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Tarp, Simon, Furst, Daniel E., Dossing, Anna, Østergaard, Mikkel, Lorenzen, Tove, Hansen,

Michael S., Singh, Jasvinder A., Choy, Ernest Ho Sing, Boers, Maarten, Suarez-Almazor, Maria E.,

Kristensen, Lars E., Bliddal, Henning and Christensen, Robin 2016. Defining the optimal biological

monotherapy in rheumatoid arthritis: a systematic review and meta-analysis of randomised trials.

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Definingtheoptimalbiologicalmonotherapyinrheumatoidarthritis:

Asystematicreviewandnetworkmeta-analysisofrandomisedtrials

Authors:

SimonTarp,1DanielE.Furst,2AnnaDøssing,1MikkelØstergaard,3ToveLorenzen,4MichaelS.

Hansen,5JasvinderA.Singh,6ErnestH.Choy,7MaartenBoers,8MariaE.Suarez-Almazor,9LarsE.

Kristensen,1HenningBliddal,1RobinChristensen1

Correspondenceto:

RobinChristensen,MSc,PhD;SeniorBiostatistician

ProfessorofClinicalEpidemiology.

HeadofMusculoskeletalStatisticsUnit,

TheParkerInstitute,Dept.Rheumatology,

CopenhagenUniversityHospital,BispebjergandFrederiksberg.

NordreFasanvej57;DK-2000CopenhagenF,Denmark.

Email:Robin.Christensen@frh.regionh.dk;

Fax:(+45)38164159

RunningTitle:Optimalbiologicalmonotherapyinrheumatoidarthritis

Keywords:RheumatoidArthritis,Meta-Analysis,Biologics,systematicreview

WordCount:

Abstract:250(MAX250)

ManuscriptText:2,759(MAX3000)

TablesandFigures:X/Y(MAX6)

References:XX(MAX50)

PROSPEROidentifier:CRD42012002800

2

Author Affiliationande-mail1SimonTarp MusculoskeletalStatisticsUnit,TheParkerInstitute,Dept.Rheum.,

CopenhagenUniversityHospital,BispebjergandFrederiksberg,Denmark.

simon.farmaceut@gmail.com2DanielE.Furst UniversityofCalifornia,LosAngeles,CA,USA

DEFurst@mednet.ucla.edu1AnnaDøssing MusculoskeletalStatisticsUnit,TheParkerInstitute,Dept.Rheum.,

CopenhagenUniversityHospital,BispebjergandFrederiksberg,Denmark.

anna.dossing@gmail.com3MikkelØstergaard CopenhagenCenterforArthritisResearch,CenterforRheumatologyandSpine

Diseases,GlostrupHospital,and

DepartmentofClinicalMedicine,UniversityofCopenhagen,Denmark

mo@dadlnet.dk4ToveLorenzen DepartmentofRheumatology,DiagnosticCentre,SilkeborgRegionalHospital,

Denmarktove@mark-lorenzen.dk5MichaelS.Hansen ReumaKlinikRoskilde,Roskilde,and

GildhøjPrivathospital,Brøndby,Denmark

msh01@dadlnet.dk6JasvinderA.Singh MedicineService,BirminghamVAMedicalCenterandUniversityofAlabamaat

Birmingham(UAB),Birmingham,AL,USA&MayoClinicCollegeofMedicine,

Rochester,MN,USA

jasvinder.md@gmail.com 7ErnestH.Choy ArthritisResearchUKandHealthandCareResearchWalesCREATECentre,

SectionofRheumatology,CardiffUniversitySchoolofMedicine,Tenovus

Building,HeathPark,Cardiff,UK

ChoyEH@cardiff.ac.uk8MaartenBoers DepartmentofEpidemiology&Biostatistics,VUUniversityMedicalCenter,

Amsterdam,TheNetherlands.

9MariaE.Suarez-Almazor, SectionofRheumatologyandClinicalImmunology

UniversityofTexasMDAndersonCancerCenter,Houston,TX,USA.

msalmazor@mdanderson.org1LarsE.Kristensen, MusculoskeletalStatisticsUnit,TheParkerInstitute,Dept.Rheum.,

CopenhagenUniversityHospital,BispebjergandFrederiksberg,Denmark.

larserik_kristensen@yahoo.com1HenningBliddal MusculoskeletalStatisticsUnit,TheParkerInstitute,Dept.Rheum.,

CopenhagenUniversityHospital,BispebjergandFrederiksberg,Denmark.

