w w w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Brief
communication
Leflunomide
in
Takayasu
arteritis
–
A
long
term
observational
study
Alexandre
Wagner
Silva
de
Souza
∗,
Renan
de
Almeida
Agustinelli,
Hemerli
de
Cinque
Almeida,
Patrícia
Bermudes
Oliveira,
Frederico
Augusto
Gurgel
Pinheiro,
Ana
Cecilia
Diniz
Oliveira,
Emilia
Inoue
Sato
RheumatologyDivision,EscolaPaulistadeMedicina,UniversidadeFederaldeSãoPaulo,SãoPaulo,SP,Brazil
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o
Articlehistory:
Received18June2015 Accepted25September2015 Availableonline2March2016
Keywords:
Systemicvasculitis Takayasuarteritis Leflunomide Therapy
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t
Objective:Toevaluatetheextendedfollow-updataonefficacyandtoxicityofleflunomide therapyinTakayasuarteritis(TA)patientspreviouslyenrolledintheoriginalopen-label studyofshort-termeffectsofleflunomideinTA.
Methods:Anopen-labellong-termlongitudinalstudywasperformedinTApatientswho fulfilledthe1990AmericanCollegeofRheumatologycriteriaforTAandhadparticipatedin apreviousstudythatevaluatedshort-termefficacyofleflunomideinTA.Complete follow-upinformationcouldberetrievedfrom12outof15patientsenrolledintheoriginalstudy. DiseaseactivitywasevaluatedbyKerr’scriteriaandbytheIndianTakayasuActivityScore 2010(ITAS2010).
Results:Themeanfollowuptimewas43.0±7.6monthsand5(41.6%)TApatientsremained onleflunomidetherapywhile7(58.3%)TApatientshadtochangetoanothertherapydueto failuretopreventrelapsesin6patientsandtoxicityinonepatient.Nosignificantdifferences werefoundbetweenpatientswhoremainedonleflunomidetherapyandthosewhochanged toanotheragentregardingageatstudyentry,timesincediagnosis,prednisonedailydoseat studyentry,baselineITAS2010,meanormaximumESRandCRP,andcumulativeprednisone doseatstudyend.AmongTApatientswhohadchangedleflunomidetoanotheragent,two hadanadditionalclinicalrelapseandneededtochangetherapy.
Conclusion: Leflunomideledtosustainedremissioninapproximatelyhalfofpatientsata meantimeof12monthsandwaswelltoleratedbyTApatients.
©2016ElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mail:[email protected](A.W.S.deSouza). http://dx.doi.org/10.1016/j.rbre.2016.02.003
Leflunomida
na
arterite
de
Takayasu
–
Estudo
observacional
de
longo
prazo
Palavras-chave:
Vasculitessistêmicas ArteritedeTakayasu Leflunomida Tratamento
r
e
s
u
m
o
Objetivo: Avaliarosdadosdeseguimentoemlongoprazoemrelac¸ãoàeficáciaetoxicidade dotratamentocomleflunomidaempacientescomarteritedeTakayasu(AT)previamente recrutadosnoestudoabertooriginaldosefeitosdecurtoprazodaleflunomidanaAT.
Métodos: Fez-se um estudo longitudinal aberto de longo prazo com pacientes que preencheramoscritériosparaATdaAmericanCollegeofRheumatologyde1990eque par-ticiparamdeumestudoanteriorqueavaliouaeficáciaemcurtoprazodaleflunomidana AT.Obtiveram-seinformac¸õescompletasdeseguimentode12dos15pacientesincluídos noestudooriginal.Aatividadedadoenc¸afoiavaliadapeloscritériosdeKerrepeloIndian TakayasuActivityScore2010(ITAS2010).
Resultados: Otempomédiodeseguimentofoide43,0±7,6meses.Cinco(41,6%)pacientes comATpermaneceramemtratamentocomleflunomida,enquantosete(58,3%)tiveramde mudarparaoutrotratamentoemrazãodafalhaemprevenirrecidivasemseispacientes etoxicidade emumpaciente.Nãoforamencontradasdiferenc¸assignificativasentreos pacientesquecontinuaramotratamentocomleflunomidaeaquelesquemudarampara outroagenteemrelac¸ãoàidadenoiníciodoestudo,tempodesdeodiagnóstico,dosediária deprednisonanoiníciodoestudo,ITAS2010inicial,valormédiooumáximodeVHSePCR,e dosedeprednisonacumulativanofimdoestudo.EntreospacientescomATquemudaram deleflunomidaparaoutroagente,doistiveramnovarecidivaclínicaeprecisarammudarde tratamento.
