsincludecardiomegalyandnonspecificmurmurs.Moreseriouscardiacinvolvement
isunusualbutpotentiallylifethreatening.Restrictivepulmonarydiseaseduetopoorchest
wallcomplianceandrespiratorymuscleweaknessiscommonandhasbeenreportedinupto
78%patients.[33]Gastrointestinalvasculitisisrarebutisaseverecomplicationwhichcan
leadtodeath.Itmanifestsasabdominalpain,haematemesisandmelaena.
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3.2.4 CourseandOutcomeofJDM
JDMtypicallyfollowsauniphasiccoursealthoughthedurationisquitevariable.Stringeret
alfollowedthecourseof84patientswithJDM.Theyfoundthatthemajority(60%)of
patientshadachronicdiseasecoursedefinedasnoremissionwithin3yearsofdiagnosis.
[34]Theyalsofoundthatasmallpercentageofpatientshadarelapsefollowingremission.
TheoutlookforpatientswithJDMhassignificantlyimprovedoverthepastdecadeswiththe
useofmoreaggressiveimmunosuppressanttherapies.Beforetheuseofcorticosteroids,this
illnesswasdevastating.Manypatientsdiedorsufferedlongtermprogressiveanddisabling
disease.Functionaloutcometodayisusuallyexcellentwith6580%ofpatientsachievinga
goodoutcome[2]Optimaloutcomeseemstobeachievedifdiagnosisismadeshortlyafter
onsetandtreatmentisvigorous.[35]Huberetalfoundthatof65childrenwithJDM,a
favourableoutcomewaspredominant.Eightpercentwereleftwithmoderatetosevere
disabilityandtherewasonedeath.[36]Contracturesandmildatrophyoccurin
approximately25%ofpatients[2]howeverinonestudycohortnoneofthepatientswere
thoughttobeeducationallyorvocationallyimpairedduetotheirillness.[23]Although
deathsarenowlessfrequent,chronicallyactivediseaseoccursinsubstantialnumberof
patientsand,inaddition,sideeffectssuchasgrowthfailurefromprolongedsteroiduseare
notinfrequent.
3.2.5OverviewofManagement
Corticosteroidsandgeneralsupportivecareinamultidisciplinaryteamsettingarethe
mainstaysoftreatmentofJDM.TheuseofcorticosteroidshasdramaticallyimprovedtooutlookforpatientswithJDM.Highsuppressivedosesareusedearlyandthentapered
graduallyoveronetotwoyears.Thedegreeofsupportivecareisdependentuponthedegree
ofdisability.Inpatientswithbulbardysfunctionorsignificantrespiratorymuscleweakness,
careneedstobedirectedtopreventionofaspirationandventilatorysupport.Physiotherapy
andoccupationaltherapyisadvisedtoavoidlossofmotionandcontracturesinthefirst
instanceandthenlatertostrengtheninordertoregainnormalfunction.
Otherimmunosuppressiveagentshavenotbeensubjectedtorandomisedcontrolledtrials
howevertheyarenowacceptedasanimportantpartofthemanagementofJDM.Four
agentshavebeendescribedinthetreatmentofJDMandtheevidencefortheirusewillbereviewedwithinthisdocument.Theyare:methotrexate,cyclosporine,azathioprineand
cyclophosphamide.
3.3SystemicLupusErythematosus
Systemiclupuserythematosus(SLE)isamultisystemautoimmunediseasecharacterisedby
inflammationofthebloodvesselsandconnectivetissuesresultingindamagetonumerous
organsystemsandassociatedwithantinuclearantibodies.ThediagnosisofSLEisbasedon
welldescribedclinicalandlaboratoryfeaturesandissupportedbytheuseoftheAmerican
CollegeofRheumatology(ACR)adultSLEclassificationcriteriafirstdevelopedin1982andthenrevisedin1997. However,therearewelldescribeddifferencesintheclinicalfeatures,
serologyandoutcomeofpaediatricpatientswithlupuscomparedwithadultpatients[37]
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andthereforetheapplicabilityofthesediagnosticcriteriahavebeenquestioned.Therehave
beenfewlargescalevalidationstudiesofthesecriteriainthepaediatricpopulation.Ferrazet
alappliedtheACRcriteriato103paediatricpatientswithlupusanddemonstrateda
sensitivityandspecificityof96%and100%respectively.[38]
TheaetiologyofSLEisunknown.SusceptibilitytothedevelopmentofSLEisconsidered
multifactorialperhapscontributedbytheinteractionofgenetic,acquiredandperhaps
environmentalfactors.ThepathogenesisinvolvesdisorderedimmunitywithautoreactiveT
andBcellsandantibodyandimmunecomplexdeposition.[2]Theclinicalmanifestationsand
courseofSLEareextremelyvariedbutcanbeassociatedwithsignificantmorbidityand
mortality.
3.3.1Epidemiology
PaediatricSLEisararediseaseandisreportedtohaveanannualincidenceestimatedat
between0.360.9per100,000peryeardependingonthepopulationinwhichitis
studied.[2]Thereisnoaccurateprevalencedata.DatafromRheumatologyclinicsurveys
reportthatSLEaccountsforbetween1%and4.5%ofclinicpopulation.[2]Approximately
15%ofpatientswithSLEhavetherediseaseonsetinchildhood.Onsetisrarebeforetheage
of5anditismorecommoningirlsthanboyswitharatioofapproximately5:1.[39,40]
TherearelimitedpopulationbasedstudiesreportingdataonthedistributionofSLEacross
racialgroups.SLEhasbeenobserveddisproportionatelyinpeopleofAfricanAmerican,
HispanicandAsianbackground.[2]
3.3.2ClinicalandSerologicalManifestations
SLEisamultisysteminflammatoryconditionandcanpresentwithinsidiousonsetorasan
acutelifethreateningillness.Thediseasecanmanifestwithrenal,CNS,cardiac,pulmonary,
musculoskeletal,cutaneous,gastrointestinal,hepaticandhaematologicalfeatures.Onelarge
cohortof256patientswithpaediatricSLEreportedthatthemostcommonclinical
manifestationswere:arthritis(67%),malarrash(66%),nephritis(55%)andCNSdisease
(27%).[40]Constitutionalsymptomssuchasfever,fatigueandweightlossarecommonin
paediatriconsetSLE.[41]Clinicalfeaturessuchasulcers,alopecia,Raynaudsphenomenon
and photosensitivitylesscommoninpaediatricSLE.[41]Onestudyreportedmoreseverediseaseonsetinpaediatricpatientscomparedtoadultpatientsandthatrenaland
haematologicalfeaturesweremorecommon.[37]Silvermanetalsupportedthisfindingin
theirstudycomparingpaediatricwithadultSLE.Theyfoundthatchildrenhadmoreactive
diseaseatonsetwithhigherfrequencyofrenaldiseaseandlowerfrequencyof
cardiopulmonarydisease.[42]
Typicalserologicalfindingsinclude:positiveantinuclearantigen(ANA),positivedouble
strandedDNA(dsDNA),antibodiespositivetoextranuclearantigens(ENA),low
complementlevelsandpositivelupusanticoagulantandantiphospholipidantibodies.
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3.3.3CourseandOutcome
SLEischaracterisedbyachronicrelapsingandremittingcourse.Flarescanoccuratanytime
inthecourseoftheillnessandarefrequentlyprecipitatedbyinfection.Althoughoverall
outcomeformorbidityandmortalityhasimprovedinrecenttimeswithcurrenttherapeutic
options,SLEremainsaseriousandlifethreateningillnesswithanunpredictableprognosis.
In1968,MeislinandRothfieldreporteda5yearsurvivalinpatientswithrenalinvolvement
andwithoutrenalinvolvementof42%and72%respectively.[43]Incontrast,in1998,Yanget
alreporteda5yearsurvivalof91%inpatientswithnephritis.[44]
3.3.4OverviewofManagement
SLEisacomplex,multisystem,chronicdiseasewithpotentialforsignificantmorbidityand
mortalityandisthereforebestmanagedbyamultidisciplinaryteamexperiencedinthe
managementpaediatricSLE.Generalaspectstomanagementinclude:avoidanceofexcessiveexposuretosunlightandprotectionagainstUVBwithsunscreenandappropriate
skincoverwithclothingandheadwear;preventionofinfectionwithimmunisation.
CorticosteroidsremainthefirstlinetherapyforthemanagementofpaediatricSLE.NSAIDs
arefrequentlyusedtomanagemusculoskeletalcomplaintsandhydroxychloroquineisused
asanadjuncttocorticosteroidsinthetreatmentoffatigue,mucucutaneousfeaturesand
arthritis.Immunosuppressivetherapyincludingcyclophosphamide,azathioprineand
mycophenolatearegenerallyconsideredearlyinthecourseofthediseaseifthereis
evidenceofdiffuseproliferativeglomerulonephritis,CNSinvolvementorpulmonary
haemorrhage.[45]Otherimmunosuppressantsconsideredincludemethotrexateandcyclosporin.Thechoiceofdrugremainscontroversial.Inotheractiveformsofthedisease
thereisnoagreementonthetimingofinitiatingimmunosuppressanttherapy.Manyof
thesepatientsareatriskofdevelopingirreversibleorgandamageand,inaddition,
potentiallyfacemanyyearsofhighdosecorticosteroidtherapywithitsassociatedtoxic
effectsandmaythereforewarranttheadditionofimmunosuppressanttherapy.