Henning.Bliddal@regionh.dk1RobinChristensen

MusculoskeletalStatisticsUnit,TheParkerInstitute,Dept.Rheum.,

CopenhagenUniversityHospital,BispebjergandFrederiksberg,Denmark.

Robin.Christensen@Regionh.DK

3

ABSTRACT

Objectives:Tosummariseandcomparethebenefitsandharmsofbiologicalagentsusedas

monotherapyforrheumatoidarthritis(RA).

Methods:WesearchedMEDLINE,EMBASE,theCochraneCentralRegisterofControlledTrialsand

othersourcesforrandomisedtrialsthatcomparedbiologicalmonotherapywithmethotrexate,

placebo,orotherbiologicalmonotherapies.PrimaryoutcomeswereAmericanCollegeof

Rheumatology50%improvement(ACR50)andthenumberofpatientswhodiscontinueddueto

adverseevents.Ournetworkmeta-analysiswasbasedonmixed-effectslogisticregression,

includingbothdirectandindirectcomparisonsofthetreatmenteffects,whilstpreservingthe

randomisedcomparisonswithineachtrial.

Results:Theanalysiscomprises28trials(8,602patients),includingallninebiologicalagents

approvedforRA.Oftheincludedtrials,8(29%)included‘DMARD-naïve’,and20(71%)‘DMARD-

Inadequateresponder’(DMARD-IR)patients.Allagentsexceptanakinraandinfliximabwere

superiortoplacebowithregardtoACR50.Etanerceptandrituximabweresuperiortoanakinra.

Tocilizumabwassuperiortoadalimumab,anakinra,certolizumab,andgolimumab.Whenincluding

onlyDMARD-IRtrials,thesamestatisticalpatternemerged,complementedwithsuperiorityof

etanerceptandtocilizumabcomparedwithabatacept.Focusingonrecommendeddoses,both

etanerceptandtocilizumabweresuperiortoadalimumabandcertolizumab.Nodifferencesin

benefitamongetanercept,tocilizumab,andrituximabwerefound.However,becauserituximab

wasevaluatedinjust40patients,ourconfidenceintheestimatesislimited,Nostatistically

significantdifferencesamongbiologicalagentswerefoundwithrespecttoharm.

Conclusions:Evidencesuggestsetanerceptortocilizumabtobethemostappropriatechoicefor

RApatientstreatedwithbiologicalmonotherapy.

4

INTRODUCTION

Inflammationinrheumatoidarthritis(RA)patientsshouldbesuppressedasearlyaspossible

{Emery,20061954/id},withpharmacologictreatmentdirectedattightcontrolofinflammation

{Huizinga,20102381/id;Smolen,20102327/id}.Disease-modifyingantirheumaticdrugs

(DMARDs)caninterferewiththediseaseprocess{Smolen,20141918/id;Singh,20122330/id}.

ConventionalsyntheticDMARDs(csDMARDs)includemethotrexate(MTX),hydroxychloroquine,

leflunomide,sulfasalazine,andglucocorticoids.csDMARDscanalsobeusedinvarious

combinations{Singh,20122330/id}.MTXisconsideredthestandardcsDMARD,butinhigh-risk

patients,earlycombinationofMTXwithprednisoloneorabiologicalagentimprovesoutcomes

{Klarenbeek,20102382/id}.

BiologicalagentsareusuallygiventopatientswithactiveRAwhohavenotachieved

satisfactoryresponsetooneormorecsDMARDssuchasMTX{Smolen,20141918/id}.Currently,

thebiologicalagentsapprovedforRAincludethefollowingninedrugs:fivetumournecrosisfactor

inhibitors(TNFi)–adalimumab,certolizumabpegol,etanercept,golimumab,andinfliximab;and

fourwithothermodesofaction–anakinra,abatacept,rituximab,andtocilizumab{Furst,2012

2331/id}.InfliximabandgolimumabareapprovedbytheU.S.FoodandDrugAdministration(FDA)

andtheEuropeanMedicinesAgency(EMA)onlywithconcomitantuseofMTX,andrituximabonly

withacsDMARD{Emery,20132499/id}.Allotherbiologicalagentsarealsoapprovedin

monotherapy,albeitabataceptandanakinraonlybytheFDA{Emery,20132499/id}.