Conclusão: Aleflunomidalevouàremissãosustentadaemaproximadamentemetadedos pacientesporumperíodomédiode12mesesefoibemtoleradapelospacientescomAT.
©2016ElsevierEditoraLtda.Este ´eumartigoOpenAccesssobalicenc¸adeCC BY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Takayasuarteritis(TA)isalargevesselvasculitisthatis char-acterizedbygranulomatousinflammationinvolvingtheaorta, itsmainbranchesandpulmonaryarteries.1TAaffectsmore frequentlyfemalesandtheonsetofsymptomsusuallyoccurs duringthesecondand thirddecadesoflife.AlthoughTAis describedinallethnicgroups,itismoreprevalentinAsians.2 The assessment of disease activity in TA is usually prob-lematic,becausearterialinflammationmayprogresstofixed vascularinjuryevenintheabsenceofovertsignsand symp-tomsofdiseaseactivity.3,4
In patients with active disease, medical therapy of TA includeshigh doseprednisone (0.5–1mg/kg/day)or equiva-lentasthefirstline.However,relapsesoccurinupto50%of TApatientsduringcorticosteroidtaperingandthus immuno-suppressiveagentsareusuallyaddedtocorticosteroidtherapy inorder to halt disease progressionand to spare corticos-teroiduse.1,5 Conventionalimmunosuppressiveagentsused totreatTAincludemethotrexate,azathioprine, mycopheno-late mofetil, leflunomide and cyclophosphamide. Recently, biologicalagentssuchasTNF␣antagonists,tocilizumaband
rituximabwereaddedastreatmentoptionsforTApatients withrefractoryorseveredisease.6
Ourgroupshowedafavorableshort-termresponse(mean
follow-up of 9.1 months) to leflunomide 20mg/day in TA
patientswithactivediseasedespitetherapywithprednisone andimmunosuppressiveagents,mainlymethotrexate.7 How-ever,dataaboutlong-termefficacyandtoxicityofleflunomide
in TAare lacking. Therefore, theaims ofthis study are to describetheextendedfollow-updataofefficacyandtoxicityof leflunomidetherapyinTApatientspreviouslyenrolledinthe originalopen-labelstudyofshort-termeffectsofleflunomide inTA.
Patients
and
methods
Thisstudyisanopen-labellong-termlongitudinalstudyto evaluateleflunomideinTA.TApatientsincludedinthisstudy fulfilledthe1990AmericanCollegeofRheumatologycriteria forTA8andhadparticipatedinapreviousstudythatevaluated short-termefficacyofleflunomideinTA.7From15TApatients enrolledintheoriginalstudy,completefollow-upinformation couldberetrievedfrom12patients,since3patientswerelost tofollow-up.
TApatientsweredividedintotwogroups:(A)TApatients
who continued long-term use of leflunomide and (B) TA
patientswhohadtochangetherapytoanother
immunosup-pressive orbiological agent.Disease activitywas evaluated by the Kerr’scriteria1 and by the IndianTakayasu Activity Score2010(ITAS2010).9Acutephasereactantsusedtoevaluate systemicinflammationincludedtheWestergrenerythrocyte sedimentation rate(ESR)andC-reactiveprotein(CRP). Arte-riallesionswereassessedbymagneticresonanceangiography
(MRA)orbycomputedtomographyangiography(CTA)ofthe
wererecorded.Study’sprotocolwasapprovedbythe Institu-tionalEthicsCommitteeandallparticipantsgaveinformed consent.
Statisticalanalysis
StatisticalanalysiswasperformedwithIBMSPSSStatisticsfor
Windows,version 20.0(Armonk, UnitedStates)andgraphs
were built with GraphPad Prism 5.0 software. Categorical
dataarepresentedastotalnumber(percentage)and
contin-uousdatawere presentedasmean±standard deviationor
asmedianandinterquartilerange asappropriate. Compar-isonsbetweengroupswereperformedwiththeFisher’sexact testforcategoricalvariablesorwiththeStudent’sttestand
Mann–WhitneyUtestforcontinuousdata. AKaplan–Meier
curvewasbuilttoshowthetimecurveofleflunomide with-drawal in TA patients. Accepted significance level was 5% (p<0.05).
