Rev. Bras. Reumatol. vol.56 número6

w w w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Review

article

Severe

infection

in

patients

with

rheumatoid

arthritis

taking

anakinra,

rituximab,

or

abatacept:

a

systematic

review

of

observational

studies

Vanderlea

Poeys

Cabral

_,

_Carlos

_Augusto

_Ferreira

_de

_Andrade

,

Sonia

Regina

Lambert

Passos

_,

_Maria

_de

_Fátima

_Moreira

_Martins

_,

Yara

Hahr

Marques

Hökerberg

a_{Fundac¸ãoOswaldoCruz(Fiocruz),InstitutoNacionaldeInfectologiaEvandroChagas(INI),ComissãodeControledeInfecc¸ão}

Hospitalar,RiodeJaneiro,RJ,Brazil

b_{Fundac¸ãoOswaldoCruz(Fiocruz),InstitutoNacionaldeInfectologiaEvandroChagas(INI),LaboratóriodeEpidemiologiaClínica,}

RiodeJaneiro,RJ,Brazil

c_{Fundac¸ãoOswaldoCruz(Fiocruz),InstitutodeComunicac¸ãoeInformac¸ãoCientíficaeTecnológicaemSaúde,RiodeJaneiro,RJ,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received11August2015 Accepted12July2016

Availableonline27October2016

Keywords:

Rheumatoidarthritis/therapy Anti-rheumaticdrugs/adverse effects

Infection

Biologicaltherapy/adverseeffects Reviewofliteratureastopic

a

b

s

t

r

a

c

t

Aquestionisraisedaboutanincreasedriskofsevereinfectionfromtheuseofbiological drugsinpatientswithrheumatoidarthritis.Thissystematicreviewofobservationalstudies aimedatassessingtheriskofsevereinfectionassociatedwiththeuseofanakinra, ritux-imab,andabataceptinpatientswithrheumatoidarthritis.Thefollowingdatabaseswere searched:PubMed,ScienceDirect,Scopus,WebofKnowledge,Scirus,Cochrane,Exerpta MedicaDatabase,Scielo,andLilacsuptoJuly2010.Severeinfectionsweredefinedasthose life-threateningonesinneedoftheuseofparenteralantibioticsorofhospitalization. Lon-gitudinalobservationalstudieswereselectedwithoutlanguagerestriction,involvingadult patientsdiagnosedwithrheumatoidarthritisandwhousedanakinra,rituximab,or abat-acept.Infourstudiesrelatedtoanakinra,129(5.1%)severeinfectionswererelatedin2896 patients,ofwhichthreedied.Withrespecttorituximab,twostudiesreported72(5.9%) severeinfectionsin1224patients,ofwhichtwodied.Abataceptwasevaluatedinonlyone studyinwhich25(2.4%)severeinfectionswerereportedin1046patients.Themainsiteof infectionforthesethreedrugswastherespiratorytract.Onepossibleexplanationforthe highfrequencyofsevereinfectionsassociatedwithanakinramaybethelongerfollow-up timeintheselectedstudies.Thehighfrequencyofsevereinfectionsassociatedwith ritux-imabcouldbecreditedtothelessstrictinclusioncriteriaforthepatientsstudied.Therefore, infectionmonitoringshouldbecautiousinpatientswithrheumatoidarthritisinuseofthese threedrugs.

©2016PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mails:carlosandrade07@gmail.com,carlos.andrade@ipec.fiocruz.br(C.A.Andrade). http://dx.doi.org/10.1016/j.rbre.2016.10.001

544

Infecc¸ões

graves

em

pacientes

com

artrite

reumatoide

em

uso

de

anakinra,

rituximab

ou

abatacept:

revisão

sistemática

de

estudos

observacionais

Palavras-chave:

Artritereumatoide/terapia Antirreumáticos/efeitosadversos Infecc¸ão

Terapiabiológica/efeitos adversos

Revisãodeliteraturacomo assunto

r

e

s

u

m

o

Existeumquestionamentosobreaumentodoriscodeinfecc¸õesgravespelousode medica-mentosbiológicosporpacientescomartritereumatoide.Estarevisãosistemáticadeestudos observacionaisobjetivouavaliaroriscodeinfecc¸õesgravesassociadasaousodeanakinra, rituximabeabataceptempacientescomartritereumatoide.Forampesquisadasasbases PubMed, Science Direct, Scopus, Webof Knowledge, Scirus,Cochrane, Exerpta Medica Database, ScieloeLilacsatéjulho/2010.Infecc¸õesgravesforamdefinidascomoaquelas comderiscodevida,necessidadedeantibióticosparenteraisoudehospitalizac¸ão.Foram selecionadosestudosobservacionaislongitudinais,semrestric¸ãodeidioma,queenvolviam pacientesadultoscomdiagnósticodeartritereumatoidequeusaramanakinra,rituximab, abatacept.Emquatroestudosrelacionadosaoanakinra,foramrelatadas129(5,1%)infecc¸ões gravesem2.896pacientes,dosquaistrêsevoluíramparaóbito.Sobreorituximab,dois estu-dosrelataram72(5,9%)infecc¸õesgravesem1.224pacientes,dosquaisdoisevoluírampara óbito.Oabataceptfoiavaliadoemapenasumestudo,noqualforamrelatadas25(2,4%) infecc¸õesgravesem1.046pacientes.Oprincipalsítiodeinfecc¸ãoparaostrês medicamen-tosfoiotratorespiratório.Umapossívelexplicac¸ãoparaafrequênciaelevadadeinfecc¸ões gravesassociadasaoanakinrapodeseromaiortempodeacompanhamentonosestudos selecionados.Afrequênciaelevadadeinfecc¸õesgravesassociadasaorituximabpoderiaser creditadaaocritériomenosrestritodeinclusãodepacientes.Portanto,devesercautelosa a monitorac¸ãodeinfecc¸õesnospacientescomartritereumatoidequeusamessestrês medicamentos.

©2016PublicadoporElsevierEditoraLtda.Este ´eumartigoOpenAccesssobuma licenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Rheumatoidarthritis(RA)isachronicinflammatorydisease ofunknownetiologythat affects0.5–1% ofthe worldadult population,predominantlyinwomen,andwiththehighest incidenceintheage rangeof30–50years.1 _Thesymmetric polyarthritis characteristicof RAcan cause pain and joint destructionanddeformity,especiallyinthejointsofthehands andwrists,aswellaspainandsystemicmanifestationssuch asfatigue,morningstiffness,andweightloss.2

RA patients may remain with active disease despite the use of synthetic (or “non-biological”) Disease Modify-ing Antirheumatic Drugs(DMARDs) such as methotrexate, leflunomide,azathioprine,andcyclosporine.Thus,since1997 new therapies, such as “biological DMARDs”, have been employed,demonstratinggreaterefficacyinthetreatmentof RA,3 _{amongwhich onecan mentiontumor-}␣ necrosis

fac-tor(TNF-␣)-antagonists(infliximab,etanercept,adalimumab,

andgolimumab)andnon-TNF-␣antagonists(abatacept,

rit-uximab,anakinra,andtocilizumab)DMARDs.4

Somerandomizedcontrolledtrialshaveshownanincrease ininfectionwiththeuseofnon-TNF-␣antagonistDMARDsin

patientswithRA,bothwithrituximab(5.2/100patient-years formethotrexate/rituximab association vs. 3.7/100 patient-yearsformethotrexateonly),5_{aswellaswithabatacept(2.9%} fortheassociationvs.1.9%formethotrexateonly).6_However, other authors havenot foundthis increase forrituximab,7 abatacept,8_oranakinra.9

Threesystematicreviews(SRs)thatevaluatednon-TNF-␣

antagonistDMARDswerepublished.4,10,11

Gartlehneretal.10_{haveexaminedthecomparativeefficacy} and safety ofthreeTNF-␣ antagonists and ofa non-TNF-␣

antagonist(anakinra)forthetreatmentofrheumatoid arthri-tis in 18 observational and experimental studies, but the authorsdidnotpresentresultsoninfections.

Basedon12clinicaltrials,Salliotetal.11_{havesuggesteda} trend(notstatisticallysignificant)forincreasedriskofsevere infection during the treatment with rituximab (odds ratio [OR]=1.45,confidenceinterval[CI]95%:0.56–3.73),abatacept (OR=1.35;95%CI:0.78–2.32),andanakinra(OR=2.75;95%CI: 0.91–8.35).

Storageetal.,4_{inasystematicreviewofeight(randomized} andopen-label)clinicaltrials,identifiedsevereinfectioninup to2.3%incasesofexclusive useofabataceptandfrom1.3 to12.7%withtheuseofabataceptassociatedwithsynthetic DMARDs.