Mycophenolateinitiallyshowedpromisingresultsinmaintainingdiseasecontrolinadult
patientswithresistantorrelapsinglupusnephritis.Ithassincethenbeensubjecttometa
analysisandfoundtohavenodifferenceoverazathioprineintermsofresponseratesor
developmentofendstagerenaldisease.[46]Itappearstohaveasaferprofilethanazathioprineespeciallyregardstohaematologicalcomplications.
Whilstcurrenttherapieshavedramaticallyimprovedsurvival,thereishopethatnewer
agentsincludingcytotoxicandbiologictherapiesmayprovidesuperiormanagementand
ultimatelyleadtocurativetreatment.[47]
4. DiseaseModifyingAntiRheumaticDrugs(DMARDs)
DMARDsarenotusedforimmediateanalgesicorantiinflammatoryeffectbutratherfor
theirlongtermbeneficialeffectsincontrollingdiseaseactivity.Thesemedicationsalsoplay
animportantroleinreducingthelongtermexposuretomedicationssuchasprednisolone
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andNonSteroidalAntiInflammatoryDrugs(NSAIDs).Historically,DMARDswereused
lateinthecourseofdiseaseprogressionastherewereinitialquestionsregardingtoxicityand
safety.Moreover,theillnessestreatedwerenotoftenconsideredlifethreateningand
thereforeDMARDtherapywasconsiderednotwarranted.Itisnowrecognised,however,
thatnotonlyaremanyofthesemedicationssafeandeffectiveforuseinchildrenbutalso
thattheiruseearlyinthecourseofthediseasemaypreventirreversibledamageand
decreasetheburdenofdisease.
ThereareanumberofDMARDsusedinthetreatmentofrheumaticillnessesinchildren.
Theseinclude:methotrexate,sulfasalazine,azathioprine,leflunomide,hydroxychloroquine
andcyclosporine.Methotrexateisoftenconsideredasthefirstchoiceanditisusedas
treatmentinmanydiseasessuchas:JIA,JDM,SLE,vasculitis,uveitisandlocalised
scleroderma.
4.1Methotrexate
4.1.1MechanismofactionandPharmacology
Methotrexateisafolicacidanalogueandaninhibitorofdihydrofolatereductaseandthereby
interfereswithDNAsynthesisbyreducingthepurineandpyrimidinesupplyinrapidly
dividingcells.Thisantiproliferativeeffectisachievedwithhighdoseregimensandisused
forthetreatmentoftumours.InlowdoseDMARDtherapy,methotrexatealsohasan
immunomodulatoryandantiinflammatoryeffect. Althoughtheexactmechanismofthis
actionremainsunknown,Methotrexateisthoughttoeffectthecellularproductionofa
varietyofcytokinesandtherebyactstoinhibitcellmediatedimmunity.
Thereissignificantvariabilityinthepharmacokineticsofmethotrexatebetweenindividuals
andalsospecificpharmacokineticqualitiesthatimpactonthedosingandrouteof
administration.Methotrexateisabsorbedbythegastrointestinaltractbyasaturableprocess.
Theaverageoralbioavailabilityis0.7butthiscanrangefrom0.25to1.49.[48]Anumberof
factorsarethoughttoimpactonthisincluding:age,sex,dose,creatinineclearance,andfed
vs.fastingstate.[49]Thereisdebateintheliteratureastowhethermealshaveanimpacton
theabsorptionoforalmethotrexate.Absorptionoforallyadministeredmethotrexatehas
beenshowninadultstudiestobereducedatdosesbeyond15mg[50,51]andsomegroups
advocatefortheuseofparenteralmethotrexatefordoseshigherthanthis.
Onceabsorbed,peakserumlevelsarereachedinapproximately1.5hourswiththe
eliminationhalflifebeing7hours.Themajorityofeliminationisthroughrenalexcretionand
circulatinglevelsfallrapidlyasthedrugisdistributedandeliminated.[2]
4.1.2EfficacyofMethotrexateinJuvenileIdiopathicArthritis
MethotrexateisthemostfrequentlyusedsecondlineagentinJuvenileIdiopathicArthritis
andthereisgoodevidenceofitsefficacy.Theevidenceforitsusehasbeendemonstratedin
randomisedplacebocontrolledtrialsaswellasfromalargenumberofretrospectiveand
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uncontrolledstudies.Furthermore,thesestudieshaveshownthatMethotrexateissafe.
Table1summarisesstudiesaddressingtheefficacyofmethotrexateinJIA.
Gianninietalpublishedametaanalysisin1993comparingmethotrexatewith
hydroxychloroquine,penicillamineandauranofininJIA.Atotalof520patientswere
enrolledinallthethreestudiesincludedintheanalysisandoutcomemeasuresincluded
physiciansglobalscaleandESR.Onlymethotrexateat10mg/m2showedimprovementin
thesedomains.[52]In2004,PaediatricRheumatologyInternationalTrialsOrganisation
(PRINTO)publishedtheresultsofatrialwhichultimatelycomparedintermediatewith
higherdosemethotrexateinpatientswhohadfailedtorespondinitiallytostandarddoses.
Theinitialscreeningphasedescribesatotalof633patientswithJIAofwhich72%responded
toastandarddoseofmethotrexate(812.5mg/m2/week)after6monthsoftherapy.[53]
TheefficacyofmethotrexateinthetreatmentofJIAhasbeendemonstratedinprospective
controlledtrials. AsystematicCochranereviewin2001setouttoevaluatetheeffectsof
methotrexateonanumberoffunctionaldomains,includingfunctionalability,rangeof
motion,qualityoflife,overallwellbeingandpain.Onlytwostudies[54,55],withatotalof
165patientswithJIA,fulfilledtheinclusioncriteriafortheCochranereviewofplacebo
controlledrandomisedclinicaltrials.BasedonthesestudiesTakkenetalconcludedthat
methotrexatehasaclinicaleffectonpatientcentreddisability.[56]Sincethentherehasnot
beenanyotherpublishedRCTsaddressingtheefficacyofmethotrexatevs.placebo.
Despitetheevidencefortheefficacyofmethotrexatetherearemanyquestionsrelatingtoits
usethatremainunansweredorwithoutsufficientevidencetoenableconcrete
recommendations.Forexample,theresponsetomethotrexatebetweenthevarioussubtypes
ofJIAhasnotbeencomparedinarigorousfashion. Wooetalfoundnodifferencein
responsetomethotrexatebetweenpatientswithextendedoligoarticularandsystemicJIA
althoughoveralltherewasasignificantimprovementofbothgroupscomparedwith
placebo.[54]Incontrast,RavellietalfoundthatwhencomparedtosystemicJIAand
polyarticularJIA, extendedoligoarticularJIAwasthemostlikelytorespondto
methotrexate.[57]
Theoptimaltimingofdiscontinuationofmethotrexatetherapyfollowingremissionisalso
unclear.Asdocumentedintable1,Gottleibetalfoundthatafterameanof8monthsin
completeremission(SD=4months)beforediscontinuationofmethotrexate,relapseoccurred
in52%atameanof11months.[58] Mostpatientsrespondwhenmethotrexateis
restarted.[58]
Insummary,methotrexateisefficaciousinJIAhoweverfurtherstudiesarerequiredto
furtheroutlinethedurationoftherapybeforediscontinuation.