Recently,concernshavebeenraisedastowhetherexternalfactors,includinglackof

adherencetocsDMARDtherapy,mightreducetheanticipatedbenefitassociatedwithuseof

biologicagentsifpatientsdiscontinueuseofaconcomitantcsDMARD.Evidencefromreal-life

registrydatashowsthatapproximatelyone-thirdofRApatientstreatedwithbiologicalagentsuse

5

themasmonotherapyandthatwhenMTXisprescribedincombinationwithabiologicalagent,

morethanhalfofthepatientsdonottakeMTXasprescribed{Emery,20132499/id}.

Asmostbiologicalagentshaveshownmorefavourableresultsincombinationwith

csDMARDtherapy{Singh,20091746/id},andmanyRApatientsmightnotadheretotheirMTX

prescription,itisimportanttoevaluatethebenefitandharmassociatedwithuseofbiological

agentsasmonotherapy,andnotonlythetraditionalcombinationtherapystrategies{Bergman,

20101744/id;Guyot,20112376/id;Guyot,20122375/id}.Therefore,theobjectiveofthisstudy

wastoassesstheefficacyandsafetyoftheindividualbiologicalagentsappliedasmonotherapyin

patientswithRAtoinformdecisionmakersontherelativeeffectivenessofbiologicalagentsused

inmonotherapy.

6

METHODS

Anetworkmeta-analysisofrandomisedtrialscombineddirectandindirectevidence.Methodsof

analysisandinclusioncriteriawerespecifiedinadvanceanddocumentedinaprotocol(PROSPERO

2012:CRD42012002800).Bothprotocolandanalyseswerepreparedaccordingtothe

‘MethodologicalExpectationsforCochraneInterventionReviews’(MECIR)program.Ourstudy

conformstothePRISMAguidelinesforreportingsystematicreviews{Liberati,20092163/id}.

Literaturesearch

WesearchedTheCochraneCentralRegisterofControlledTrials,Medline,Embase,and

ClinicalTrials.govforpublishedreportsfrominceptionofeachdatabasethroughDecember16,

2014(SupplementTable1).Wecombinedtermsforrheumatoidarthritiswiththeninebiological

agentsofinterest(abatacept,adalimumab,anakinra,certolizumabpegol,etanercept,golimumab,

infliximab,rituximab,andtocilizumab).Searchresultswerelimitedtorandomisedcontrolledtrials

(RCTs)byapplyingappropriatefilters.Wethencollatedadditionalreportsidentifiedinrelevant

systematicreviewsnotretrievedthroughtheelectronicdatabases.Wealsoscrutinizedrelevant

reportsonFDA'sandEMA'swebsitesandsearchedrelevantpharmaceuticalcompanies’websites

toidentifyunpublishedtrialdata.

Trialselection

Double-blindrandomisedtrialsstudyingtheadministrationofoneoftheeligiblebiologicalagents

wereconsideredeligibleiftheywereusedasmonotherapyinan(FDA/EMA)-approvedrouteof

administrationinRApatients.Trialswereconsideredeligibleifatleastonewithin-study

comparisonwasavailablewithplacebo,MTX,oranotherapprovedbiologicalagentas

7

monotherapy.Wedidnotincludeopenlabeltrials,trialswithnofullEnglishtextavailable,trials

notreportingACR50responses,trialscomparingthesamebiologicalagentwithandwithoutMTX,

ortrialscomparingdifferentdosesofthesamebiologicalagentinmonotherapy.

Outcomemeasures

Thecore-outcomedataineachstudyconsistofthesamplesizeofthegroupsandthenumberof

patientsineachgroupwhometthepredefinedoutcomesofinterest.Aprioriitwasdecidedtouse

theoutcomeassessmentat6months,ifavailable.If6monthsdatawereunavailable,weused

dataclosestto6monthsineachtrial.Twomajoroutcomeswereconsideredco-primary

{Ghogomu,20142462/id}:benefit–definedastheACR50responsecriteria{Chung,20061641

/id};andharmbyproxy–determinedbythenumberofwithdrawalsbecauseofadverseevents

{Ioannidis,20041372/id}.ACR50isconsideredavalidated,clinicallymeaningfulbinarymeasure

ofbenefit{Singh,20091746/id}.Withdrawalsthatoccurbecauseofadverseeventsareameasure

ofpatients’toleranceofadverseeventsreportedconsistently{Singh,20091746/id}.The

secondaryoutcomeswereACR20,ACR70,totalnumberofpatientswhowithdrewfromthestudy,

andthenumberofpatientswhoexperiencedatleastoneseriousadverseevent(SAE).

