Journal
of
Coloproctology
w w w . j c o l . o r g . b r
Original
article
Comparison
between
infliximab
and
adalimumab
in
the
treatment
of
perianal
fistulas
in
Crohn’s
disease
Carlos
Henrique
Marques
dos
Santos
UniversidadeFederaldeMatoGrossodoSul(UFMS),CampoGrande,MS,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received25February2014
Accepted15May2014
Availableonline14June2014
Keywords: Crohn’sdisease Infliximab Adalimumab Perianalfistula Age
a
b
s
t
r
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c
t
Introduction:The fistulizing form of Crohn’s disease (CD) represents a great challenge regardingtreatment,especiallyperianalfistulas,foritshighprevalence.
Objective:Toassessfactorsrelatedtotheresponsetosurgicaltreatmentassociatedwith anti-TNFinpatientswithCDandperianalfistulas.
Method:RetrospectivestudyofpatientswithCDandperianalfistulaswhousedIFXorADA inassociationwithsurgicaltreatment.
Results:30patientswithameanageof35yearswerestudied;16weretreatedwithADA(9 ADA+AZA)and14withIFX(10IFX+AZA);tenofthosetreatedwithADAresponded,and ofthesixnon-respondents,onlyonerespondedtoIFX;eightrespondedtoIFX,andamong thosenon-respondents,nooneshowedresponsewithADA;amongtherespondents,there
were10menandninewomen;ofthosenon-respondents,eightweremenand3women;
ofthoseunder40years,16respondedcomparedwithonlythreenon-respondents;ofthose over40years,threerespondedversuseightnon-respondents;astothetimeelapsedbetween theonsetofthediseaseandthebeginningofanti-TNF,14(<2years),one(2–5years)and four(>5years)responded,andfive(<2years),four(2–5years)andtwo(>5years)were non-respondents.
Conclusion:Therewasnodifferenceinresponsebetweentheanti-TNFagentsused;abetter responsewasnotedinthosewhousedanti-TNFincombinationwithazathioprine,among women,inthoseunder40yearsandinthosetreatedwithintwoyearsoftheonsetofthe disease.
©2014SociedadeBrasileiradeColoproctologia.PublishedbyElsevierEditoraLtda.All rightsreserved.
E-mail:chenriquems@yahoo.com.br(C.H.M.dosSantos) http://dx.doi.org/10.1016/j.jcol.2014.05.001
Comparac¸ão
entre
Adalimumabe
e
Infliximabe
no
tratamento
das
fístulas
perianais
na
Doenc¸a
de
Crohn
Palavras-chave: Doenc¸adeCrohn Infliximabe Adalimumabe Fístulaperianal Idade
r
e
s
u
m
o
Introduc¸ão: AformafistulizantedaDoenc¸adeCrohn(DC)apresentaumgrandedesafio quantoaoseutratamento,especialmenteasfístulasperianaispelasuaaltaprevalência. Objetivo: Analisarosfatoresrelacionadosàrespostaaotratamentocirúrgicoassociadoao anti-TNFdepacientescomfístulasperianaisporDC.
Método:EstudoretrospectivodepacientescomfístulasperianaisporDCquefizeramusode IFXouADAassociadoaotratamentocirúrgico.
Resultados:Foramestudados30pacientescommédiadeidadede35anos;16foramtratados
comADA(9ADA+AZA)e14 comIFX(10IFX+AZA);10dostratadoscomADAtiveram
resposta;edosseisquenãoresponderam,apenasumteverespostacomIFX;oitotiveram respostacomIFX;edosquenãoresponderam,nenhumapresentourespostacomADA;dos
queresponderam,10eramhomensenovemulheres;dosquenãoresponderam,oitoeram
homensetrêsmulheres;daquelescommenosde40anos,16responderamcontraapenas
trêsquenãoresponderam;doscommaisde40anos,trêsresponderamcontraoitoquenão responderam;quantoaotempodecorridoentreoiníciodadoenc¸aeoiníciodoanti-TNF, 14(<2anos),um(2-5anos)equatro(>5anos)responderam,ecinco(<2anos),quatro(2-5 anos)edois(>5anos)nãoresponderam.
Conclusão: Nãohouvediferenc¸aderespostaentreosagentesanti-TNFutilizados;houve melhorrespostanosqueutilizaramanti-TNFem associac¸ãocomazatioprina,entreas
mulheres,nospacientescommenosde40anosenaquelestratadoscomatédoisanos
doiníciodadoenc¸a.
©2014SociedadeBrasileiradeColoproctologia.PublicadoporElsevierEditoraLtda. Todososdireitosreservados.