Although performing a meta-analysis of observational studiesonthesafetyofbiologicalDMARDs,Bernatskyetal.12 studied only TNF-␣ antagonists. Thus, we emphasize that

except for abatacept, systematic reviews of observational studiesontheriskofsevereinfectionassociatedwith non-TNF-␣ antagonists (anakinra, rituximab, and tocilizumab)

havenotyetbeencarriedout.

Method

The description of this systematic review was conducted accordingtoapre-specifiedprotocol,basedonthePreferred ReportingItemsforSystematicReviewsand Meta-Analyses (PRISMA)guideline.13_{Thefollowingarethemaindefinitions} andstepsdescribed intheprotocol.Severeinfections were definedasthoseinwhichthereisariskforthepatient’slife, andthenecessityofparenteralantibioticsorof hospitaliza-tioninadultpatientswithRAusersofanakinra,rituximab, andabatacept.Onlylongitudinalobservationalstudieswere selected, including post-marketing evaluation studies and clinicaltrialfollow-upstudies(e.g.,open-labelclinicaltrials). Thefollowingelectronicdatabasesweresearched:PubMed, LiteraturaLatino-AmericanaedoCaribeemCiênciasdaSaúde (LILACS), Scopus, Web ofScience, Science Direct,Excerpta Medica Database (EMBASE), SciELO, and Scirus. For each base search, a strategy combining the following descrip-tors– infection, bacterial infections,antirheumatic agents, adverse effects, therapeuticuse, rheumatoid arthritis, and drugtherapy – were developed.There were no restrictions on language. The strategy used in Pubmed was: ((infec-tion [MeSH Terms] OR bacterial infections [MeSH Terms]) AND(antirheumaticagents/adverseeffects[MeSHTerms]OR antirheumaticAgents/therapeutic use [MeSHTerms])) AND (arthritis,rheumatoid/drugtherapy[MeSHTerms]).Equivalent strategieshavebeenformulatedfortheotherbases.TheScirus basealsocoveredgrayliterature.Searchesincludedstudies publisheduptoJuly2010,coveringpriorperiodswithout lim-itationofpublicationdate.Thereferencelistsofallarticles weremanuallyinvestigated,inapursuitofnewarticles (cross-references).

Adatabasefortheelectronicsearcheswascreatedwiththe helpoftheEndNoteX1program.Duplicatequotationswere deleted.Potentiallyrelevanttitlesandabstractswereselected independently by peer reviewers VPC/CAFA and VPC/SRLP, whoalsotookthereadingsofthefulltext,extracted informa-tion,andassessedthequalityofstudies.Disagreementswere resolvedbyconsensusand,wherenecessary,theopinionof thethirdauditor(externaltothepairofpeerreviewers)was requested.

Theextractionofindependentdatawasbasedon comple-tingastandardformwithrelevantdataabouteachstudy(full reference,countryofitsproduction,samplesize,design, dura-tion,clinicalanddemographiccharacteristicsofpatients,the resultsfortheriskofsevereinfection,andqualityassessment scores).Theauthorswerecontactedfordatarequestneeded andnotcontainedinthepublishedversionofarticles.

Astotheinterpretationofthefrequencyofsevere infec-tions,weusedtheclassificationproposedbyMeyboomand Egberts14_{foradversedrugreactions: commonly,whenthey} happenin1–10%ofusers;unusually,0.1–1%;andrarely,inless than0.1%.

Toevaluatethequalityofobservationalstudies,an instru-mentadapted,basedontheNewcastle-OttawaScale,15_was used.Threeitemswereconsidered;eachreceivedonepoint whenthe requiredstandardwas met:(1)mannerof selec-tionofparticipants–adescribedsample,representativeofthe targetpopulationbybeingcomplete,randomorsystematic;

(2)percentageoflosses–withdescription,andunder20.0%; and (3) manner of outcome assessment – an available or describedmeasuringinstrument.Inthosearticlesthatwere scoredforthethreeitems,thestudywasconsideredasbeing ofhighquality;articlesthatreceivedpointsfortwoitemswere consideredofintermediatequality;andwhenonlyoneitem wasscored,thestudywasconsideredoflowquality.

ThisstudywasapprovedbytheResearchEthics Commit-teeoftheInstitutoNacionaldeInfectologiaEvandroChagas, OswaldoCruzFoundation(Opinion017/2010).