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15
Author,
Year
Popn Type of
study
Number of
patientsSubjects Duration
of study
Intervention Primary outcomes m
Giannini,
1992[55]
US and
SovietUnion
Multicentre
randomisedplacebocontrolled
38x 10mg/m2
MTX37x 5mg/m2MTX39x placebo
JIA 3
joints
6 months 5mg/m2 vs
10mg/m2 vsplacebo
Joint ROM
Swollen jointsPain on joint movementPhysician global score
Woo,2000 [54]
UK andFrance
RCT doubleblindcrossover
88 Extendedoligo JIA(EOA) and
SoJIA
12 months 15mg/m2 (up to30mg/m2) vsplacebo
Joint ROMNumber active jointsPhysician global score
Parent/child global scoreESR
Cespedes-Cruz,2008[59]
Patients frommulti-centre
internationalRCT
521 PolyJIA 12 months 50 item Child HealthQuestionnaire (CHQ)
Silverman,
2005[60]
Multicentre
internationalRCT
Double blind
86 completed
16 weeks,70 entered
extensionstudy
PolyJIA
3-17 yrsold
16 week
+/-32 weekextension
MTX vs
leflunomide
ACR Pediatric 30 (30%
improvement compared wbaseline in 3 of 6 variab
included in ACR core set(swollen joints, active joiparent global assessmentphysician global assessmCHAQ, ESR)
Ruperto,
2004[53]
Multicentre
international
RCT 633 patients
screened inphase one.80 patients
deemed to benonresponders
wererandomised
Poly JIA 6 months Standard vs
higher parenteraldose of MTX (15vs 30mg/m2/week)
ACR Pedi 30 definition o
improvement
Table 1. Evidence for the efficacy of Methotrexate in JIA
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Ravelli,1999[57]
Italy Retrospectiveanalysis
80 SoJIA 37polyJIA 20oligo JIA
23
6 months 6 month clinical responsecomplete disease control,relapse, hepatotoxicity, G
toxicityAl-Sewairy,1998 [61]
SaudiArabia
Retrospectiveanalysis
18 SoJIA Mean 18months
MTX Range 2.5-15 mg/week
Joint evaluationFever, rashLAD and splenomegalySerositisESR, Hb, WCC and plts
Gottleib,1997[58]
USA Retrospectiveanalysis2 centres
25 patients inremission for amean durationof 8 months
Poly, pauciand SoJIA
Meanfollow upof patientspost
discontinu-ation was
15 months
MTX range 5.2 15.9 mg/m2/dose
Length of time to relapsecontinued remission follodiscontinuation of MTX
Huang,1996[62]
Taiwan Retrospectivechart review
26 JIA Meanfollow up3 years
Mean weeklydose MTX 10-15mg/m2
Reiff,1995[63]
USA Retrospectivechart review
21 (13/21SoJIA)
RefractoryJIA
Meanduration15.2
months
Mean weeklydose MTX 27 mg
Disease activity score baschanges in concomitant thlabs, physician global,
radiological
Ravelli,1994[64]
Italy Retrospectivechart review
19 SoJIA 6 monthstherapy
MTX dose range7.5-11
mg/m2/week
Response defined as 50reduction in number of jo
active arthritis
Harel,1993[65] USA 23 (5 SoJIA) 17/23responders6/23 nonresponders
Median 2.5yrs MTX 7.5-10mg/m2 Assessed radiological proon serial wrist XR
Wallace,1993[66]
USA 49 PolyJRA(16/49SoJIA)
At least 1year
MTX 15mg/m2
Table 1. Evidence for the efficacy of Methotrexate in JIA
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4.1.3EfficacyofmethotrexateinJuvenileDermatomyositis
Methotrexateisthemostfrequentlyusedoftheimmunosuppressiveagentsdescribedinthe
treatmentofJDM.ArecentsurveyofPaediatricRheumatologistsdemonstratedconsiderable
variationinthemanagementofJDM.[34]Thisvariancereflectsthelackofdataavailableon
whichtobasetreatment.Morerecentlythreeconsensusprotocolsweredevelopedata
consensusmeetinginTorontoinvolving12PaediatricRheumatologists.Eachofthese
protocolsinvolvedtheuseofcorticosteroidsandmethotrexate.[67]
Methotrexatehasnotbeensubjectedtoaprospectiverandomisedcontrolledtrialand
thereforeevidenceforitsuseisderivedfromobservationalstudiesonly.In2005Ramananet
aldemonstratedinaninceptioncohortstudytheeffectivenessofmethotrexate.Thirtyone
patientswithJDMwerecommencedmethotrexateasfirstlinetherapyatameandoseof
15mg/m2andtheirsteroidsaggressivelytapered.Thesepatientswerecomparedto22
historicalcontrolstreatedwithprednisolonealone.Patientsinthestudygroupwerefound
tohaveashortertimetodiscontinuationofcorticosteroidsandalsoreducedcumulative
dose.[68]However,thisstudyfailedtodemonstratewhetheraggressivetaperofsteroids
alonewithouttheadditionofmethotrexatehadasimilaroutcome.Improvedoutcomewith
theearlyinitiationofprednisoloneandmethotrexatewasalsodemonstratedbyAlMayoub
etalinasmallseriesofpatientswithJDMandassociatedcutaneousulcerationand/or
dysphagia.[69]Inaretrospectivechartreview,initiationofmethotrexateinpatientswho
hadfailedtorespondtosteroidtherapywithin6weekswasthoughttobebeneficialin
reducingtheoverallriskoflongtermcomplicationsincludingcalcinosis.[31]
Thereiscurrentlyaninternationalmulticentreprospectivelyrandomisedtrialcoordinated
byPRINTO(PaediatricRheumatologyInternationalTrialsOrganisation)whichis
comparingprednisolonealonewithprednisolone/methotrexatecombinationand
prednisolone/cyclosporinecombinationinpatientsnewlydiagnosedwithJDM.Theresults
ofthistrialareeagerlyawaitedinordertoguidethemanagementofJDM.
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Author/
Year
Popn Typeof
study
Number
of
patients
Subjects Durationof
study
Groups/Intervention O
Ramanan,2005[68]
Singlecentre,
Canad
a
Prospectivecohort
study
with
historical
controls
53 31patientsprospectively
studiedwith22
controls
Controlpatients
followedfor4
years;study
patients
followedfor
average34.6
months
2groups.Studygroup:MTX1020mg/m2/week
(max25mg/week)and
prednisolone2mg/kg/d
(max75mg)withpred
aggressivelytaperedevery
2weeks
Timstero
dose
Dise
mus
calc
Al
Mayouf,
2000[69]
Saudi
Arabia
Prospective
cohort
study
12newly
diagnosed
JDM.
Patientswith
dysphagia,
dysphonia,GI
bleeding,cutaneousulcerationorresp
muscleinvolvement
werestartedMTX
early
Meanduration
oftherapywas
23.5months
2groups:early(
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4.1.4EfficacyofmethotrexateinUveitis
Methotrexatehasbeenusedinchildrenwithuveitisformanyyears.Itsuseissupportedby
evidencelargelyfromretrospectivecohortstudies.
Aretrospectivechartreviewfoundmethotrexatetobeaneffectiveagentinthetreatmentof
uveitis.[71]Twentyfivepatientswithuveitisreceivedmethotrexate(meandoseof
15.6mg/m2)andremissionwasachievedafterameanof4.25months.Sixpatientshad
methotrexateceasedafterremissionfor12months andofthese4patientswerestillin
remissionafter7.5months.Othercaseserieshavedemonstratedtheeffectivenessof
methotrexateinuveitisresistanttotopicalcorticosteroids.[72,73]
4.1.4 DoseandadministrationinJIAandJDM
Methotrexateisadministeredweekly.Although,aspreviouslymentioned,theserumeliminationhalflifeofmethotrexateis67hoursitsmetabolitescanbemeasured
intracellularlyover1week.Methotrexatecanbeadministeredorallyorparenterally.The
standardguidelineformethotrexateuseisaninitialdoseof10mg/m2/weekgradingupto
15mg/m2/week.[2]Oralmethotrexateshouldbegivenonanemptystomachasfood
decreasesitsbioavailability.Rupertoetaldemonstratedthattherewasnoadditionalbenefit
ofparenteraldosesabove15mg/m2.[53]Parenteraladministrationisrecommendedfor
doses>15mg/m2/weekbecauseofbetterbioavailabilityandgastrointestinaltolerability.
Parenteraldosingshouldalsobeconsideredinthosechildrenwhohaveapoorresponseto
oralmethotrexateorwherepoorcomplianceimpactsondiseasecontrol.[2]Thereisno
differenceinthebioavailabilityofsubcutaneousandintramusculartherapy.[74]
4.1.5 Druginteractionandfolatesupplementation
Anumberofmedicationsincreasethebioavailabilityofmethotrexate.Theseinclude:
phenytoin,oralcontraceptivepill,tetracycline,barbituratesandtranquilizers.Co
trimoxazoleshouldbeavoidedwithmethotrexateasitcancauseseverebonemarrow
suppressionandskinulcerations.Inadditionanumberofmedications,includingpenicillins
andcyclosporine,canlowertheeliminationofmethotrexatebydecreasingrenalclearance.
Methotrexateiscontraindicatedinrenalfailure.
Thereisgoodevidencetosupporttheuseoffolicacidsupplementationtoalleviatethe
commongastrointestinalandoralmucosalsideeffectsassociatedwithmethotrexatewithout
impactingonthebeneficialantiinflammatoryeffects.[75]
TheuseofmethotrexateissafeincombinationwithNSAIDSandcorticosteroids.Thereis
someexperienceofcombinedDMARDshowevercontrolledsystematicstudiesarelacking
tosupportthisstrategyinthetreatmentofJIA.
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20
Author,
Year
Typeof
studyDuration
ofstudy
Subjects
and
numbers
Drugand
monitoring
Hepatotoxicity Haematological
abnormality
G
Ortiz
Alvarez,
2004[76]
Pro
spective
study
89JIA MTX
Monthly
bloodtests
14%patienthadsignificantly
elevatedLFTs(>2xULN)
52%hadmildelevatedliver
functests
26%patientshad
abnormalFBE(low
granulocyteor
lymphocytecountor
Hb)
95%ofpatientswith
abnhadviralinfection
atthetimeofblood
test.
Lahdenne,
2002[77]
Retro
spective
review.
Liverbx
correlated
withlab
findings
Patients
onMTX
atleast
2.4yrs
34JIA MTX(20
30mg/m2)for
duration>2.4
yrs
All24ptstreatedwithlow
doseMTXhadgradeI
Roenigkchanges.
Of10patientson>20mg/m2,
4ptsgradeIIhistologyand5
gradeI.Nofibrosisor
cirrhosis
Graham,
1992[78]
Retro
spective
review
84296
weeks
62poly
JIA
MTX(5
10mg/m2),
3monthly
bloodtests,
PFTson46
pts
Transientliverfunctionabn
occurredin9/62(14%)
12patientshadliverbiopsy
nofibrosisorcirrhosis
Macrocyticanaemiain
onepatientonco
trimoxazole
NocasesonTPor
neutropenia
Nau
occ
14/6
Pep
4/62
also
con
NSA
Giannini,
1992[55]
US/Soviet
Multi
centreRCT
6months 89JIA3
joints
MTX5or10
mg/m2
OnepatienthadLFTabn 8pa
GIu
Woo,
2000[54]
DBRCT
crossover12
months
88
EOAJIA
andSoJIA
15mg/m2(up
to30)vs
placebo
Total20patientsonMTX
hadASTabnvs16placebo
patients
Bonemarrowfailure
didnotoccur
Nau
ups
ins
num
pat
Table 3. Adverse Effects of Methotrexate
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21
Author,
Year
Typeof
studyDuration
ofstudy
Subjects
and
numbers
Drugand
monitoring
Hepatotoxicity Haematological
abnormality
G
Hashkes,
1999[79]
Liver
biopsies
compared
withRFfor
hepatotox
25
patients,
33
biopsies
2biopsiesshowedgradeIIIa
Roenigkchanges
4showedgradeIIchanges
and27gradeI.