Introduction
Initself,Crohn’sdisease(CD)constitutesamajorchallenge forthephysiciantreatinginflammatoryboweldiseases.Those caseswithfistulizing disease,particularly perianal fistulas, becomeevenmorechallenging,asthereisgreatdifficultyin achievingitscontrolinthelong-term,evenwiththe therapeu-ticadvancesmadeinrecentyears.1
Todayweknowthatthe besttherapeuticoptionforthis
presentationofCD istheassociation ofsurgicaltreatment
withthe useofanti-TNF agents, andin thissense,
“surgi-caltreatment”isnottheclassicfistulotomyorfistulectomy, butsuccessivecurettagesandsetonplacements,allowingthat thebiologicalsactinthehealingprocesswithoutformationof abscesses.2
Theconventionaltreatmentofperianalfistulasinpatients
withoutCDproducesexcellentresults;butinpatientswith
CDonecannotemploytheusualtechniquesinmostcases,
giventhe highprobabilityofdevelopingfecalincontinence.
Thissituationchangedpositivelywiththeemergenceof
bio-logicalagents,whichsignificantlychangedthetreatmentof
thisdisease.
Atthebeginningoftheuseofbiologicalagents,anincrease intheincidenceofperianalabscesseswasalsonoted(because oftheexternalorificeclosurebythedrug),butovertimeitwas foundthatthecombinationofbiologicalswithfrequent curet-tageoffistulasandsetonplacementconstitutedaneffective
strategy,havingbecomethestandardtreatmentforperianal
fistulasinpatientswithCD.3
Whatisbeingdiscussedtoday,infaceoftheinexistence
ofclearscientificevidence,iswhethertherearedifferences
betweentheavailablebiologicals,especiallyadalimumaband
infliximab,whicharethemostusedinBrazil.Thus,theaim
ofthisstudyistocomparethesetwoagentsastothe
differ-encesinresponsetotreatmentwithanti-TNFassociatedwith
surgicaltreatmentinCDpatientswithperianalfistulas.
Objective
To assess factors related tothe responseto surgical
treat-mentassociatedwithanti-TNF(adalimumabandinfliximab)
ofpatientswithperianalfistulasinCrohn’sdisease.
Method
Aretrospectivestudyofmedicalrecordsofpatientsfromthe
InflammatoryBowelDiseasesOutpatientClinic,Hospital
Uni-versitarioMariaAparecidaPedrossian,UniversidadeFederal
deMatoGrossodoSul,fromtheHospitalRegionaldeMato
GrossodoSul,andfromtheprivatepracticeoftheauthor.
Patients withperianal fistulasand Crohn’sdisease with
prescription and who made use of anti-TNF agents were
included.Allpatientsincludedwerepreviouslyinvestigated
forpresenceofTBandHepatitisB.
Thestudyperiodwasfrom June2000toJuly2013.
Anti-TNFagentswereusedatrecommendeddosesandintervals:
100
10
ADA IFX
Fig.1–Anti-TNFagentsusedaccordingtothepreferenceof
thepatient.
every8weeks,andadalimumab(ADA)160mgatweek0,80mg
atweek2andthen40mgevery2weeks.
Allpatientsweretreatedbycurettageandsetonplacement, withsuccessivechangesifnecessary,untiltherewasthe pos-sibilityofremovingthelesion.Onaverage,thebeginningof thebiologicaltherapyoccurredoneweekaftersurgery.
Absenceofpainanddischargeformorethansixmonths
wasconsideredasasatisfactoryresponsetotreatment. TheresultswerestatisticallyanalyzedbyStudent’sttest andchi-squaredtest,andP<0.05wasconsideredstatistically significant.
Results
30patients (18male and12 female)were studied.Theage
rangedfrom16to58years,withameanof35years.
Thechoiceofananti-TNFagentwasbasedonthe availabil-ityandpreferenceofpatients,similarlytothedatafromthe literatureonthesubject.4,5Ofthe30patients,16weretreated withadalimumaband14withinfliximab(Fig.1).
Theperiodofuseoftheseanti-TNFagentsrangedfrom3
to30months,withameanof18months.
Ofthose16patientsusingADA,ninewerealsotreatedwith
azathioprine(AZA),whileofthose14whoweretreatedwith
IFX,10alsousedAZA.
InthegrouptreatedwithADA,10hadresponseand
con-tinued their treatment. Of the six non-respondents, three
stoppeditsusealtogetherandthreeothersstartedusingIFX.
Ofthese,onlyonehadaresponse,remainingonthis
medica-tion.InthegrouptreatedwithIFX,eightresponded.Ofthose
six non-respondents, one stopped using anti-TNF and the
otherfivestartedusingADA.Ofthese,noonehadaresponse andtheanti-TNFtreatmentwasdiscontinued(Fig.2).
Therewasno differenceinourresultswhencomparing
anti-TNF agents(P=0.22). However,it became evidentthat
thecombinationofanti-TNFwithAZA wassuperiorversus
monotherapywiththisagent(P=0.01).
When analyzing the resultsaccording togender, it was
observedthat10menversusninewomen(P=0.13)responded,
whereas eight menversus three women(P=0.03) failed to
respond(Fig.3).