Results

A flow chart(Fig. 1)describing the resultsof bibliographic search performedwas prepared.Initially, thesesearchesin eight databases provided1583 abstracts, ofwhich 19 were selectedforfull-articlereading.Apartfromtheseabstracts,we selected44ofthe49abstractsobtainedbycross-references, resultingin63fullstudies.Ofthesestudies,onlysevenwere approvedandincludedinthesystematicreview:five open-label articles (Nuki et al.,16 _{Fleischmann et al.,}17 _Keystone etal.,18_{Genoveseetal.,}19_{andSchiffetal.}20_{),onecohort-nested} case–controlstudy,21_{andonecohortstudy}22_(Fig.1).

Table1presentsthegeneralcharacteristicsofeachstudy. Thesevenobservationalstudiesincludedinthisreviewhad atotaldurationoffollow-upperiodsfromsixto63months, wereconductedinEuropeancountries,intheUnitedStates (USA) and Mexico, and addressed5166 patients diagnosed withRAtreatedwithoneofthreedrugs(anakinra,rituximab, abatacept). A meta-analysiswas notperformed dueto the presenceofmultiplesourcesofheterogeneityamongstudies, andalsotothelimitednumberofpublicationsforthestudied drugs(differenttypesofstudydesigns,eligibilitycriteria,and medicines).

Anakinra

Intotal,2896patientsweretreatedwithanakinraand evalu-atedinfourstudieslastingfrom12to63months:onecohort study,22 _{two open-labelarticles,}16,17 _{and one cohort-nested} case–controlstudy21_(Table1).

Among the evaluated patients, the female gender pre-vailed, with a mean age from 52.8 to 54.8 years,with RA durationrangingfromfourto13years,andwithaveryactive disease,accordingtothenumberofswollenorpainfuljoints, C-reactiveprotein,andadiseaseactivity indexbasedon28 joints (DAS28>5.1). In those two articles that reported on comorbidities,21,22_{theirauthorsobservedmainlychroniclung} disease and diabetes mellitus.Concomitant use of cortico-steroidsrangedfrom45.9%to87.0%,andtheuseofvarious syntheticDMARDsrangedfrom71.4%to80.5%(Table2).

Brassard et al.21 _{onlyevaluated the riskoftuberculosis,} adding demographic data from the use of three biological DMARDs(infliximab,etanercept,andanakinra). Despitethe establishmentofacontactwiththeauthor,therewereno spe-cificdemographicdataforanakinra,aswellasforthesitesof infection.

546

Identified abstracts in electronic databases

(n=1583)

Cross-references (n=49)

Screened abstracts (n=1429)

Studies read in full and assessed for

eligibility (n=63)

Full studies excluded (n=56): 18 revisions

13 clinical trials 8 other medicines

4 without a diagnosis of rheumatoid arthritis 4 no information about infections

3 letters to the editor 3 case reports

2 not restricted only to rheumatoid arthritis 1 animal studies

Duplicates removed

Identification

Screening

Total of abstracts (n=1632)

Excluded abstracts (n=1366)

Eligibility

Included

Included studies (n=7)

(n=203)

Fig.1–Flowchartofselectionofstudiesforthesystematicreview.

treatedwithanakinra,alongwiththeirrespectiveincidences (frequenciesandrates).

Thefrequencyofinfectionforanakinra rangedfrom 1.3 to11.1%.Nuki etal.16 _{andBrassard etal.}21 _{showedsimilar} frequencies(1.3%).Fleischmannetal.17_{reportedpneumonia}

(23.8%)andcellulitis(14.8%)asthemostfrequentinfections, but without detailing their clinical aspects. These authors weretheonlyoneswhoreporteddeathsrelatedtotheuseof anakinra.Nukietal.16_{didnotspecifythesitesofthefourcases} ofsevereinfectionandalthoughtheseauthorshaveinformed

Table1–Descriptionofthesevenpublications(2002–2009)ontheriskofsevereinfectionsinpatientswithrheumatoid

arthritisassociatedwithuseofnon-anti-TNF-␣biologicalDMARDs.