Datacollectionandrisk-of-biasassessment

Outcomemeasureextractionswerebasedontheintention-to-treat(ITT)populationwhenever

possible.Twoindependentreviewers(STandAD)extractedallthedata.Datawerecollectedon

thegeneralcharacteristicsoftheRCTandsamplesize.Theinterventionsbeingcomparedwere

extracted,includingdosagesandfrequencyoftheadministereddrugs.

Theinternalvalidityoftheincludedstudieswasevaluatedonthebasisofthe

8

apparentriskofbiaswithineachRCT;domains(includingselectionbias,performancebias,

detectionbias,attritionbias,andreportingbias)wereassessedusingtheitemsoftherisk-of-bias

toolasrecommendedbytheCochraneCollaboration{Higgins,20111853/id}.

Datasynthesisandanalysis

Weusedrandomeffectsmeta-analysesbydefault,assumingthetruetreatmenteffectdiffers

fromstudytostudy{Riley,20112502/id}.Unlikeacontrast-based(standard)meta-analysis

approach{DerSimonian,1986525/id},anarm-basedapproachwasusedtoincludemultiple

comparisonsinthenetworkmeta-analysis{Salanti,20082039/id}inordertocombinebothdirect

andindirectcomparisons.Weperformedmixed-effectslogisticregressionusingan(arm-based)

randomeffectsmodelwithinanempiricalBayesframework{Singh,20091746/id;Platt,1999

2711/id}.Thegeneralisedlinearmixedmodel(GLMM)incorporatesavectorofrandomeffects

andadesignmatrixfortherandomeffects{Platt,19992711/id}.Allowancewasmadefor

differencesinheterogeneityofeffectsbetweendifferentdrugsbyspecifyingthatthelinear

predictorvariesatthelevelofstudyandasaninteractionbetweenstudyanddrug.Inthenetwork

meta-analyses,wemeasuredheterogeneity(i.e.,between-studyvariance)fortheanalysisusingT2

(anestimateforTau-squared),whichexaminesheterogeneitybecauseofStudyandStudy×Drug

interaction(smallervaluesindicateabettermodelperse).

Sensitivityanalyses

Posthocsensitivityanalysesontheprimaryoutcomeswereconductedtoexploreimpactof

csDMARDhistoryanddose:(i)exclusionofstudiesnotevaluatingcsDMARDinadequateresponder

9

patients;(ii)exclusionoftrialarmsnotevaluatinganFDA-orEMA-recommendedaverage

maintenancedose(definedinSupplementTable2),includingMTXcomparatortrialarmsnot

evaluatinganoralMTXdoseofatleast10mgweekly(orsubcutaneousinequivalentdose).Ifonly

onetrialarmevaluatedarecommendeddose,thewholestudywasexcludedfromthesensitivity

analysis(placebotrialarms[i.e.,nobiologicalorcsDMARDtreatment]werecategorisedas

recommendeddosefortechnicalreasons).

10

-Figure1.(Flowdiagram)AroundHere-

RESULTS

Characteristicsofreviewedstudies

Searchesoffourprimaryelectronicdatabasesandreviewsidentified4,405uniquereferences.Of

thetotal,818provedpotentiallyrelevantforfull-textreview,and45referencesthatreported28

uniquerandomisedtrialsofall9FDA/EMAapprovedbiologicalagentsprovedeligible(Figure1).

The28randomisedtrials,comprisingatotalof79uniquetrial-arms,included8,602

patientswithRA:abatacept(2trials;350patients),adalimumab(6trials;1,928patients),anakinra

(1trial;472patients),certolizumab(2trials;421patients),etanercept(5trials;2,047patients),

golimumab(4trials;1,279patients),infliximab(1trial;58patients),rituximab(1trial;80patients),

andtocilizumab(6trials;1,967patients).Theincludedtrialshaddifferentstudydesigns:13

comparedabiologicalagentinmonotherapywithplacebo;14comparedabiologicalagentin

monotherapytoMTX;andonlyonestudycomparedtwobiologicalagents(tocilizumabin

monotherapyvs.adalimumabinmonotherapy){Gabay,20132418/id}(Table1).Thenetworkof

eligiblecomparisonsfortheprimaryefficacyoutcome(ACR50)isshowninFigure2.Thenetwork

forwithdrawalsbecauseofadverseeventswasessentiallythesame.Ofthe28includedtrials,8

(29%)included‘csDMARD-naïve’,20(71%)‘csDMARD-IR’,and0(0%)enrolledbiologicalagent

inadequateresponderpatients(Table1;referencesavailableinSupplementTable3).