Whentheresultsoftreatmentofperianalfistulas
accord-ingtoagewereanalyzed,weobservedthatyoungerpatients
hadbetterresponseversusolderparticipants(P=0.00002).Of
7.00
5.25
3.50
1.75
ADA ADA+AZA IFX IFX+AZA 0
Non-respondents Respondents
Fig.2–Comparisonbetweenpatientstreatedwith
infliximabandadalimumab,combinedornotwith
azathioprine,inCDpatientswithperianalfistula.
thoseagedlessthan40years,16respondedversusthree
non-respondents, whileinthose agedmorethan40 years,only
threerespondedversuseightnon-respondents(Fig.4). Intheanalysisoftheresponsetotreatmentwithanti-TNF inrelationtothetimeelapsedbetweenthediagnosisof
peri-analfistulainCDpatientsandthebeginningofthetherapy
withthebiologicalagent,itwasfoundthat19patientsstarted
anti-TNF therapy beforetwo yearsofdisease, fivepatients
betweentwoandfiveyears,andsixpatientsaftermorethan
fiveyearsofdiagnosis.
Ofthosewho started thetreatmentwithintwoyearsof
diagnosis,14respondedversusfivenon-respondents/withlost response.Ofthosetreatedfromtwotofiveyearsofdiagnosis,
onlyoneresponded,whilefourwerenon-respondents/with
lostresponse.Inthegrouptreatedwithanti-TNFmorethan
fiveyearsafterdiagnosis,fourshowednoresponseversustwo respondents(Fig.5).
Women Men
Non-respondents Respondents
10.0
7.5
5.0
2.5
0
Fig.3–Comparisonbetweengendersastoresponseto
20
15
10
5
<40 years >40 years 0
Non-respondents/with lost response
Respondents
Fig.4–Evaluationofresponsetoanti-TNFinthetreatment
ofanalfistulasinCDpatientsaccordingtoage.
Discussion
A recent Brazilian publication on the epidemiology of CD
showedthathalfofpatientstreatedwiththebiologicalagent
presented perianal disease, mainly perianal fistulas,
high-lightingtheimportanceofthisformofthediseaseandthe
needforaneffectivetreatment.1
Inastudyofgreatrelevanceonthissubject,Sandsetal.6 observedthatonly36%oftheirCDpatientswithfistulas
main-tainedresponseafter54weeksofIFXuse.Thisdemonstrates
that,despitethegreatcontributiongivenbythebiologicalsto thetreatmentofCD,particularlyinthefistulizingvariety,the majorityofpatientsstilldonotachieveasatisfactoryresponse withthistherapy.Althoughthedesignofthisarticledoesnot
allowadirectcomparisonwiththeSands etal.paper,6 we
observedacompleteresponsein60%ofcases.
Thoseindividualswhoshowagoodinitialresponseto bio-logicalsusuallykeepitovertime.7Thisfactwasalsoobserved
Non-respondents/with lost response
Respondents
<2 years 2-5 years >5 years
15.00
11.25
7.50
3.75
0
Fig.5–Evaluationofresponsetoanti-TNFtherapyinCD
patientswithperianalfistulaintimeelapsedbetween
diagnosisandtheuseofabiologicalagent.
inthepresentstudy.TheCHARMstudyalsoshowedefficacy
ofADAin33%ofcasesofperianalfistulasatweek56,afinding verysimilartothatpresentedinthestudyofSandsetal.
AlthoughtheCHOICEstudyhasshownencouragingresults
regardingtheuseofADAinpatientsthatfailedwithIFX,the
same could notbeobservedinthepresent study.Lichtiger
et al. observed that 39% of patients who had failed with
IFX were successfulin the healingofperianal fistulas and
improved their quality oflife. In ourstudy, onlyone
non-respondentpatientwithADAwassuccessfulwithIFX.8
There are many publications on this subject, several of
themofgreatconsequence,butthereisashortageofarticles evaluatingotherfactorsinvolvedintheresponseto biologi-calagentsinCDpatientswithperianalfistulas.Itseemedto
usquiteinterestingtonotethatwomenhadlesstreatment
failuresversusmenwiththeuseofbiologicals.Inthemedical literature,thereislittleinformationonthissubject.
Inthepresentstudyweobservedabetterresponseinthe
youngergroupofpatients,butthereisnosimilarevidencein theliterature.Weissetal.9foundnodifferenceinresponseto treatmentwithanti-TNFastotheageofpatientsinarecently publishedstudy,inwhichtheseauthorsanalyzedthisvariable inrelationtoagegroup.
Currently,thetimeelapsedbetweentheonsetofsymptoms
ofCDandthetreatmentwithanti-TNFhasbeenvalued,since
theshorterthistime,thebettertheresponsetothetherapy.10
Thesamephenomenonwasobservedinthepresentstudy,
giventhatthegrouptreatedatlessthan twoyearsof
diag-nosisobtainedbetterresultsthan those treatedwithinthe
periodbetween twoand fiveyears.And this second group
obtainedbetterresultsthanthegrouptreatedafterfiveyears ofdiagnosis.
Conclusion
Therewasnodifferenceinresponsebetweenanti-TNFagents
used;therewasabetterresponseforthosewhoused
anti-TNFincombinationwithazathioprine,amongwomen,inthe
groupunder40yearsandinthosetreatedwithintwoyearsof onsetofthedisease.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
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