Results
Themean ageofTApatientsatstudy entrywas34.9±12.5 yearsand11(91.7%)werefemales.Themeanfollowuptime
was 43.0±7.6 monthsand 5 (41.6%) TApatients remained
onleflunomidetherapywhereas7(58.3%)TApatientshadto changetoanothertherapyduetofailuretopreventdisease relapsesin6patients.Adverseeventswereobservedintwo patientsandincludeddiarrheaandgastrointestinalupset,but onlyoneofthemwithdrewleflunomideduetotheseadverse events.Leflunomidewasreplacedbyinfliximabin4patients, byazathioprinein2patientsandbyadalimumabin1patient.
Only one out of seven TA patients who changed therapy
developedadverseeventsafterwards,shewasoninfliximab andpresentedmanifestedrecurrentlowerurinarytract infec-tions.Fig.1illustratestheKaplan–Meiercurveforthetime
toreplace leflunomideby other therapies. Themean time
forleflunomidewithdrawalwas12.8±8.6months.GroupsA andBhadsimilartimetoprednisonewithdrawal[20.8(range 7.8–26.1)monthsvs.34.1(1.7–42.3)months;p=0.571].Ingroup A,onepatientrefusedtouse prednisonesincestudyentry
and another could not taper prednisone below 20mg/day,
whereasingroupBtwopatientscouldnottaperprednisone aswell.
0 20 40 60 80
0.0 0.5 1.0 1.5
Leflunomide Changed therapy Time, months
Fraction survival
Fig.1–Timetoreplaceleflunomidetoanother immunosuppressiveorbiologicalagent.Kaplan–Meier curveshowstwogroupsofTApatients:groupA (continuousline)comprisingpatientswhocontinued leflunomideandgroupB(dashedline)withTApatients whochangedtherapytootheragents.Themeantimeto replaceleflunomidetoanotheragentwas12.8±8.6 months.
No significant differences were foundbetween group A
andgroupBregardingageatstudyentry,timesince diagno-sis,prednisonedailydoseatstudyentry,baselineITAS2010,
meanormaximumESRandCRP,andcumulativeprednisone
doseatstudyend(Table1).AmongstTApatientswhochanged leflunomidetoanothertherapy,twohadaclinicalrelapseand
neededtochangetherapywithinfliximabandadalimumab
toetanerceptandinfliximab,respectively.Newangiographic
lesion was documented in 4 TA patients during the
clini-calrelapsethatledtoleflunomidewithdrawal.Nonetheless, twopatientsdevelopednewangiographiclesionsevenafter changingleflunomidetoanotheragent,whilenonew angiog-raphiclesioncouldbeobservedinpatientswhoremainedon leflunomideuntilfollowupcompletion(p=0.469).
Discussion
Inthislong-termfollowupstudy,weobservedthat lefluno-midehadtobereplacedbyanothertherapy,mostlybiological
Table1–ComparisonsbetweenTApatientswhoremainedonleflunomide(groupA)andthosewhoneededtochange therapy(groupB).
Variables GroupA(n=5) GroupB(n=7) p
Ageatstudyentry,years 41.4±12.7 30.3±11.1 0.138
Diseaseduration,months 95.0(73.0–144.0) 77.0(62.0–112.0) 0.465
Prednisonedoseatstudyentry,mg 11.0±8.9 31.4±19.5 0.056
ITAS2010atbaseline 6.0±3.5 5.6±3.3 0.864
MeanESRduringstudy,mm/h 21.5±15.8 31.4±21.5 0.407
MeanCRPduringstudy,mg/L 5.6±4.5 10.3±10.6 0.379
MaximumESRduringstudy,mm/h 38.8±28.6 56.0±31.2 0.354
MaximumCRPduringstudy,mg/L 9.4±9.9 25.3±15.3 0.072
Cumulativeprednisoneatstudyend,mg 6,324.8±5,023.2 13,366.1±10,492.6 0.247
agents,inmorethan halfofTApatients.Themainreason for leflunomide withdrawalwas failure to prevent disease
relapses, even though a good disease control had been
achieved on the short-term open-label study.7 Moreover,
leflunomidewas shown to berelatively safeand only one
patient could not tolerate this agent due to diarrhea and gastrointestinalupset.Limitationsofthisstudy includethe lownumberofpatientsevaluatedand thelackofacontrol group.
