Adalimumab in rheumatoid arthritis treatment.docx

Adalimumab in rheumatoid arthritis treatment.docx

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Adalimumabinrheumatoidarthritistreatment

Adalimumabinrheumatoidarthritistreatment:

asystematicreviewandmeta-analysisofrandomizedclinicaltrials

MarinaAmaraldeÁvilaMachadoI,*;AlessandraAlmeidaMacielI;LíviaLovatoPiresdeLemosII;JulianaOliveiraCostaI;AdrianaMariaKakehasiIII;EliIolaGurgelAndradeIV;MariangelaLealCherchigliaV;FranciscodeAssisAcurcioVI

IPost-GraduationPrograminPublicHealth,SchoolofMedicine,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil

IIPost-GraduationPrograminMedicationsandPharmaceuticalCare,SchoolofPharmaceuticalSciences,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil

IIIDepartmentofMusculoskeletalSystem,SchoolofMedicine,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil

IVPost-GraduationPrograminDemographics,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil 

VPost-GraduationPrograminPublicHealth,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil 

VIPost-GraduationPrograminAnimalSciences,SchoolofVeterinaryMedicine,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil

ABSTRACT

Sincethediscoveryoftheroleoftumornecrosisfactorinthephysiopathologicalprocessofrheumatoidarthritis,fivedrugsthatblockthiscytokinehavebeenusedastherapeuticoptions.Toevaluatetheefficacyandsafetyofadalimumabinthetreatmentofrheumatoidarthritisweperformedasystematicreviewandmeta-analysisofrandomizedcontrolledtrials.AsearchofrelevantstudiesinMedline（throughPubMed）andLILACSinJune2011wascarriedout.Studyselection,datacollectionandanalysiswereperformedinpairsandindependentlybytworeviewersandbyathirdreviewerincasesofdisagreement.Themeta-analysiswasperformedusingthesoftwareReviewManager® 5.1usingtherandomeffectsmodel.Elevenarticlesrelatedtoadalimumabwereincludedandconsideredninestudieswith3461patients.Tenstudiesshowedlowriskofbiasregardingtheblindingofparticipantsandpersonnelandblindingofoutcomeassessment.Patientswhoreceivedthecombinationtreatmentofadalimumabandmethotrexateshowedbetterefficacyresultsandlowerradiographicprogressionwhencomparedtoplacebo+methotrexatein24-104weeks.Patientswhoreceivedadalimumabasmonotherapyshowedbetterefficacyoutcomeswhencomparedtoplaceboin24and26weeks.Theresultsofthemeta-analysesofadverseeventswerenotstatisticallysignificant,exceptforreactionsattheinjectionsite,whichfavoredthecontrolgroup.AdalimumabefficacywasdemonstratedinmonotherapyandwhenassociatedtoaDMARD,buttheevidenceforcombineduseismorerobust.

Keywords:

 Rheumatoidarthritis;Adalimumab;Tumornecrosisfactor;Systematicreview;Meta-analysis

Introduction

Evidence-basedMedicineistheconscientious,explicitandsensibleuseofbestevidencefordecision-makinginpatientcare.Thepracticeofevidence-basedMedicineintegratestheindividualexperienceofthephysicianwiththebestevidenceavailablethroughsystematicresearch.1

SystematicreviewsareconsideredLevelIevidenceandhavestringentmethodsthatdecreasetheoccurrenceofbiaseswhencomparedtonarrativereviews.2 Thebenefitsofthemonoclonalantibodyadalimumabinthecontrolofrheumatoidarthritis（RA）havebeenwidelyreportedintheliteratureand,inBrazil,thisisthesecondmostuseddrugofthisclassofbiologicalagentsforthetreatmentofthisdisease.3-5 Theannualcostofthistreatmentishigh,beingestimatedinBrazilatR$71,117.00andwitharatioofincrementalcost-effectivenessperquality-adjustedlifeyear（QALY）,whencomparedtotherapywithmethotrexate（MTX）,ofR$628.124,00.6 Thishighcostemphasizestheimportanceofsystematizationofalltheevidenceavailabletoaiddecision-makinginhealthcare.

RAisasystemicinflammatory,chronicandprogressivediseaseofunknownetiologythataffectsthesynovialmembraneofjoints,leadingtocartilageandbonedestruction.Thisautoimmunedisorderaffectsthejoints,ofteninthehandsandfeet,onbothsidesequallyandsymmetrically.3,7 Theprevalenceisestimatedat0.5-1.0%ofthepopulationandismorefrequentinwomen,accordingtostudiesperformedintheUnitedStates,EuropeandBrazil.8,9

ThecareofpatientswithRAincludestheuseofdiseasemodifyingantirheumaticdrugs（DMARDs）,nonsteroidalantiinflammatorydrugs（NSAIDs）andcorticosteroids,inadditiontonon-pharmacologicaltreatmentsuchasoccupationaltherapyandphysicaltherapy.10 BiologicalDMARDsrepresentabreakthroughintherapyandRAandhavebeenindicatedincaseswherepatientsdonotrespondtoconventionaltreatment.

Thetumornecrosisfactor（TNF）blockersadalimumab,etanercept,infliximab,certolizumabandgolimumabareincludedinthisclass.3,10,11

Aimingtocontributetothepracticeofevidence-basedMedicine,weperformedasystematicreviewandmeta-analysisofrandomizedcontrolledtrialstoevaluatetheefficacyandsafetyofAdalimumabinthetreatmentofRA.