Firstauthor,year Drug Design Place Samplesize Durationof

studyin months

Nuki,a₂₀₀₂16 _{Anakinra Openlabel Europe(11countries) 309 12–18}

Listing,200522 _{Anakinra Cohort Germany 70 18}

Brassard,b₂₀₀₆21 _{Anakinra Case–controlnestedincohort USA 1414 63}

Fleischmann,c₂₀₀₆17 _{Anakinra Openlabel USA 1103 36}

Keystone,200718 _{Rituximab Openlabel – 1039 6}

Genovese,200919 _{Rituximab Openlabel 9internationalstudies 185 12}

Schiff,200920 _{Abatacept Openlabel USA,EuropeandMexico 1046 6}

DMARDS,DiseaseModifyingAntirheumaticDrugs;USA,UnitedStatesofAmerica.

a _{218inuseofanakinraand71withplacebointhefirstsixmonthsofthedouble-blindclinicaltrial,allincludedintheextensionphasewith}

openlabel(12months).

b _{Theoutcomewastuberculosis.}

r

e

v

b

r

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s

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m

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t

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l

.

2

0

1

6;

5

6(6)

:543–550

547

Firstauthor,year Drug Sample,n Women (%)

Meanage (SD)

Rheumatoid arthritis

activity

Yearsof disease(SD)

Comorbidities (%)

Corticosteroids, n(%)

Useof synthetic DMARDs,

n(%)

Useof synthetic DMARDs, n(SD)

Nuki,200216 _{Anakinra 309 75.1 52.8(13.0) NPJ33.5(13.1)}

NSJ25.9(9.3)

CRP3.9(3.8)

4.0(2.4) – 142(45.9) 223c_{(72.2) 1.2}c_(1.0)

Listing,200522 _{Anakinra 70 77.1 54.3(11.6) 6.1(1.2)}a _{13.0(7.0–22.0)}b _Chroniclung

disease(12.9)

Diabetes(11.4)

Psoriasis(1.4)

61(87.0) 50d_{(71.4) 4.2(1.9)}

Brassard,200621 _{Anakinra 1414 – – – – Diabetes.}

Silicosis

CKD.Solidorgan

transplantand

carcinoma(...)

– – –

Fleischmann,e₂₀₀₆17 _{Anakinra 1103 74.3 54.8(19–85)}f _{NPJ22.2(0–68)}

NSJ18.2(0–66)

CRP2.7(0.1–25.6)

10.3(0.2–59.5)f _–g _{654(59.3) 888}d_{(80.5) –}

Keystone,200718 _{Rituximab 1039 80.0 51.9(11.4) 6.8(1.0)}a _{11.2(8.2) –}h _{– – 2.5}e_(1.6)

Genovese,200919 _{Rituximab 185 78.4 51.2(12.3) 7.0(0.9)}a _{11.9(9.2) – – – 4.0}f_(2.4)

Schiff,200920 _{Abatacept 1046 81.2 54.4(12.4) 6.2(0.7)}a _{11.6(9.5) – 611(58.4) 1003}e_{(96.2) –}

DMARDS,DiseaseModifyingAntirheumaticDrugs;SD,standard-deviation;NPJ,numberofpainfuljoints;NSJ,numberofswollenjoints;CRP,C-reactiveprotein;n,number.

a _{ArthritisrheumatoidactivitybyDAS28(SD)–indexofactivityofthediseasewith28joints.}

b _{Interquartilerange.}

c _{Prioruseofnon-biologicalDMARDs}

d _{Concomitantuseofnon-biologicalDMARDs.}

e _{Patientswhoparticipatedinthefirstsixmonthsofplacebo-controlledclinicaltrialwereincluded.}

f _{(minimumandmaximum).}

g _{Diabetesandcancerexcluded.}

548

Table3–Resultsrelativetotheriskofsevereinfectionsassociatedwiththeuseofnon-anti-TNF-␣biologicalDMARDSin

patientswithrheumatoidarthritis.