Nosignificantfibrosis
Hashkes,
1997[80]
Liver
biopsies
compared
withRFfor
hepatotox
14JIA 13/14gradeIRoenigk
changes
1/14gradeIIchanges
Nobxwithsignificant
fibrosis.
13/14LFTabnbutonly5had
>3xULN
Kugathasan,
1996[81]
Liver
biopsies>3years
ofMTX
9JIA 10mg/m2/wk Noclinicalorbiochemical
evidenceofliverinjury
Allbiopsieswerenormal
Table 3. Adverse Effects of Methotrexate
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4.1.6 Safety
Methotrexateisgenerallywelltoleratedinchildren,however,ithasanumberofpotentially
seriousadverseeffects.Themostcommonsideeffectisnauseaandvomitingforwhichfolic
acidhasbeenreportedtobebeneficial.[75]Mostoftheothersideeffectsaremildand
reversible.Oralulceration,alopecia,moodchanges,rash,pepticulcerandheadachehave
beenreportedtooccur.Table3summarisesreportedadverseeffectsofmethotrexate.
Hepatictoxicityisoneofthemainpotentiallyseriousadversereactionswithmethotrexate
use.Theexactmechanismisnotclearlyunderstood.[82]Childrenarethoughttohavea
reducedriskofmethotrexateassociatedhepatotoxicitycomparedwithadultsasthey
generallyhavefewercoexistingdiseasesandfewerenvironmentalexposuressuchas
alcohol.Acutemildliverfunctionabnormalitiesoccurinapproximately9%ofchildrenon
lowdosetherapy.[83]Thesechangesareusuallytransientandimprovewithaperiodof
cessation.Itisdifficulttoassessthetrueeffectofmethotrexateasitisoftenusedin
combinationwithNSAIDswhichmaycontributetoatransaminaserise.
Thepotentialforlongtermliverdamagewithfibrosisandcirrhosishasraisedconcernsin
thepasthoweverthereareonlyafewreportsoffibrosisinchildrenandnoreportsof
cirrhosissecondarytomethotrexate.Refertotable2forsummaryofseriesaddressingliver
fibrosisandcirrhosis.
Haematologicalabnormalitiesarerarewiththeuseofmethotrexate.Themaintoxiceffects
describedinclude:macrocyticanaemia,leukopenia,thrombocytopeniaandpancytopenia.[2]
OnlycasereportsofchildrenwithhaematologicalsideeffectsofMTXexist,however,the
adultliteraturereportsafrequencyof13%.[84]Inpatientswithmildbonemarrow
suppression,spontaneousrecoveryisusualwithin2weeks.[2] Malignancydueto
methotrexateremainsanareaofcontroversy.Therehavebeenafewcasesdescribedin
childrenwithJIAonmethotrexateofHodgkinsandNonHodgkinslymphoma.[85,86]
Methotrexatehasbeenreportedtohavecausedfoetaldeathandcongenitalabnormalities
andthereforeitsuseisnotrecommendedforuseinpregnancy.Itissuggestedthat
pregnancyisavoidedforaminimumof3monthsaftercompletionoftherapyinmale
patientsandforatleastoneovulatorycycleinfemalepatients.
4.1.7Monitoring
and
supervision
ChildrenwithJIAonlongtermmethotrexaterequireregularclinicalandlaboratory
monitoringbothfortheresponsetothemedicationandforitspotentialtoxicities.
HashkesetalexaminedliverbiopsiesinchildrenwithJIAonmethotrexateandfounda
relationshipbetweenbiochemicalliverfunctionchangesandhistopathologicalchanges
consistentwithmildfibrosis.[79]Whilstthedegreeoffibrosisinthisserieswasnot
consideredsignificant,thepotentialhepatotoxiceffectsofmethotrexatehavepromptedthe
introductionofguidelinesforthemonitoringoflivertoxicityinpatientstakingmethotrexate.
Theseguidelinesweredevelopedin1994andrepresentanexpertconsensusonthe
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monitoringoflivertoxicitywithmethotrexateuseinadultRheumatoidArthritis.Although
developedbasedonadultdata,theseguidelinesformthebasisformonitoringofchildren
withJIAonmethotrexate.[87]
Itisgenerallyrecommendedthatliverfunction,renalfunctionandfullbloodexaminationbe
performedatbaselineforallpatients.MonitoringofLFTs48weeklywasrecommendedby
Kremeretalintheinitialguidelinespublishedin1994.[87]Sincethen,OrtizAlvarezetal
monitored89patientswithJIAprospectivelyandfoundthatLFTabnormalitieswereusually
mildandresolvedspontaneouslyandthatmoresevereabnormalitiessettledrapidlywith
discontinuationofmethotrexate.[76]Whentherearenoothercoexistingriskfactors,3
monthlymonitoringfollowinginitialbimonthlyforafewmonthsseemstobeappropriate.
4.1.8 Formulary
Australianbrandname:Methoblastin:Tablets:yellowanduncoated,2.5mg(round),10mg(capsuleshaped);Injection:25mg/ml,1000mg/10ml
UKbrandname:Maxtrex:2.5mg,10mgtablets;Metoject:prefilledsyringe10mg/ml(7.5mg,
10mg,15mg,20mg,25mg)
USbrandnames:Rheumatrex:2.5mg;Trexall:tablets2.5mg,5mg,7.5mg,10mg,15mg
Canadianbrandnames:ApoMethotrexate;RatioMethotrexate
4.1.9 Summaryrecommendations
MethotrexatehasbeenshowntobeaneffectiveandsafetherapyinthetreatmentofJIA.Itis
associatedwithanumberofpotentiallyseriousadverseeffectsandthereforeitsuserequiresmonitoringwithbloodtestsandwithcloseclinicalsupervisionfromamedicalspecialist
familiarwiththepotentialrisks.Itisnotrecommendedforuseifaccesstothissupervisionis
unavailable.ItisrecommendedforinclusionontheWHOcomplementarylistofessential
medicines.
4.2Leflunomide
4.2.1MechanismofactionandPharmacology
Leflunomideisanimmunomodulatorymedicationthatinhibitspyrimidinesynthesis
throughitsinhibitionoftheenzymedihydroorotatedehydrogensase.Lymphocyte
proliferationdependsonpyrimidinesynthesisforproliferationandleflunomidetherefore
hasbothantiproliferativeandantiinflammatoryeffects.
TheactivemetaboliteisA771726towhichleflunomideisactivelyconvertedviahepatic
metabolism.A771726ishighlyproteinboundandhasahalflifeofupto18daysreachinga
steadystateafterapproximately20weeks.[88]
Thepharmacokineticsofleflunomideanditsactivemetabolitesarenotaffectedbyfoodintakeorbygender.Itisexcretedalmostequallyinurineandfaeces.Thepharmacokinetics
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oforalleflunomidewasstudiedin73paediatricpatientsaged317yearswithpolyarticular
JIA.[89]Thisanalysisdemonstratedthatpaediatricpatientswithbodyweights
40kg.[89]Theuseofaloadingdosemayincreasetoxicityinchildren.(MIMS2009)
4.2.4 Safety
Themostcommonlyreportedadverseeffectisgastrointestinalupsetwhichisreportedto
occurin17%ofpatients.Thisincludes:abdominalpain,dyspepsia,diarrhoeaandgastritis.
Othercommonsideeffectsinclude:headache,rashandalopecia.
Liverfunctionabnormalitiesarelessfrequentlyreportedthanwiththeuseofmethotrexate.
[60]Thereappearstobeaparticularriskwhenusedincombinationwithmethotrexate.[92]
InstudiesofleflunomideinadultswithRheumatoidarthritis,liverfunctionabnormalities
arereportedinapproximately5%ofpatients.Thesechangesaremildandreversible.More
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seriousliverdysfunctionisuncommonandisassociatedwithconcomitantalcohol
consumption,viralhepatitisorotherpreexistingliverdisease.
Leflunomideisteratogenicandthereforeitisrecommendedthatpatientshaveanegative
pregnancytestbeforestartingtreatmentandusereliablecontraceptionduringtherapy.
4.2.5 Druginteractions
Theenzymesinvolvedinthemetabolismofleflunomidearenotentirelyknown.Invitro
studiesindicatethatleflunomideinhibitscytochromep450andthereforecautionshouldbe
takenwhencoadministeredwithotherdrugsinvolvedincytochromep450metabolic
pathways.
4.2.6 Monitoringandsupervision
Monitoringisrecommendedwithbaselineandmonthlyfullbloodcountandliverfunctionfor6months,whichcanbereducedto68weeklyifstable.
4.2.7 FormularyBecausesafetyandefficacyinchildrenhasnotbeenclearlyestablishedwiththeexisting
evidence,mostmanufacturersdonotlistleflunomidewithpaediatricadvice.
Australianbrandnames:Arava(tablets10mg,20mg,100mg);Arabloc(tablets:10mg,
20mg)
USbrandnames:
Canadianbrandnames:
4.2.8Summaryrecommendations
Insummary,despitelimitedstudiesinthepaediatricpopulation,leflunomidehasbeen
showntobeeffectiveforthetreatmentofJIAbothasamonotherapy[60]andincombination
withmethotrexate[91].Itsuseinthetreatmentofrheumaticdiseaserequiresmonitoring
withbloodtestsandcloseclinicalsupervisiontoensurethatthepotentialsideeffectsareminimised.Itisnotrecommendedforuseifaccesstothissupervisionisunavailable.Itis
recommendedforinclusionontheWHOcomplementarylistofessentialmedicines.
