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
Safe
use
of
biological
therapies
for
the
treatment
of
rheumatoid
arthritis
and
spondyloarthritides
Licia
Maria
Henrique
da
Mota
a,∗,
Bóris
Afonso
Cruz
b,
Claiton
Viegas
Brenol
c,
Daniel
Feldman
Pollak
d,
Geraldo
da
Rocha
Castelar
Pinheiro
e,
Ieda
Maria
Magalhães
Laurindo
f,
Ivânio
Alves
Pereira
g,
Jozélio
Freire
de
Carvalho
h,
Manoel
Barros
Bertolo
i,
Marcelo
de
Medeiros
Pinheiro
j,
Max
Victor
Carioca
Freitas
k,
Nilzio
Antônio
da
Silva
l,
Paulo
Louzada-Júnior
m,
Percival
Degrava
Sampaio-Barros
n,
Rina
Dalva
Neubarth
Giorgi
o,
Rodrigo
Aires
Corrêa
Lima
p,
Luis
Eduardo
Coelho
Andrade
qaMedicineSchool,UniversidadedeBrasília,Brasília,DF,Brazil
bInstitutoBIOCOR,BeloHorizonte,MG,Brazil
cDepartmentofInternalMedicine,MedicineSchool,UniversidadeFederaldoRioGrandedoSul,PortoAlegre,RS,Brazil
dEscolaPaulistadeMedicina,UniversidadeFederaldoEstadodeSãoPaulo,SãoPaulo,SP,Brazil
eMedicalSciencesSchool,UniversidadedoEstadodoRiodeJaneiro,RiodeJaneiro,RJ,Brazil
fMedicineSchool,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil
gUniversidadedoSuldeSantaCatarina,Florianópolis,SC,Brazil
hCentroMédicoAlianc¸a,Salvador,BA,Brazil
iMedicalSciencesSchool,HospitaldeClínicas,UniversidadeEstadualdeCampinas,Campinas,SP,Brazil
jOutpatientClinicofSpondyloarthritidesandOsteoporosis,RheumatologyService,EscolaPaulistadeMedicina,UniversidadeFederaldo
EstadodeSãoPaulo,SãoPaulo,SP,Brazil
kRheumatologist,Fortaleza,CE,Brazil
lMedicineSchool,UniversidadeFederaldeGoiás,Goiânia,GO,Brazil
mFaculdadedeMedicinadeRibeirãoPreto,UniversidadedeSãoPaulo,RibeirãoPreto,SP,Brazil
nRheumatologyService,MedicineSchool,UniversidadedeSãoPaulo,SãoPaulo,SP,Brazil
oDiagnosticsandTherapeuticSector,RheumatologyService,HospitaldoServidorPúblicoEstadualdeSãoPaulo,SãoPaulo,SP,Brazil
pTeachingHospitalofBrasília,HospitaldeBasedoDistritoFederal,Brasília,DF,Brazil
qRheumatologyService,EscolaPaulistadeMedicina,UniversidadeFederaldoEstadodeSãoPaulo,SãoPaulo,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received25June2013 Accepted30June2014
Availableonline27November2014
a
b
s
t
r
a
c
t
Thetreatmentofautoimmune rheumaticdiseaseshasgraduallyimprovedoverthelast halfcentury,whichhasbeenexpandedwiththecontributionofbiologicaltherapiesor immunobiopharmaceuticals.However,wemustbealerttothepossibilitiesofundesirable effectsfromtheuseofthisclassofmedications.TheBrazilianSocietyofRheumatology (SociedadeBrasileiradeReumatologia)producedadocumentbasedonacomprehensive literaturereviewonthesafetyaspectsofthisclassofdrugs,specificallywithregardtothe
∗ Correspondingauthor.
E-mail:[email protected](L.M.H.daMota). http://dx.doi.org/10.1016/j.rbre.2014.06.006
Keywords:
Rheumatoidarthritis
Spondyloarthritis Biologicals Immunobiologicals Security
treatment ofrheumatoidarthritisandspondyloarthritides. Thethemesselectedbythe participatingexperts,onwhichconsiderationshavebeenestablishedasthesafeuseof biologicaldrugs,were:occurrenceofinfections(bacterial,viral,tuberculosis),infusion reac-tions,hematological,neurological,gastrointestinalandcardiovascularreactions,neoplastic events(solidtumorsandhematologicneoplasms),immunogenicity,otheroccurrencesand vaccineresponse.Fordidacticreasons,weoptedbyelaboratingasummaryofsafety assess-mentinaccordancewiththepreviousthemes,bydrugclass/mechanismofaction(tumor necrosisfactorantagonists,T-cellco-stimulationblockers,B-celldepletorsand interleukin-6receptorblockers).Separately,generalconsiderationsonsafetyintheuseofbiologicalsin pregnancyandlactationwereproposed.Thisreviewseekstoprovideabroadandbalanced updateofthatclinicalandexperimentalexperiencepooledoverthelasttwodecadesofuse ofimmunobiologicaldrugsforRAandspondyloarthritidestreatment.
©2014ElsevierEditoraLtda.Allrightsreserved.