Firstauthor,year Drug Sample,n Infectedpatients (numberof

episodes)

Severeinfections %(95%CI)b

Rateofsevere

infections/100 person-years

(95%CI)

Infectionsites,n

(%)

Deaths,n

Nuki,200216 _{Anakinra 309 4(4) 1.3(0.4–3.3) – – 0}c

Listing,200522 _{Anakinra 70 1(2) 2.9(0.4–9.9) 3.2(0.4–11.5) Arthritis:1}

Acute

osteomyelitis:1

0

Brassard,200621 _{Anakinra 1414 19(19) 1.3(0.8–2.1) – – 0}

Fleischmann,a

200617

Anakinra 1103 105(122) 11.1(9.3–13.1) 5.4(4.5–6.4) Pneumonia:29

Cellulitis:18

Sepsis:5

Other:70

3(sepsis)

Keystone,200718 _{Rituximab 1039 –(59) 5.7(4.4–7.3) 5.1(4.0–6.6) UTI:–}

Bronchitis:–

Sepsis:–

UTI:–

2

(bronchopneu-moniaand

sepsis)

Genovese,200919 _{Rituximab 185 12(13) 7.0(3.8–11.7) 7.0(4.1–12.0) Gastroenteritis:}

4

Pneumonia:2

Diverticulitis:2

Bronchitis:1

UTI:2

Cellulitis:1

Septicarthritis:

1

0

Schiff,200920 _{Abatacept 1046 25(25) 2.4(1.6–3.5) – Pneumonia:6}

Bronchitis:3

0

CI95%,confidenceintervalof95%;URTI,upperrespiratorytractinfection;UTI,urinarytractinfection.

a _{Patientswhoparticipatedinthefirstsixmonthsoftheplacebo-controlledclinicaltrialwereincluded.}

b _{TheWinPepiprogramwasusedforcalculations,with95%CI,Fisher’sexacttest.}

c _{Theauthorofthisarticlereportedtheoccurrenceoftwodeathsnotattributedtoanakinra.}

twodeaths,theydidnotconsideranakinraasacausal fac-tor.Listing etal.22 _{reportedapatientwhodevelopedseptic} arthritis,whichprogressedtoosteomyelitis.

Threestudies17,21,22_{wereclassifiedasofintermediate} qual-ity,andafourthstudyreceivedalow-qualification16_(Table4).

Rituximab

Rituximabwas administered in 1224 patients evaluated in twoopen-labelclinicaltrialswithdurationsfromsix18_to1219 months(Table1).Heretoofemalegenderprevailed, witha meanage of51.8 years,withhigh RAactivity,according to DAS28(>5.1),andwithameandiseasedurationrangingfrom 11to12years(Table2).

Table3liststhetwostudiesrelatedtorituximabinwhich 72 episodesofsevere infection (5.9%)were reported inthe totalnumberofpatientstreated,andthehighestincidence wasnotedinthestudybyGenoveseetal.19_{Theseinfections} occurredinvarioussites,particularlyupperrespiratorytract (URT),urinarytract,andgastrointestinaltract.

AlthoughKeystone et al.18 _{havenot specifiedall severe} infectionsites,theseauthorsreportedtwodeathsattributed totheuseofrituximab:oneofthemdueto bronchopneumo-niaandtheotherduetoneutropenicsepsisaftertheuseof trimethoprim.

Both studies18,19 _{were classified as high-quality trials} (Table4).

Abataceptandtocilizumab

Onlyanopen-labelclinicaltriallastingsixmonthsevaluated abatacept.20_{Theauthorsincluded1046patientswithsimilar} characteristicsastogender,age,andRAdurationand activ-ityreportedinthestudiesrelatedtoanakinraandrituximab. Pneumoniaandbronchitiswerethemaintypesofinfection observed(Tables2and 3).Thequalityofthe Schiffetal.20 studywasconsideredintermediate(Table4).Intheperiodof thereview,noobservationalstudyevaluatedinfectionsinRA patientstakingtocilizumab.

Discussion

Table4–Qualityassessmentofselectedstudiesontheriskofsevereinfectionsinpatientswithrheumatoidarthritis

associatedwiththeuseofnon-anti-TNF-␣biologicalDMARDsusinganinstrumentbasedontheNewcastle-OttawaScale.

Assessmentofeachitem(selectionofparticipants,losses,outcome,andselectionofvariables)andofthetotalscore.