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26
Author,
Year
Popn Typeof
study
Duration
ofstudy
Numberof
patients
Subjects Studygroups Primaryo
measu
Silverman,2005[60]
Multicentreinternational
DBRCT 16week+/32
week
extension
86completed16weeks
70entered
extension
study
PolyarticularJIA
317yrsold
MTXvsleflunomide PercentageofpaACRPedi30(3
improvementco
baselinein3of
includedinACR
(swollenjoints,a
count,parentglo
assessment,phy
assessment,CHA
Silverman,
2005[90]
Open
labelstudy
26weeks 27patients
Only63%patients
completed
study
Refractory
polyarticularJIA(failed
responseor
intolerantof
Methotrexate)
Leflunomideloadingdose
~100mgfollowedby10mg/day(+/ increaseto
20mg/dat8wks)
ACRPedi30
Gao,
2003[91]
China 26weeks 40patients Polyarticular
JRA
Leflunomide(loadingdose
of1mg/kg/day)D13then
0.20.4mg/d)plusMTX
(0.3mg/kgivevery2wks
untilremissionthen
0.2mg/kgweeklyorally)vs
MTXalone
Tenderandswo
parentandphys
evaluationscore
functionscore,E
SEdocumented
Table 4. Evidence for the efficacy of leflunomide in JIA
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27
Author
,
Year
Popn Type
of
study
Duration
ofstudy
Number
of
patients
Subjects Studygroups Outcomes
Van
Rossum,
1998[93]
multicent
re
DBRCT 24weeks 69 Oligoand
Polyarthriti
s
SSZ50mg/kg/d
(max2g/d)
Placebo
ACRPediatric30
(withoutfunctional
measure)
AEs
44%imp
placebo
MoreAEpatients
AEswer
Leukope
anorexia
Burgos
Vargas,
2002[94]
DBRCT 26weeks 33 ERA SSZ30
60mg/kg/d(max
2g)
Placebo
Reductioninactivejoints 46%inS
Significa
patienta
Ansell,
1991[95]
multicent
re
Pilot
study,
Uncontrolle
d
52weeks 51 JIA(oligo,
polyand
SoJIA)
SSZ40mg/kg/d
increased
incrementally
over6weeks.
Activejointcount,patient
assessment,ESR
AEs
24%goo
response
8patien
Huang,
1998[96]
Single
clinic
Retrospe
ctive
chart
review
Mean
duration
therapy
2.5yrs
36 ERAand
JIA
SSZ50mg/kg/d
(max2g)
Activejointcount, ESR
Remissionor
improvement(definedas
25%reductioninjoint
numberfortwo
consecutivevisits)
39%pat
11%pat
Nodiffe
Van
Rossum,2007[97]
multicent
re
Pro
spectivecohort
Median9
years(range7
10)
61 Patientsinitially
managedwithSSZ(32)vs
thosemanaged
withplacebo
(29)
ACRPediatric30 Effective
hasbene
Hoza,
1991[98]
DBRCT 26weeks 39 Oligoand
polyarthriti
SSZ20
30mg/kg/d
Anyimprovementin4
criteria:
48%SSZ
Chloroq
Table 5. Evidence for the efficacy of Sulfasalazine in JIA
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Author
,
Year
Popn Type
of
study
Duration
ofstudy
Number
of
patients
Subjects Studygroups Outcomes
s
Chloroquine3
4mg/kg/d
Activejoints,pain,
morningstiffness,ESR,
functionalcapacity
MoreAE
Ozdoga
n,1985[99]
414
months
18 Alltypes
JIA
ESR
JointtendernessActivejointcount
Significa
count
Table 5. Evidence for the efficacy of Sulfasalazine in JIA
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4.3Sulfasalazine
4.3.1MechanismofactionandPharmacology
Theexactmechanismofactionofsulfasalazineisnotclearlyunderstood.ItsroleinthetreatmentofJIAispossiblyduetoitsimmunoregulatoryandantiinflammatoryeffect
including,amongstotherthings:theinhibitionofprostaglandinsynthesis;inhibitionof
bacterialgrowth;inhibitionofleukotrieneformation;modulationofleucocytefunction;
inhibitionofDNAsynthesis;impairmentoffolatemetabolismandeffectsoflymphocyte
numberandfunction.
Sulfasalazineispoorlyabsorbedinthesmallintestine.Inthecolon,sulfasalazineisreduced
totwomajoractivemetabolites(5aminosalicylicacidandsulfapyridine)bycolonicflora.
Sulfapyridineisrapidlyabsorbedandmetabolisedbyacetylationintheliver.Therateofthis
processvariesbetweenindividualsandisgeneticallydetermined.
Both5aminosalicylicacidandsulfapyridinehaveanaffinityforcollagenrichtissueand
concentrateinthesynovialfluidaswellaspleuralspaces,intestinalwallandperitoneum.
4.3.2 EfficacyofSulfasalazineinJIA
TheuseofsulfasalazineinthetreatmentofJIAwasfirstreportedin1986[99],althoughit
hadbeenusedformanyyearspriortothisforthetreatmentofadultRheumatoidarthritis.
Table4summarisesthestudiesaddressingefficacyofsulfasalazineinJIAandasis
illustratedinthetable,whilsttherearefewcontrolledstudies,thereissomeevidenceto
supportitsuseinJIA.
Inarandomiseddoubleblindedplacebocontrolledtrialof69patients,VanRossumetal
foundthatsulfasalazinereducedtheoverallarticularseverityscore,globalassessmentsand
laboratoryparameters.[ref]Adverseeventsweremorefrequenthoweverthesewerefound
tobetransientandreversible.
Ozdogansstudyin1986[99]wasasmalluncontrolledtrial(n=18)whichdemonstrated
benefitsofSSZ.Elevenpatientshadanexcellentresponsewithonly3patientsshowingno
response.SimilarlyinanotheropenlabelstudybyJoosetal[100],21of41patientsachieved
remissionandsignificantimprovementwasseenin12.Inthisstudy,nochangewasseenin
onepatientandtheconditionworsenedinthree.ImundoandJacobs[100,101]observedthat
thebestresponseratewasANApositiveyounggirlswitholigoarticularJIA,andthatthe
worseresponse(indicatedbyahighfailurerate)wasinsystemicJIA.Only28%had
completeremission.Otheropenlabelstudieshaveshownthatsulfasalazineismosteffective
inboysolderthan9andadolescentswitholigoarticularJIA,raisingthequestionofitsusein
enthesitisrelatedarthritis(ERA).
Theothercontrolledstudiesincludeaplacebocontrolledrandomisedblindedstudyof
patients(n=33)withERA.[94]Burgosdemonstratednosignificantdifferenceinresponse
ratehoweversomeimprovementinphysicianandpatientglobalassessments.Hozaetalalso
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[98]demonstratednosignificantdifferencewhensulfasalazinewascomparedtochloroquine
inoligoarticularandpolyarticularJIA.
SulfasalazinedoesnothaveconsistentefficacyacrosssubtypesofJIA.Thereisabroad
experienceinopen,uncontrolledtrialswhichsuggestthebenefitofsulfasalazineinJIA,and
thisissupportedbytheaforementionedblindedcontrolledVanRossumtrial.Someopen
labeltrialsfoundanincreaseresponseinolderHLAB27positivechildrenwitholigoarticular
disease,howeverthisfindingwasnotconvincinglysupportedinasmallblindedcontrol
study.[94]Basedonbestavailableevidence,sulfasalazineismosteffectiveinpolyandoligo
articulardiseaseandtheredoesnotappeartobeadifferenceinresponseratesbetweenthese
groups.Onthecurrentevidence,sulfasalazineisnoteffectiveinthemanagementofSoJIA
and,infact,itsuseispotentiallycomplicatedbyanincreasedriskoftoxicity.
4.3.3 Doseandadministration
SulfasalazineisadministeredorallyinchildrenwithJIA.Initiationoftherapyshouldbegin
withasmalldosefollowedbyagradingupatweeklyintervals. Therecommendedstarting
doseis5mg/kgtwicedailyforoneweek,then10mg/kgtwicedailyforoneweek,then
20mg/kgtwicedailyforoneweek,thenamaintenancedoseof2025mg/kgtwicedaily.The
maximumrecommendeddoseinchildrenis2g/day.
Sulfasalazineshouldbeadministeredaftermealsorwithfoodandshouldnotbe
concurrentlytakenwithantacids.
4.3.4Safety
Intoleranceandadverseeventsarefrequentlyassociatedwithsulfasalazineadministration.
Adversereactionsfrequentlyreportedinclude:rash,gastrointestinalsymptomsand
haematologicalabnormalities.Onestudy[93]reportsadiscontinuationrateof
approximately30%.Theyfoundthat86%ofpatientsonsulfasalazinereportedatleastone
adverseeventandthisresultedin10patients(28.5%)requiringwithdrawalfromthestudy.
Onepatientwasconsideredashavingaseriousadverseeventbuttheauthorsnotedthatall
oftheadverseeventswerereversiblewithdiscontinuationoftherapy.[93]
Gastrointestinalintoleranceisthemostfrequentlyreportedsideeffect.Symptomsinclude:anorexia,nausea,abdominaldiscomfortanddiarrhoea.Liverfunctionabnormalitiesalso
occurcommonlyestimatedtooccurinapprox4%patients.Moresevere(andpotentially
fatal)hepatotoxicityhasbeenreportedinassociationwithDRESSsyndrome(DrugReaction
withEosinophiliaandSystemicSymptoms)ahypersensitivityreactionthoughtduetothe
sulfapyridinemetabolite.Featuresinclude:fever,rash,raisedliverfunctiontests,
eosinophiliaandlymphadenopathy.Corticosteroidtherapyisfrequentlyrequiredtotreat
DRESSsyndrome.