-Figure2.(Networkdiagram)AroundHere-

11

Benefitandharmaccordingtoprimaryoutcomes

AsillustratedinFigure3A,mostbiologicalagents(aswellasMTX)werestatisticallysignificantly

morelikelythanplacebotoleadtoanACR50response;exceptionswereanakinraandinfliximab.

Ofthe28includedstudies(allreportingACR50),24reportedwithdrawalsbecauseofadverse

events.Comparedtoplacebo,withdrawalsbecauseofadverseeventswerenotstatistically

significantlyhigheramongpatientsforanyofthedrugs(Figure3B).Forsensitivity,directpairwise

meta-analyseswereconductedforbothprimarybenefitandharmoutcome.Aspresentedin

SupplementFigure1-4,estimatesfromthenetworkmeta-analysiswereinagreementwiththe

directevidence(i.e.,pointestimatefromthenetworkmeta-analysiswereincludedwithinthe

95%CIofthedirectestimate).Theonlyexceptionwastocilizumabcomparedwithplacebofor

withdrawalbecauseofadverseevents,wherethepointestimatefromthenetworkmeta-analysis

(1.84)wasnotincludedwithinthe95%CIofthedirectestimate(0.04to1.29).Further,forbenefit

thedirectpairwisemeta-analysisfoundrelevantinconsistencyforcertolizumabpegolcompared

withplacebo(I2=71%),withnoobviousexplanation.Relevantinconsistencywasalsofoundfor

etanerceptandtocilizumabcomparedwithMTX(I2=83%and80%respectively),probably

explainedbythelowMTXdose(8mgweekly)usedintwoJapanesetrials(etanercept{Takeuchi,

2012};tocilizumab{Nishimoto,2009}.Thesetwotrialswereexcludedinthesensitivityanalysisof

recommendeddose.Forharm,relevantinconsistencywasalsofoundforetanerceptcompared

withMTX(I2=79%),probablyexplainedbethelowMTXdoseappliedintheJapanesetrial.

-Figure3A&B.(Networkmeta-analysisforestplotsofprimarybenefit/harmeach

biologicalagentcomparedwithplacebo)AroundHere

12

Figure4presentsallcomparisonsamongtheninebiologicalagentsinmonotherapy,MTX,and

placebointermsofbothbenefit(ACR50)andharm(withdrawalsbecauseofadverseevents).

Etanerceptwasmorelikelytoleadtoclinicalresponsethananakinra(OR=3.38;95%CI,1.26to

9.01)andMTX(1.54;1.03to2.32;Figure4).Rituximabalsoappearsmoreeffectivethananakinra

(4.26;1.01to17.86).Tocilizumabappearssuperiorwhencomparedwitheachofthefollowing:

adalimumab(1.97;1.22to3.17),anakinra(3.97;1.49to10.53),certolizumabpegol(2.35;1.06to

5.24),golimumab(1.77;1.00to3.13),andMTX(1.82;1.23to2.68).Allothercomparisonsamong

biologicalagentsinmonotherapywerenotstatisticallysignificantlydifferent.Whenharmswere

monitoredbyproxyaccordingtoallcomparisons(Figure4),noneofthedrugsincludedinthe

networkappearedmorelikelythanotherstoleadtodiscontinuationduetoadverseevents.

Figure4.(PrimaryBenefitandharmofallbiologicalagentsaccordingtothe

networkmeta-analysis)AroundHere

Benefitandharmaccordingtosecondaryoutcomes

Fromtheprimaryanalysis,basedontheprimarybenefit-outcome,statisticalevidencesuggested

etanercepttobemoreefficaciousthananakinraandMTX.Insecondaryoutcomeanalyses,this

findingwassupportedforACR20butnotforACR70,whereetanerceptwasnotstatistically

significantlydifferentfromMTX(1.47;0.92to2.36)(SupplementTable4).Rituximabwas

statisticallysignificantlysuperiortoanakinrafortheprimarybenefit-outcome,whichwas

supportedbyanalysesofACR20andACR70.Tocilizumabwasstatisticallysuperiortoadalimumab,

anakinra,certolizumabpegol,golimumab,andMTXforACR50,aneffectthatappearedrobust

13

whenACR20andACR70rateswereevaluated(SupplementTable4)withoneexception;

tocilizumabwasnotstatisticallysignificantlysuperiortogolimumab(1.85;0.97to3.52).