Indeed,asubgroupofTApatientspresentedasustained responsetoleflunomidewithlong-termremissionleadingto prednisonewithdrawalwhilethedevelopmentofnewarterial lesionswashalted.Althoughnosignificantdifferencescould
befoundbetweenTApatientswhoremainedonleflunomide
andthosewhoneededtochangetherapy,itispossiblethat thelattergrouppresentedamoreseverediseasecourse,since atrendtohigherprednisonedoseatstudyentryandhigher
maximumCRPlevelswereobservedinthesepatientsfrom
groupBaswellasafterchangingtherapy,2patientsdeveloped newangiographiclesionsdespitetheuseofaTNF␣
antago-nist.
Todate,no randomizedcontrolledtrialshaveevaluated medicaltherapyinTA.6 Immunosuppressive andbiological agentswereassessedinTAonlybyopen-labelstudieswith asmallnumberofpatientswhatmaybeapotentialsourceof bias.Furthermore,studiesthatevaluatedtherapyinTAused differentcriteriatoassessdiseaseactivityandhead-to-head comparisonsarenotpossible.3,10 Recently,theITAS2010has beenvalidatedtoevaluatediseaseactivityinTAandthis out-comemeasureyieldsanumericscorethatisusefulforpatient monitoring.9TheOMERACTVasculitisWorkingGroupis devel-opingavalidatedsetofoutcomemeasuresfordiseaseactivity inTA.10Inthisstudy,wepreferredtouseKerr’scriteriaand ITAS2010toassessdiseaseactivityinordertoincrease sen-sitivitybyusingtwodifferentoutcomemeasures.Actually,in somecaseswedetectedadiseaserelapsewhenpatients pre-sentednewangiographiclesionandelevatedESRdespitethe
absenceofnewcomplainsorchangesinphysical
examina-tion,inotherwordsITAS2010scoredidnotchangeinsomeof thesilentrelapsesofourTApatients.
Regardingimmunosuppressiveagents,therateof remis-sioninductioninTApatientsformethotrexate,azathioprine
and mycophenolate mofetil was 81.0%, 76.7% and 90.0%,
respectively.11–13Inanotherstudy,theuseofmycophenolate mofetilinTApatientswithactivediseaseledtoadecrease inmedian ITAS2010 from 7.0 (range0.0–19.0) to1.0 (range 0.0–7.0),p=0.001,aswellasasignificantreductionofsteroid dose,ESRandCRPvalues.14 TheseratesofremissioninTA observedwiththeuseofotherimmunosuppressiveagentsare similartoourfindingswithshort-termleflunomidetherapy forTA (80% ofpatients in remission at9.1months of fol-lowup).7 However,those studies donotreportthe relapse rate for the long-term follow up. The follow up period of our study is slightly higher (3.6 years) than in the above mentioned studies(i.e. 2.8,1.0and 3.0years,respectively). The reasons for this apparently lower efficacy of lefluno-mideinkeepingsustainedremissionmightbetheinclusion ofmoreseverelyill TApatients ortheabsence of informa-tion about relapses after remission was attained in other studies.11–13
TheuseofbiologicalagentsinTAhasalsobeenevaluated inopen-labelstudies.StudiesthatevaluatedTNF␣antagonists
inTA(i.e.infliximab,etanerceptand adalimumab)reporta responserateof89%but arelapserateof37%whereasfor tocilizumabtheresponseratewas100%andarelapserateof 18%.15Thus,leflunomideinducesremissioninactiveTA simi-larlytoTNF␣antagonistsbutseemstobeinferiortobiological
agentsinpreventingdiseaserelapsesinTA.
In conclusion,leflunomide leadstosustained remission
and prevents the development of new arterial lesions in
approximately41%ofTApatientsatameanfollowuptime of43months.LeflunomidetherapywaswelltoleratedbyTA
patients and the main reason for withdrawal leflunomide
therapyisthefailuretopreventdiseaserelapsesratherthan adverseevents.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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