Haematologicalsideeffectssuchasleucopeniahaveanincidenceacrosstheliteratureof3%
[102].Whilstleucopeniaisreversiblewithcessationofthedrug,othermorerarebutseverehaematologicalsideeffectssuchasagranulocytosishavebeenreported.Agranulocytosisis
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saidtooccurin1%ofpatientsandusuallybeginswithin512weeksofonsetoftherapy[103]
andispotentiallyfatal.
SkinrashisalsoacommonsideeffectandoccurredinhalfofthepatientsintheVanRossum
trial[93].Sulfasalazinehasalsobeenassociatedwithotherrarercomplicationssuchasdrug
inducedlupuserythematosus.Thismayoccurafterseveralorevenyearsoftherapyand
resolvesfollowingwithdrawal.
4.3.5 Druginteraction
Sulfasalazineisgenerallywelltoleratedwithothermedications.Sulfasalazinemaydecrease
thebioavailabilityofcyclosporin.Therearealsoreportsofpossibleadditivehepatotoxicity
whenusedincombinationwithmethotrexate.Careshouldbetakenwhenprescribing
sulfasalazineasnumerousotherdruginteractionshavebeenreported.
4.3.6 Monitoringandsupervision
FullbloodcountandLiverfunctiontestsshouldbeperformedfrequentlyfollowinginitiation
ofsulfasalazine.Productinformationsuggestsbaselineteststhen2weeklyfor3months,
monthlyfor3monthsandthenmonthlythereafter.Itisrecommendedthatpatientsbe
followedupclinicallyatleast3monthlytoensureongoingtoleranceofsulfasalazine.
4.3.7 Formulary
SulfasalazineisFDAapprovedforuseinchildrenforJIApolyarticularcourse.ItisnotlicensedforuseintheUK.
Australianbrandnames:Pyralin,entericcoatedtablets:500mg;SalazopyrinandSalazopyrin
ENtabstablets:500mg
UKbrandname:SalazopyrinandSalazopyrinENtabs500mg;Salazopyrinsuspension
250mg/5mlandsuppositories500mg.
USbrandnames:Azulfidine, AzulfidineENtabs,SulfazinandSulfazinEC,500mg
Canadianbrandnames:AltiSulfasalazineandSalazopyrin
4.3.8 Summaryrecommendations
Thecurrentliteraturesuggeststhatsulfasalazinehasaroleasdiseasemodifyingtherapyin
thetreatmentofJIAandparticularlyoligoarticularandpolyarticulardisease.Itisnotthe
firstDMARDofchoiceespeciallygiventheevidencesupportingmethotrexate.The
considerationofsulfasalazineasanalternativeDMARDinJIAshouldbeunderspecialist
supervision.Sulfasalazinetherapyalsorequiresspecialistsupervisionparticularlywith
respecttothefrequentriskofadverseeffects.Inaddition,regularmonitoringwithblood
testsisrecommended.SulfasalazineisrecommendedforinclusiononthecomplimentaryWHOessentialmedicinelistprovidedtheseresourcesareavailable.
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4.4 CyclosporinA4.4.1 MechanismofactionandPharmacology
CyclosporinA(CyA)isapotentimmunomodulatoryagentusedtoinhibittheadaptiveimmuneresponseandthereforeeffectiveindiseasesknowntobeofautoimmuneorigin.Itis
usedtopreventrejectioninsolidorgantransplant. Theeffectsontheimmunesystemare
likelymultifactoral.Calcineurin,animportantproteinintheprocessofTandBcell
activation,isboundandinhibitedbyCyA. Thisresultsinimpairedproductionofanumber
ofcytokinesimportantintheproliferationofTcells.TheeffectsofCyAontheTcellappear
tobespecificandreversible.Cyclosporinmayhaveothereffectsincludingeffectsonantigen
presentation.
CyAisincompletelyabsorbedformthegastrointestinaltract.Microemulsionpreparations
arethoughttoprovideimprovedabsorptionandbioavailability.Ithasmultiplehepaticmetabolicpathwaysandismetabolisedtomanymetabolitesbeforeexcretedinthebile.Only
asmallpercentageisexcretedintheurine.Thehalflifeisapproximately18hours.
4.4.2 EfficacyofCyclosporininJIAandMAS
TheroleofcyclosporininthetreatmentofJIAhasnotbeenclearlydefined.Itmaybe
particularlyimportantinthetreatmentofSoJIAespeciallyinassociationwithMAS.As
illustratedinTable6,thereislittlestrongevidencesupportingitsefficacyandthereareno
controlledtrials.Evidenceincludesobservationalstudiesandcaseseries.
Gerlonietaldescribedagroupof34patientswithSoJIAinaprospectiveopentrial[104]in
whomtherewasbenefitincontroloffeverandinreducingsteroidexposure.Twentysix
percentofpatientswithdrewfromCyAtreatmentthoughduetoadverseevents.Inaddition,
50%withdrewduetolackofefficacyorflareofdisease.Stephanetalreportedthe
effectivenessofCyAin12patientswithreactivehaemophagocyticsyndrome.Infivepatients
CyAwasusedasfirstlinetherapyandinsevenpatientsitwasusedwhensteroidshad
failed.[105]Reiffetaldescribed22patients(17withJIAofwhich14/17hadSoJIA)and
concludedthatCyAresultedinimprovementinthemajorityofpatients.[106]Jointcount
improvedin70%patientsandinpatientswithSoJIA,feverresolvedin91%,anaemia
improvedin33%andconcomitantprednisolonetherapywasreducedin77%ofpatients,[106]supportingthehypothesisthatCyAismorebeneficialinthetreatmentofsystemic
symptoms(suchasfeverandanaemia)thanthecontrolofarthritis.Mouyetallookedata
smallgroupofpatientswithMAStreatedwithCyAanddemonstratedrapidimprovement
inallpatients.[107]
4.4.3 EfficacyofCyclosporininJDM
Thereareanumberofsmallretrospectivestudiesandcaseseriesreportingthebenefitsof
CyAinpatientswithJDM.ThesestudiesaresummarisedinTable7. SimilartoJIA,thereare
currentlynocontrolledtrialshoweverthereiscurrentlyaninternationalmulticentre
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prospectivelyrandomisedtrialcoordinatedbyPRINTO(PediatricRheumatology
InternationalTrialsOrganisation)whichiscomparingprednisolonealonewith
prednisolone/methotrexatecombinationandprednisolone/cyclosporinecombinationin
patientsnewlydiagnosedwithJDM.Theresultsofthistrialareeagerlyawaitedinorderto
guidethemanagementofJDM.
Heckmattetalstudied14patientswithJDMwhohadnotfullyrespondedtocorticosteroids
orotherimmunosuppressants(methotrexate,azathioprineorcyclophosphamide)andhada
chronicallyactivecourseaveragingthreeyears.[108]Manyofthesepatientshadserious
complicationsofthediseaseoroftheirprevioustreatment.Mostpatientsweretreatedwith
2.57.5mg/kg/d(dividedtwicedaily)andallpatientswerefoundtohaveimprovedmuscle
strengthandsteroiddosereductions.
4.4.4 Doseandadministration
Thegenerallyaccepteddoseforthemanagementofpaediatricrheumaticdiseasesis3
5mg/kg/day[2]orallyandisusuallydividedtwicedaily.Thisissimilartotherecommended
dosinginadultpatientswithrheumatoidarthritis.InonestudyofchildrenwithJDM,adose
rangingbetween2.5to7.5mg/kg/daywassufficient.[108]
4.4.5 Safety
Cyclosporinisassociatedwithpotentiallyconsiderabletoxicityandrequirescareful
monitoringandsupervision.Mostsideeffectsaredosedependentandresponsivetodose
adjustment.Cyclosporindosesaresignificantlyhigherinthetreatmentofsolidorgantransplantationcomparedtorheumatologicalindicationsandthereforetheratesofside
effectsiscomparativelyhigher.
Renalfunctionabnormalitiesandhypertensionarethemostconcerningsideeffectsand
responsibleforthemajorityofwithdrawalsoftherapy. Risesincreatinineandureaduetoa
reducedglomerularfiltrationratehavebeendemonstrated.Theexactmechanismforthisis
unclearbutthesechangesareusuallyreversible.Inoneseriesof22patientswithJIAand
JDMonCyA,[106]serumcreatininedoubledin6patientsandGFRwasreducedinoneof14
patients. Ostensenstudied14patientsonCyAandfoundmarkedriseinserumcreatininein
5patientsnecessitatingwithdrawal.[109]Thesefindingsnecessitateclosemonitoringofrenalfunction.Interstitialfibrosisandtubulardamagemayalsooccur[110]andmaybe
irreversible.Cyclosporininducedhypertensionisalsofrequentlyseeninchildrenandin
adultshasbeenestimatedtocausehypertensioninapproximately10%ofadultstreated.A
recentCochranereviewdemonstratedstatisticallysignificantincreasesinbloodpressure
withCyAinadoserelatedfashion.Theyconcludedthatprescribersshouldfindthelowest
effectivedoseinthosepatientsrequiringlongtermuse.[111]
Otherencounteredsideeffectsinclude:hypertrichosis,gingivalhyperplasia,gastrointestinal
disturbance,tremorandparesthesias,hepaticdysfunctionandbonemarrowsuppression.