Whensecondaryharmmeasures,SAEs,andthetotalnumberofwithdrawals

(SupplementTable5)wereexamined,nostatisticallysignificantdifferencesoccurredforSAEs

(anakinrawasnotincludedduetolackofreporting).Forthetotalnumberofwithdrawals,

tocilizumabwasstatisticallysignificantlymorefavourablethanabatacept,adalimumab,anakinra,

andMTX.

Sensitivityanalysesintrialsusingtherecommendeddose

Whentheanalysisoftheprimarybenefitoutcome(ACR50)wasbasedontreatmentwiththe

recommendedmaintenancedose(SupplementTable6),anakinraandinfliximabwerenot

included,asthesebiologicalagentswerenotevaluatedattherecommendeddoses.Theapparent

superiorityofetanerceptoverMTXcouldnotbeconfirmedstatisticallyforitsrecommendeddose

(OR= 1.25;0.90to1.72).However,initsrecommendeddose,etanerceptwasnowmorelikelyto

leadtoclinicalresponsethanadalimumabandcertolizumabpegol.Thefindingsfortocilizumab

appearedrobust,withsuperiorityoveradalimumab,certolizumabpegol,andMTX.However,the

apparentsuperiorityoftocilizumabovergolimumabcouldnotstatisticallybeconfirmedfor

recommendeddose(OR= 2.07;0.89to4.85).Monitoringharmsbyproxyaccordingtoall

comparisons(SupplementTable6),adalimumab,etanercept,tocilizumabattheirrecommended

doses,andMTX(≥10mgweekly)wereallmorelikelythanplacebotoleadtodiscontinuationdue

toadverseevents.However,nodifferencesamonganybiologicalagentsorMTXwerestatistically

significant.

14

SensitivityanalysesamongDMARD-IRpatients

Whentheanalysisoftheprimarybenefitoutcome(ACR50)wasbasedonstudiesofpatientswho

hadhadaninadequateresponsetocsDMARDs(DMARD-IR;seeSupplementTable7),thefindings

foretanerceptwererobustasitwasstillmorelikelytoleadtoclinicalresponsethananakinraand

MTX.Theapparentsuperiorityofrituximaboveranakinracouldnotbestatisticallyconfirmed

(3.03;0.66to14.29).Also,thefindingsfortocilizumabappearedrobust,withsuperiorityover

adalimumab,anakinra,golimumab,andMTX.However,theapparentsuperiorityoftocilizumab

overcertolizumabpegolcouldnotbeconfirmedinthesensitivityanalysisbasedonDMARD-IR

patientsonly(2.18;0.89to5.32).

Further,toexplorehowmuchimpacttheonly“biologicshead-to-head”comparisonstudy

(ADACTA){Gabay,20132418/id}hadontheestimatesinthenetwork,theDMARD-IRsensitivity

analyseswereperformedwithexclusionoftheADACTAstudyontocilizumabagainstadalimumab

inDMARD-IRpatients(SupplementaryTable8),revealingsparsedatasupportingsuperiorityof

tocilizumabcomparedwithotherbiologicalagentspriortotheADACTAstudy(e.g.,vs.

adalimumab1.81;0.80to4.15).IntheADACTAstudy,tocilizumabwasstatisticallysignificantly

superiortoadalimumab(2.33;1.47to3.69).

15

DISCUSSION

Thisstudysuggeststherearedifferencesineffectivenessbutnotinharmamongbiologicalagents

appliedasmonotherapyinRA.Patient-importantbenefitssuchasACR50occurredmore

frequentlywithetanerceptortocilizumabmonotherapythanwithotherbiologicalagents.

Althoughtocilizumabwassuperiortoahighernumberofagentsthanthenumberetanerceptwas

superiorto,nostatisticallysignificantdifferencebetweentocilizumabandetanerceptwasfound

throughouttheconductedanalyses.Further,inrecommendeddose,bothetanerceptand

tocilizumabweresuperiortoadalimumabandcertolizumabpegol.Despiterituximab'sbeing

superiortoanakinra,hadresponseratescomparabletoetanerceptandtocilizumabagainst

placebo,andnodifferencesbetweenrituximabandetanerceptortocilizumabwerefound,

evidenceonrituximabwasbasedononestudyonly,where40patientsweretreatedwith

rituximabmonotherapy,therebylimitingourconfidenceinthesefindings.