Firstauthor,year Selectionofparticipantsa _Lossesb _Outcomec _Totalscore

Nuki,200216 _{1 0 0 1}

Listing,200522 _{1 0 1 2}

Brassard,200621 _{1 0 1 2}

Fleischmann,200617 _{1 0 1 2}

Keystone,200718 _{1 1 1 3}

Genovese,200919 _{1 1 1 3}

Schiff,200920 _{1 1 0 2}

DMARDs,DiseaseModifyingAntirheumaticDrugs.

a _{Selectionofparticipants–1pointfordescribedsamplerepresentativeofthepopulation(complete,randomorsystematic).}

b _{Losses–1pointforproportionofdescribedlossesunder20.0%.}

c _{Outcomeevaluation–1pointforavailableordescribedoutcomemeasurementinstrument.}

Thestrengthsofthisreviewconsistofthewidesearch con-ducted,ofthe broaddefinitionofsevere infections,and of itsoriginality,takinginto accountthat, althoughother SRs fromobservationalstudieshavebeenpublished,such stud-iesdonotseparatelyevaluatethesesamedrugs.Wedetected only one review23 _{of observational studies that, although} assessingthesafetyofthetherapeuticdrugsevaluatedinthis study,presentedtheirresultscollectively,alsoincludingTNF-␣

antagonists.

Curtisetal.24_{describedacohort(1998–2011)inwhichthe} ratesofsevere bacterialinfections associatedwiththe use ofrituximabwere4.4(95%CI3.1–6.4)and,forabatacept,2.8 (95%CI1.7–4.7),per100patient-years.Ourresultsweresimilar sincethefrequencyofinfectionwasalsohigherforrituximab versusabatacept.

Ameta-analysispublishedbySinghetal.,25_which evalu-atedsevere infectioninpatientswithRAtreatedwithnine biologicdrugs, includedthesethreemedications studiedin ourSR,buttheauthorsdidnotincludeobservationalstudies andpresentedcollectiveresultsfortheninedrugs,showing anincreaseinsevereinfectionswiththeuseofbiologicalsin conventionaldoses(OR=1.90;95%CI1.50–2.39).

Theincidenceofinfectionsrelatedtotheuseofabatacept inthisstudy(2.4%),possiblyduetotheshortfollow-upperiod (sixmonths)ofthesingleidentifiedtrial,20_{wassimilartothe} incidencefoundbySalliotetal.11_{(2.5%)inarandomizedtrial} lasting12months.26

InthisSR,severeinfectionratesforanakinrawere hetero-geneous,rangingfrom1.3%inthesmallerfollow-upstudies (Nukietal.16 _{–12months,andListingetal.}22_–18months) to11.1%inthestudywiththelargestsample(1103patients) andwitha36-monthfollow-up.17_{InanSRthatincludedfour} clinicaltrialswithasix-monthduration,Salliotetal.11_found only1.4%ofsevereinfections.

In the studies included in our SR which evaluated rituximab,18,19_{thefollow-uptimes,ofsixto12months,were} similartothoseofthethreetrialsincludedbySalliotetal.11 Thus,thehighestfrequencyofsevereinfectionsattributedby ustorituximabcouldbepartiallycreditedtotheinclusion cri-terionofKeystoneetal.,17_{whoadmittedpatientsdiagnosed} withdiabetesmellitus,unlikethecaseinSalliotetal.’sSR.11

InthecomparisonofourSRversusSRspublishedbySalliot etal.11 _{andStorageetal.,}4_{weobservedthattherespiratory}

tractisthemainsiteofinfectionwithrespecttoanakinraand abatacept. However,withtheuse ofrituximab,urinary and gastrointestinaltracts(inadditiontotherespiratorytract)are alsomainsitesofsevereinfection,bothinourSRasinSalliot etal.11

Thenumberofpublishedobservationalstudiesonadverse events with the use of non-TNF-␣ antagonist DMARDs is

scarce.Thisisalimitationthataffectsthepresentreviewand alsootherpublishedreviewsonthistopic.11,27

Weemphasizethatinadditiontothefactthatsevere infec-tionshaveoccurredwithafrequencyconsideredascommon, theseinfectionshaveresultedindeaths(threein125severe infectionswithanakinra,twoin72withrituximab,andzero withabatacept).Ifwetakeintoaccountthatthemaximum follow-uptimeinmostofthestudiesanalyzedwasonlyabout threeyears,notallowingtheobservationofagreaternumber offatalcases,weemphasizetheimportanceofSRstothe clin-icalpracticeofrheumatology.Consideringtheriskofsevere infectionsbroughtaboutbythesedrugs,patientsshouldhave theirrespiratoryandurinarytractsregularlymonitoredwith anactivesurveillanceforinfections,particularlythosemore severeones,inordertopreventconditionssuchas bronchop-neumoniaorsepsis.

Funding

InstitutoNacionaldeInfectologiaEvandroChagas,Fundac¸ão OswaldoCruz.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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