Theseadverseeffectsaremostlyreversiblewithreductionorcessationoftherapy. Inone
seriesof22patients,doseslessthen3.5mg/kg/dwereunlikelytocausehepatotoxicityand
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bonemarroweffectsandthathypertension,gumhyperplasiaandhypertrichosiswerenot
observed,suggestingthatinchildrenthesesideeffectsmaybelesscommon.[106]SinceCyA
isanimmunosuppressiveagent,childrenadministeredCyAareatincreasedriskofinfection.
4.4.6 Druginteraction
Cyclosporinshouldbeusedwithcautionwhenadministeredincombinationwithother
potentiallynephrotoxicmedications.Inparticular,NSAIDsarefrequentlyusedinpaediatric
rheumaticdiseaseandmayexacerbatethetoxiceffectsofCyA.Inthissituationclose
monitoringofrenalfunctionisrecommended.ThebioavailabilityofCyAincreaseswhenthe
drugistakenwithgrapefruitjuice.
4.4.7 Monitoringandsupervision
Itisrecommendedthatbloodpressurebemonitoredatleastweeklyforthefirstmonthoftherapyandthenmonthlythereafter.[2]Inaddition,laboratorymonitoringisrequired
monthlyparticularlyscreeningforrenal,bonemarroworhepaticeffects.Doseadjustmentis
recommendedifserumcreatinineincreasesby>30%.
TheneedformonitoringofCyAlevelsinnontransplantpatientsisunclear.Itisgenerally
recommendedthatwholebloodtroughlevelsbemaintainedbetween125and175g/ml.[2]
Monitoringmaybeparticularlyimportantinpatientswithunexpectedtoxicity.
4.4.8 FormularyAustralianBrandnames:Neoral(caps10,25,50and100mg,solution100mg/ml),
Sandimmun;Cicloral(caps25,50and100mg)
U.S.BrandNames:Gengraf(caps25and100mg,solution100mg/ml);Neoralcaps25and
100mg,solution100mg/ml);Sandimmunecaps25and100mg,solution100mg/ml)
CanadianBrandNames:ApoCyclosporine;Neoral;Rhoxalcyclosporine;Sandimmune
I.V.;SandozCyclosporine
4.4.9Summary
recommendations
Cyclosporinhasaroleinthemanagementofpaediatricrheumaticdisease.Several
observationalstudiesprovideevidenceforitsefficacyintreatingJIAandinparticularSoJIA
andassociatedMASandalsointhetreatmentofJDM.Cyclosporinisapotent
immunosuppressiveagentandisassociatedwithanumberofpotentiallyseriousadverse
effects.Theadministrationofcyclosporinshouldbeunderspecialistsupervisionwiththe
facilitytofrequentlymonitorwithbloodtests.ItisrecommendedfortheWHOessential
medicinescomplimentarylist.
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Author/
Year
Popn Typeof
study
Number
of
patients
Subjects Durationof
study
Intervention Outcomesme
Reiff,
1997[106]
US Retrospectiv
eobservationa
l
22 17JRA,5JDM Meanperiod
16months(642months)
AllpatientsreceivedCyA
meandose3.2mg/kg/d.Mostpatientsreceived
concomitantCSand
16/22patientsreceived
concomitantMTX.
Labvariables;joint
jointswelling;morstiffnessinpatients
Muscleweaknessa
enzymelevelsinJD
Pistoia,
1993[112]
Italy Caseseries 12 9patientswith
JCA(7SoJIA,2
poly);3patients
withJDM
CyAgivenfor
948months
AllpatientsreceivedCyA
atmeandose5mg/kg/day
afterfailureofCStherapy
Clinicalandlabora
measuresofdiseas
Heckmatt,
1989[108]
UK Caseseries 14 14patientswithJDMnot
respondedfullytoCSandother
immuno
suppressantswith
chronicallyactive
diseaseavg3yrs
Average12
months
therapytotimeof
publication(5
28months)
CyAstartingat2.5
mg/kg/ddividedbdand
increasedaccordingtoclinicalresponse.Max
12mg/kg/d
Muscleweakness,
rash,serumCK,
MonitoringofSEicBP,serumcreatinin
levels.
Zeller,
1996[113]
Retrospectiv
ecasereview6 Patientswith
refractoryJDM
Meanfollow
up51.5
months
CyA Clinicalmarkersof
MedicationSE,Ste
Table 7. Evidence for the efficacy of Cyclosporin in JDM
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4.5 Azathioprine
4.5.1 MechanismofactionandPharmacology
Azathioprineisapurineanaloguemetabolisedinthelivertoitsactivemetabolite6mercaptopurine(6MP).6MPisthenfurthermetabolisedviathreemajorpathways,the
metabolitesofwhichinhibitDNAsynthesisthroughthesuppressionofguanineandadenine
synthesis.AzathioprineinhibitscellmediatedimmunitythroughinhibitionofTcellgrowth
andresultsinreducedantibodyproduction.
Thebioavailabilityofazathioprineisapproximately50%.[114]Itisrapidlymetabolisedin
theliveranditsmetabolite,6MP,hasahalflifeof0.73hours.Smallamountsare
eliminatedasunchangeddrugandmetabolitesarepredominantlyrenallyexcreted.
4.5.2Efficacy
of
Azathioprine
in
SLE
AzathioprinehasbeenusedforthemanagementofSLEinchildrenfordecades.Despitethis
longexperience,therearenocontrolledtrialsaddressingitsefficacyinpaediatriclupusand
thereforeitsuseremainscontroversial.
AzathioprineisusedinavarietyofclinicalcircumstancesinSLEbutmostfrequentlyin
combinationwithcorticosteroids.Theadditionofazathioprineassecondlinetherapymay
beindicatedtopermitsteroiddosereductioninpatientsrequiringunacceptablyhighdoses
ofcorticosteroids.[2]Inadultpatientsthiswasfoundtobeassociatedwithfewer
hospitalisations.[115]
Theroleofazathioprineinthemanagementofpaediatriclupuscomplicatedbynephritisis
evenlesswelldefined.Thereisconflictingevidenceintheadultliteratureaboutitsusein
thiscontext.Somestudiesareinfavourofitsuse.Aretrospectivecohortstudyof26adult
patientswithSLEandassociatedproliferativelupusnephritisweremanagedlongtermwith
prednisoloneandazathioprine.[116]Thisstudyconcludedthatazathioprinewaswell
toleratedandthat510yearsurvivalratesweresimilartothoseofcyclophosphamidebased
therapies.[116]Oneoutcomestudyofchildrenwithlupusnephritisconcludedthatlong
termoutcomewasexcellentwith94%survivalatmeanfollowupof11years.Inthisgroupof
patients,azathioprinewasthemostfrequentlyprescribedagent.[117]
AlthoughthereislimitedevidencefortheefficacyofazathioprineinSLEandinparticular
paediatricSLE,manyrheumatologistsacknowledgethatitdoeshavearoleintherapy.In
particular,itisusedtocontrolserologicdiseaseflares,allowreductionofsteroiddosesand
maintaindiseasecourseafterparenteralcyclophosphamide.[45]
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4.5.3 EfficacyofAzathioprineinJIA
Theevidencefortheefficacyofazathioprineisbasedoncaseseries,casereportsand
uncontrolledtrials.Todatethereisonlyonerandomiseddoubleblindplacebocontrolled
trialaddressing
the
efficacy
of
azathioprine
in
the
treatment
of
32
JIA
[118]
Statistically
significantimprovementwasonlyseenintwodiseaseactivitymeasurementsanditis
thereforenotconsideredtohavegreaterefficacythanplacebo.Itisnotusedroutinelyinthe
treatmentofJIA.Seetable8fordetailsofstudies.
Anuncontrolledprospectivetrialinvolving129patientswithrefractoryJCAdemonstrated
improvementinbothclinicalandlaboratoryoutcomeswithacceptablesideeffectprofile.
[119]Afurtherretrospectivestudyof24patientsdemonstratedclinicalimprovementin
62.5%ofpatientsandremissionin37.5%.[120]Whilstthestrengthofthisevidenceisnotas
compellingasthatofotherDMARDsusedinthetreatmentofJIA,thesestudiessuggestthat
theremaybearoleofazathioprineinJIA.
4.5.4 Doseandadministration
Azathioprineshouldbestartedat11.5mg/kg/dayincreasingtoamaximumdoseof2
2.5mg/kg/day.Itisgenerallyconsideredthataminimumof12weeksisrequiredtoachieve
adequatetherapeuticresponse.Azathioprineshouldbeadministeredwithfoodtoreduce
gastrointestinaldisturbance.
4.5.5 Safety
Gastrointestinalsideeffectsmanifestingasnausea,vomiting,diarrhoeaandepigastricpain
arecommonwithazathioprine.Thesesideeffectscanbediminishedifthedosedividedorif
administeredwithmeals.Upto12%ofpatientsexperiencethesesymptomsandinone
study10%ofadultpatientswithrheumatoidarthritiswithdrewfromtherapydueto
gastrointestinalintolerance.[121]
Otherlessfrequentlyobservedsideeffectsinclude:pancreatitis,livertoxicity(abnormalliver
functiontests),interstitialpneumonitisandrash.Itisdifficulttoestimatetheincidenceof
thesesideeffectsinthepaediatricrheumaticdiseasepopulationasstudiesoftheuseand
safetyofazathioprinearefrequentlyintheadultpopulationandinconditionsotherthanrheumaticdiseases.