Ourfindingsarerelevantbecausesubstantialnumbersofpatientseitherdonot

tolerateMTX(orothercsDMARDs),ordiscontinuetheseagentsforunknownreasons{Emery,

20132499/id}.RegistrydataconfirmthatbiologicalmonotherapyisacommontreatmentinRA

{Yazici,20084353/id;Jorgensen,20154352/id;Emery,20132499/id}.Inthesensitivityanalysisof

csDMARD-inadequateresponderpatients,mostagentshadresponseratescomparableto

continueduseofMTXmonotherapy,whereonlyetanerceptandtocilizumabmonotherapywere

superiortoMTX.

Onlyonehead-to-headtrialcomparingmonotherapywithtwobiologicalagents,

tocilizumabandadalimumab,hasbeenpublished{Gabay,20132418/id}.Wetherefore

performedanetworkmeta-analysistoindirectlycompareotherevaluatedtherapies,cognisantof

thelimitationsofthisapproach{Mills,2012}.Thismethodologyreliesuponassumptionsaboutthe

16

similaritiesoftheincludedtrialsintermsofcomparabilityofpatientandstudycharacteristics

{saliati2014}.However,thecomparativeeffectivenessparadigmdictatesthatguidelinepanelsas

wellascliniciansandpatientsarechallengedwiththedilemmaofchoosingamongthesetherapies

intheabsenceofrobustcomparativedataabouttheirrelativebenefitandharmdifferences.

Other(recent)networkmeta-analyses,toalargeextent,supportourfindingsregarding

etanercept’sandtocilizumab’sfavourableprofilesintermsofACR50{Buckley,20154355

/id;Migliore,20154356/id;Orme,20124357/id}.However,duetodifferentstudy

inclusion/exclusioncriteriaanddifferentmethodologicalapproaches,thesestudiesdifferwith

respecttothecomparativeeffectivenessbetweenetanerceptandtocilizumab.Inthestudyby

Buckleyetal.{Buckley,20154355/id},tocilizumabmonotherapywasnotstatisticallysignificantly

differentfromTNFimonotherapy(i.e.,allTNFi’swerecombined).Miglioreetal.{Migliore,2015

4356/id},whorestrictedtheireligibilitycriteriatostudiesofbiologicalagentsapprovedinEUfor

RAasmonotherapy;foundthattocilizumabwassuperiortoetanercept.Otherdiscrepancieswhen

comparedtoourstudyincludedtheminimumtreatmentdurationof16weeks,thedateofsearch,

andomissionofunpublishedtrials(e.g.,thenowpublishedFUNCTIONstudy[tocilizumab

monotherapyvs.MTX]{Burmester2015}hadresultsavailableonlineApril2013inthecompany

trialdatabase).AlthoughMiglioreetal.waslimitedtodouble-blindRCTs,aswasourstudy,it

includedtheopen-labelSAMURAIstudy(tocilizumabmonotherapyvs.csDMARDs;only x-ray

reader-blinded).Further,theadalimumabmonotherapystudyCHANGE{Miyasaka,2008}andthe

etanerceptmonotherapystudybyTakeuchietal.{Takeuchi2012}werenotincluded,although

bothfulfilledinclusioncriteriaandwerepublishedbeforedateofsearch(September2013).The

thirdnetworkmeta-analysisbyOrmeetal.{Orme,20124357/id}showedtocilizumab

monotherapywasnotstatisticallysignificantlydifferentfrometanerceptmonotherapy.

17

Ourevidencesynthesisalsohaslimitations.Theincludedstudiesspana17-yearperiod,

from1998through2015;sopatientsenrolledinearlystudiesmaydifferfromthoseincludedin

morerecentstudies.Moreover,theRApatientsenrolledinthedifferentmonotherapystudiesare

tosomeextentheterogeneous(encompassingdifferentdurationofdiseasesanddifferencesinthe

extentofpriorMTXfailure).Further,onlyonehead-to-headtrialwasidentified,reducingour

confidenceinthecomparativeestimates.Inotherwords,futurebiologicalagentmonotherapy

head-to-headtrialswilllikelyhaveanimportantimpactonourestimates.Apriori,wedefineda

hierarchicallistofoutcomes,givingpriorityto6monthsdatawhenavailable.Whentheywerenot

available,othertimepointswereused(e.g.,ninestudieslastedonly16weeksorless,andinsix

studiessafetydatawereavailableonlyafteroneyearormore.Comparisonsamongstudiesacross

differenttimepointscouldpotentiallylimittheinterpretationofourresults.Further,whetherour

resultscanbeextrapolatedtolong-termefficacyandsafetyisnotclear.

Inconclusion,trialevidencesuggestsetanerceptortocilizumabtobethemostappropriate

choicetoRApatientstreatedwithbiologicalmonotherapy.