Methods

Thisstudyispartofasystematicreviewofrandomizedcontrolledtrialsontheefficacyandsafetyofthedrugsadalimumab,etanercept,infliximabandrituximabinthetreatmentofrheumatoidarthritis.

Eligibilitycriteria

RandomizedcontrolledtrialswritteninPortuguese,EnglishandSpanishwereselectedforthereview.WeconsideredcomparisonsofAdalimumab40mgonceevery15daysasmonotherapyorcombinedwithDMARDsvs.controlgroupinpatientswithrheumatoidarthritisdiagnosisaccordingtotherevisedcriteriaoftheAmericanCollegeofRheumatologyandactivedisease.12

Articlesearch

ThesearchforstudieswascarriedoutintheMedlinedatabase（throughPubmed）andLILACSinJune2011andsupplementedbymanualsearchinginreferencesofsystematicreviewsandthestudiesthatwerefound.Thesearchstrategyconsistedofthefollowingwords:

rheumatoidarthritis,monoclonalantibodies,D2E7antibody,Humira®.ThesearchinPubmedwasstructuredfromMesh（MedicalSubjectHeadings）termsandasensitivesearchwasperformedforrandomizedcontrolledtrials.

Studyselectionanddatacollection

Studyselectionwascarriedoutbyanalysisofthetitlesandabstractsofstudiesselectedbythesearch.Datawerecollectedusingastandardizedform.

Tworeviewersindependentlyassessedandextracteddatafromeachstudyanddisagreementswereresolvedbyconsensusorbyathirdreviewer.Dataoncharacteristicsofthestudydesignandthepopulation,durationofdisease,previousorconcomitantuseofDMARDs,interventionandoutcomeswerecollectedforeachtrial.

TheprimaryoutcomewastheACR20responsedefinedbytheAmericanCollegeofRheumatology（ACR）.ACR20responseoccurswhenthereisadecreasedof20%inthecountofjointswithpainandedemaandimprovementin3ofthe5variables:

overallassessmentbythepatientandphysician,pain,HealthAssessmentQuestionnaire（HAQ）scaleandacutephaseinflammatorymarkers（C-reactiveproteinorerythrocytesedimentationrate-ESR）.13 ThesecondaryoutcomeswereACR50andACR70responses,inwhichthereare50%and70%improvementinthesameparameters,inadditiontofunctionality,measuredbytheHAQscale,radiographicoutcomes,losstofollow-upandsafety.Theauthors,ifnecessary,werecontactedtoprovideadditionalinformation.

Methodologicalqualityandriskofbias

Theassessmentofmethodologicalqualityandriskofbiaswasperformedindependentlybytworeviewerswithaccesstotheauthor'sname,institutionandthejournalthatpublishedthestudyanddisagreementswereresolvedbyconsensus.QualityassessmentbythemodifiedJadadscaleandriskofbiasassessmentproposedbytheCochraneCollaborationwereemployed.Thesetoolsassessmethodologicalaspects,suchasrandomization,blindingandlossofparticipants.ThemodifiedJadadscalescoresclinicaltrialsfrom0-6andthehigherthescore,thebetterthemethodologicalquality.14,15

Meta-analysis

Themeta-analysiswasperformedusingtheReviewManager® 5.1software.Weusedtheweighteddifferenceinmeansforcontinuousoutcomesandrelativeriskfordichotomousdata,bothconsideringaconfidenceintervalof95%.

Thepresenceofheterogeneitybetweenstudieswasconsideredapremiseandthereforetherandomeffectsmodelwasapplied.StatisticalheterogeneitywasconsideredifP<0.10forthechi-squaretestandI2 >40%andinthosecases,thepotentialfactorsthatinfluencedthisphenomenonwereinvestigated.16

Results

Thesearchforstudiesofthefourdrugs（Adalimumab,Etanercept,InfliximabandRituximab）resultedin3620articlesinPubmedand84inLILACS,aswellasninearticlesfoundbymanualsearch.ElevenarticlesrelatedtoAdalimumabwereincludedandconsideredninestudieswith3461patients（Fig.1）.

Studycharacteristics

SevenstudiesevaluatedgroupsofpatientstreatedwithAdalimumab（ADA）40mgevery2weekscombinedwithsomeDMARDsvs.DMARDsasmonotherapy（plusplacebo）:

insixstudiespatientsusedMTXandintheSTARstudysubjectsreceivedsomeDMARDs,amongthemMTX,chloroquine,hydroxychloroquine,leflunomide,parenteralgold,oralgoldcompounds,sulfasalazine,oranycombinationofthese.17 Mostpatients（82.1%groupADA+DMARDsand84.9%groupplacebo+DMARDs）usedoneormoreDMARDsduringthestudyandMTXwasthemostcommon（56.0%groupADA+DMARDsand62.6%groupplacebo+DMARDs）.TwotrialswereperformedingroupsusingADA40mgevery2weeksasmonotherapycomparedtoplacebo.OnlythePREMIERstudyincludedarmsofcomparisonbetweenADAmonotherapyvs.MTXmonotherapy.18

PatientshadactiveRAinallstudies.ThestudyGUEPARDdefinedactivediseasebyDAS28（diseaseactivityscore）g