Dosedependenteffectsonthebonemarrowhavealsobeenwelldescribedinassociation
withazathioprinecausinggranulocytearrestandleukopeniaand,lessfrequently,anaemia
andthrombocytopenia.Thisisthoughttobeduetoreducedactivityofthiopurine
methyltransferase(TPMT).TMPTactivityisloworabsentin0.3%ofthepopulationand
causesthesehaematologicaleffectsshortlyafterinitiationoftherapy.LowerTMPTactivity
hasbeenobservedinAfricanAmericanindividualscomparedtoCaucasianAmericans.
[122]DistinctTMPTmutationshavebeenidentifiedandaredetectableonPCRbased
technique.
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4.5.6 Druginteraction
Anumberofmedications,usedconcomitantly,havebeenreportedtoenhancethe
myelosuppressiveeffectofazathioprineincludingtrimethoprim. 5ASAderivativesmay
decreasethe
metabolism
of
thiopurine
analogs.
The
toxic
effects
of
leflunomide
may
also
be
enhancedwhenusedwithazathioprineandrequiremorestringentmonitoringofbone
marrowtoxicity.Azathioprinemayalsodecreaseplasmacyclosporinlevels.
4.5.7 Monitoringandsupervision
Toxicitymonitoringshouldoccurthroughouttreatment. Itisgenerallyrecommendedthat
clinicalevaluationoccurat12monthsthen3monthlythereafterorearlierifdiseaseseverity
warrants.Laboratorymonitoringshouldinclude:weeklyFBEwithdifferentialuntilstable
thenmonthlythereafterandmonthlyLFTsandUEC.[2]AnalysisofTMPTgenotypeshould
beconsideredforpatientswhodevelopsevereleukopeniaonazathioprine.
Azathioprineshouldbeceasedifthereissignificantleukopenia,thrombocytopeniaor
elevatedliverenzymes.
4.5.8 Formulary
Australianbrandname:Imuran(tablets25mg,50mg,powderforreconstitution50mg)
UKbrandnames:Imuran(tablets25mg,50mg,powderforreconstitution50mg)
USbrandnames:Imuran(tablets25mg,50mg,powderforreconstitution50mg);Azasan
Canadianbrandnames:AltiAzathioprine;ApoAzathioprine;GenAzathioprine;Imuran;MylanAzathioprine;NovoAzathioprine
4.5.9 Summaryrecommendations
AzathioprineappearstohavearoleinthemanagementofbothpaediatricSLEandJIA
althoughconclusivestrongevidencewithRCTsislacking.Azathioprineisassociatedwith
potentiallyserioussideeffectsinparticularrelatingtobonemarrowsuppression.
Administrationofazathioprineshouldbeunderthesupervisionofspecialistcarewithaccess
toappropriateclinicalandlaboratorymonitoring.Azathioprineisrecommendedfor
inclusiononthecomplementaryWHOessentialmedicineslist.
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40
Author/
Year
Typeof
study
Number
of
patients
Subjects Durationof
study
Intervention Outcomesmeasu
Kvien,
1986[118]
RDBPCT 32 JIAalltypes 16weeks AZA22.5mg/kg/d
Vsplacebo
Laboratory(ESR,FBE)
Numberofclinicalmeaincludingactivejointc
functionalcapacity,
physiciansoverall
assessment
Savolaine
n
1997[119]
Uncontrolled 129 RefractoryJCA Median
treatment13
months,
Lin,
2000[120]
Retrospectiv
echart
review
24 JRAtreatedpreviouslywith
azathioprine
Meanduration
treatment13
months,meanfollowup45
months
AZA(avgmaxdose
1.9mg/kg/d)
12patientsreceivedDMARDspriortostartof
AZA
Table 8. Evidence for the efficacy of Azathioprine in JIA
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4.6 Hydroxychloroquine
4.6.1 MechanismofactionandPharmacology
Hydroxychloroquineisanantimalarialagentusedinthetreatmentofrheumaticdisease.HydroxychloroquineinhibitsthesynthesisofDNA,RNAandproteinbyinteractingwith
nucleicacid.Itsimmunosuppressiveeffectisviaanumberofmechanismsincluding:
alterationinlysosomalpHandinterferenceinantigenprocessing; stabilizationoflysosomal
membranes;inhibitionofantigenantibodyreactions;suppressionoflymphocyteresponse
andinhibitionofneutrophilchemotaxis.[2]
Hydroxychloroquineisrapidlyabsorbedfromtheintestinewithanoralbioavailabilityof
74%.[123]Thehalflifeis40days,steadystateisreachedin2to6monthsanditisprimarily
renallyexcreted.[123]
4.6.2 EfficacyofHydroxychloroquineinJIA
HydroxychloroquinehasnotbeenconvincinglyshowntobeeffectiveinthetreatmentofJIA.
Thereisoneplacebocontrolledtrialaddressingtheefficacyofhydroxychloroquineinthe
treatmentofJIA.[124]Thisrandomiseddoubleblindedtrialof162patientswith
polyarticularJIAcomparedhydroxychloroquinewithpenicillamineorplacebo.Therewas
nosignificantdifferencebetweengroups.
Kvienetaldemonstratedinanopenrandomisedtrial(notplacebocontrolled)of72patients
witholigoandpolyarticularJIA,thathydroxychloroquinewasnotmoreefficaciousthangoldorpenicillamine.[125]Interestingly,ametaanalysisin2000ofallRCTsandCCTs
comparinghydroxychloroquinetoplaceboinadultpatientswithrheumatoidarthritis
revealedanoverallmoderateeffectandwithalowtoxicityprofile.[126]
4.6.3 EfficacyofHydroxychloroquineinpaediatricSLE
Hydroxychloroquineisfrequentlyusedasanadjuncttosteroidtherapyattheonsetof
treatmentofjuvenileSLE.However,therearenotrialsaddressingtheeffectivenessof
hydroxychloroquineinthepaediatricpopulation.Evidenceforitsefficacywasdemonstrated
inarandomised,doubleblinded,placebocontrolledwithdrawaltrialbytheCanadian
HydroxychloroquineStudyGroup.[127]Patientsassignedtotheplacebogrouphada
significantlyhigherrelativeriskofflareandthatthetimetoflarewasshortercomparedto
thosepatientswhocontinuedHCQ.
TherehavesincebeenmanyotherstudiessupportingitsuseinSLE.Recentsystematic
reviewdemonstratedhighlevelsofevidencethathydroxychloroquinepreventsSLEflaresan
increaseslongtermsurvival.[128]Therewasmoderateevidenceofprotectionagainst
irreversibleorgandamage,thrombosisandbonemassloss.[128] Recommendationsarethat
hydroxychloroquineshouldbecommencedinmostpatientsandcontinuedthroughoutthe
courseofthedisease.
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4.6.4 Doseandadministration
Theusualdoseofhydroxychloroquineinchildrenis35mg/kgkg/daydivided12timesper
daywithamaximumof400mgperday.Itshouldbeadministeredwithfoodtoreducethe
occurrenceof
gastrointestinal
intolerance.
4.6.5 Safety
Hydroxychloroquineisgenerallyconsideredtobeaverysafemedication.Thefrequencyand
severityofadverseeffectsislowevenafterprolongeduse.Thereisalargeamountof
supportingevidenceforthisintheadultliterature.[128]
Gastrointestinaldisturbanceoccursinapproximately10%ofadultpatients.Itisconsidered
lesscommoninchildren.Centralnervoussystemsideeffectsarecommonandinclude:
headache,lightheadedness,insomnia,nervousness,nightmaresandconfusion.
Themostconcerningsideeffectisoculartoxicity.Thisoccursrarelybutcancauseblindness.
Retinaltoxicityisthoughtnottooccurinadultsifthedoseremainslessthan
6.5mg/kg/day.[129]Protocolsandpracticesvaryworldwide,howeveritisgenerally
recommendedthatophthalmologicalexaminationsareperformedyearly.Localprotocols
shouldbeestablishedbetweentheprescribingphysicianandthetreatingophthalmologist.
Retinalabnormalitiesshouldpromptimmediatecessationofthemedication.
Hydroxychloroquineisconsideredsafeinpregnancyandbreastfeeding.
4.6.6 Druginteraction
HydroxychloroquinelevelsmaybedecreasedbyEchinacea.Inadditionthereareanumber
ofmedicationsthatshouldbeavoidedormonitoredcarefullyorincreasedordecreased
effectwhenusedconcomitantlywithhydroxychloroquine.Theseinclude:betablockers,anti
psychoticsandothers.
4.6.7 Monitoringandsupervision
Whilsthydroxychloroquineisasafemedication,itdoesneedregularmonitoring.Fullblood
examinationissuggestedonaregularbasisandophthalmologyexaminationshouldoccuratleastyearly.
4.6.8 Formulary
HydroxychloroquineisnotFDAapprovedfortheuseinpaediatricSLE.IntheUK
hydroxychloroquineislicensedforuseinJIA,SLEanddiscoidLEandotherdermatological
conditionscausedbyoraggravatedbythesun.
Australianbrandnames:Plaquenil(200mgtablets)
UKbrandnames:Plaquenil(200mgtablets)
USbrandnames: Plaquenil
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Canadianbrandnames:ApoHydroxyquine;GenHydroxychloroquine;Plaquenil;Pro
Hydroxyquine
4.6.9 Summaryrecommendations
Hydroxychloroquineappearstobeasafeandeffectivetreatmentinthemanagementof
juvenileSLE.IthasnoprovenroleinthemanagementofJIA.Hydroxychloroquineis
recommendedfortheuseinjuvenileSLEprovidedpatientshaveaccesstospecialistcare
includingophthalmologicalandlaboratoryassessments.Itisrecommendedforinclusionon
theWHOessentialmedicinescomplementarylist.
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