18

ContributorsConceptionanddesign:RC,ST,DEF,MØ,TL,MSH,JAS,BJE,HB.Analysisand

interpretationofthedata:All.Draftingofthearticle:ST,RC,andHB.Criticalrevisionofthearticle

forimportantintellectualcontent:All.Finalapprovalofthearticle:All.Statisticalexpertise:RC,ST,

DEF,MØ,TL,MSH,JAS.Collectionandassemblyofdata:RC,ST,DEF,AD.Obtainingoffunding:RC,

MØ,TL,MSH,andHB.

FundingThisstudy,includingtheprotocol,wassupportedbyagrantfromRoche,Denmark;the

grantwasprovidedasanunrestrictedgranttoMusculoskeletalStatisticsUnit,TheParker

Institute.Thesponsorofthestudyhadnoroleindatacollection,dataanalysis,data

interpretation,orwritingofthemanuscript.Thecorrespondingauthorhadfullaccesstoallthe

datainthestudyandhadthefinalresponsibilityforthedecisiontosubmitforpublication.

CompetinginterestsST:Researchgrantspaidtoinstitute:AbbVieandRoche;Speakersbureau:

PfizerandMSD.RC:Consultingfeespaidtoinstitute:Abbott/Abbvie,Bristol-MyersSquibb,EliLilly,

Hospira,MSD,Novartis,Pfizer,andRoche;Researchgrantspaidtoinstitute:Abbott/Abbvie,MSD,

Mundipharma/Norpharma,Novartis,andRoche.DEF:hasreceivedresearchgrantsorhasan

advisoryroleforAbbott,Amgen,BMS,Janssen,Pfizer,Roche/GenentechandUCB.Heisamember

ofaspeaker’sbureauforAbbottandUCB(CMEonly).AD:Nonedeclared.MØ:hasreceived

consultancy/speakerfeesand/orresearchsupportformAbbott/Abbvie,BMS,Boehringer-

Ingelheim,Celgene,Eli-Lilly,Centocor,GSK,Janssen,Merck,Mundipharma,Novartis,Novo,Pfizer,

Schering-Plough,Roche,Takeda,UCB,andWyeth.TL:HasreceivedconsultantfeesfromPfizerand

Roche.MSH:HasreceivedconsultantfeesfromRoche.JAS: hasreceivedresearchgrantsfrom

TakedaandSavientandconsultantfeesfromSavient,Takeda,Regeneron,Merz,Bioiberica,

19

CrealtaandAllergan.JASservesastheprincipalinvestigatorforaninvestigator-initiatedstudy

fundedbyHorizonpharmaceuticalsthroughagranttoDINORA,Inc.,a501(c)(3)entity.JASisa

memberoftheexecutiveofOMERACT,anorganizationthatdevelopsoutcomemeasuresin

rheumatologyandreceivesarms-lengthfundingfrom36companies;amemberoftheAmerican

CollegeofRheumatology's(ACR)AnnualMeetingPlanningCommittee(AMPC);ChairoftheACR

Meet-the-Professor,WorkshopandStudyGroupSubcommittee;andamemberoftheVeterans

AffairsRheumatologyFieldAdvisoryCommittee.“Theviewsexpressedinthisarticlearethoseof

theauthorsanddonotnecessarilyreflectthepositionorpolicyoftheDepartmentofVeterans

AffairsortheUnitedStatesgovernment”.EHC:hasreceivedresearchgrantsand

consultancy/speakerfeesfromAbbottLaboratories,Allergan,Amgen,AstraZeneca,Biogen,BMS,

BoehringerIngelheim,Celgene,ChugaiPharma,DaiichiSankyo,EliLilly,FerringPharmacuetical,

GSK,Hospira,ISIS,JazzPharmaceuticals,Jenssen,MedImmune,MerrimackPharmaceutical,MSD,

Napp,Novimmune,Novartis,Pfizer,Regeneron,Roche,Sanofi-Aventis,Synovate,Tonix,andUCB.

MB:Nonedeclared.MES-A:hasreceivedaresearchgrantfromPfizerandconsultantfeesfrom

Abbvie.LEK:Nonedeclared.HB:hasreceivedresearchgrantsand/ortravelandcongresssupport

fromAbbott,Bristol-MyersSquibb,Lilly,MSD,Pfizer,Roche,UCB,andWyeth.

Acknowledgment:TheParkerInstituteissupportedbygrantsfromtheOakFoundation.

20

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