Seguranc¸a
do
uso
de
terapias
biológicas
para
o
tratamento
de
artrite
reumatoide
e
espondiloartrites
Palavras-chave:
Artritereumatoide Espondiloartrites Biológicos Imunobiológicos Seguranc¸a
r
e
s
u
m
o
Otratamentodas doenc¸asreumáticasautoimunessofreuumaprogressiva melhoraao
longodaúltimametadedoséculopassado,quefoiexpandidacomacontribuic¸ãodas ter-apiasbiológicasouimunobiológicos.Noentanto,háqueseatentarparaaspossibilidades deefeitosindesejáveisadvindosda utilizac¸ãodessaclassedemedicac¸ões.ASociedade BrasileiradeReumatologia(SBR)elaborouumdocumento,baseadoemamplarevisãoda literatura,sobreosaspectosrelativosàseguranc¸adessaclassedefármacos,mais especifica-mentenoquedizrespeitoaotratamentodaartritereumatoide(AR)edasespondiloartrites. Ostemasselecionadospelosespecialistasparticipantes,sobreosquaisforam estabele-cidas considerac¸õesquantoà seguranc¸adousode drogasbiológicas,foram:ocorrência deinfecc¸ões(bacterianas,virais,tuberculose),reac¸õesinfusionais,reac¸õeshematológicas, neurológicas,gastrointestinais,cardiovasculares,ocorrênciasneoplásicas(neoplasias sóli-dasedalinhagemhematológica),imunogenicidade,outrasocorrênciaserepostavacinal. Optou-se,pormotivosdidáticos,porsefazerumresumoda avaliac¸ãodeseguranc¸a,de acordocomostópicosanteriores,porclassededrogas/mecanismodeac¸ão(antagonistas dofatordenecrosetumoral,bloqueadordaco-estimulac¸ãodolinfócitoT,depletorde linfóc-itoBebloqueadordoreceptordeinterleucina-6).Emseparado,foramtecidasconsiderac¸ões geraissobreseguranc¸adousodebiológicosnagravidezenalactac¸ão.Estarevisãoprocura oferecer umaatualizac¸ão amplae equilibrada das experiências clínicae experimental
acumuladasnasúltimasduasdécadasdeusodemedicamentosimunobiológicosparao
tratamentodaAReespondiloartrites.
©2014ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
The treatment of autoimmune rheumatic diseases has
gradually improved over the last half century, and has
been expanded with the contribution of biological or
immunobiological therapy (also called biological agents or
disease-modifyingdrugs–DMD-biologicals).Thisentire
pro-cesshasbeenimplicatedinimprovingtherapeuticoutcomes
andthequalityoflife,aswellasinreducingthemorbidityand mortalityofpatients.1,2
Concomitantly,therehasbeenaproportional
strengthen-ingofRheumatologyasamedicalspecialty.Suchascenario
isvery favorableand signals an auspiciousperspective for
individualssufferingfromautoimmunerheumaticdiseases.
Monoclonalantibodiesandrecombinantmolecules(orfusion
proteins), able to interfere with the signaling of cellular
processes,multiplyinafastpace,andnewtherapeutic possi-bilitieswillbeprogressivelyadded.3–5
However,aswithanydrugclass,wemustbealerttothe
possibility ofundesirableeffects from the use of
immuno-biologicalmedicines–anaspectwhichbecomesevenmore
important,giventheintenseactionofthesemoleculeson vari-ousimmunologicalprocessesofcriticalimportance.Addedto this isthefactthatmanyofthetargetsofthesemolecules participateinmultiplephysiologicalprocesses,extendingthe rangeofpossibleeffectsoftherespectiveinhibitorsor antag-onistdrugs.
Security issues are important for the patient to attain
apositionofmaximumpossiblewell-being;suchquestions
tothe use ofimmunobiological agents usedin Rheumato-logy,theapplicationofthispremisecanhelpinchoosingthe bestoptionforeachpatient.Withtheadventofnew thera-pies,themainquestionsfrompatientsandphysiciansfocus notonlyonthebenefitsandcosts,butalsoonthesafetyof thesemedications.Thus,inadditiontoconsideringthe
mech-anismof action and pharmacological peculiarities of each
agent,includingdosage,plasmaandbiologicalhalf-lifeand routeofadministration,aswellastheopinion,adherenceand
thedegreeofunderstandingofthepatient,the
rheumatolo-gistmustweighthemajoradverseeventsforeachparticular scenario.6
With these considerations in mind, the Brazilian
Soci-etyofRheumatology(SociedadeBrasileiradeReumatologia/SBR) deemedappropriatetoelaborateatextonthesafetyaspectsof thisclassofdrugs.Thisdocumentrepresentstheconsensusof
themembersoftheCommissiononRheumatoidArthritis(RA)
ofSBRandofseveralinvitedexperts,includingmembersofthe
SBR’sCommissiononSpondyloarthritidesandother
rheuma-tologistswhoattended theIVForumonBiologicalAgents–
FocusonSafety,sponsoredbySBR.
Objective
Theaimofthisstudywastoprovideadocumentrepresenting theopinionofexperts,basedonextensiveliteraturereviewon aspectsrelatingtothesafeuseofimmunobiologicaldrugsin Rheumatology,specificallywithregardtothetreatmentofRA andspondyloarthritides.
Method
Themethod ofelaborationofthis paper includeda
litera-turereview, conductedbyrheumatology experts, members
oftheCommissiononRAofSBRandotherinvitedexperts,
membersoftheCommissiononSpondyloarthritidesofSBR
andparticipantsofIVForumonBiologicalAgents–Focuson Security,heldonJuly20/21,2012,inSãoPaulo,Brazil.The bib-liographicalsurveycoveredexistingpublicationsinMEDLINE,
SciELO, PubMed and EMBASEup to February 2013.
Recom-mendationswerewrittenandre-evaluatedbyallparticipants
duringmultipleroundsofquestioningandcorrectionsmade
viatheInternet.
Thethemesselectedbythe participating experts,about
considerations given regarding the safety of the use of
biological drugs in rheumatology, were: occurrence of
infections (bacterial,viral, tuberculosis), infusionreactions,
hematological, neurological, gastrointestinal and
cardio-vascular reactions, neoplastic events (solid tumors and
hematological lineage neoplasms), immunogenicity, other
occurrences and vaccine response. For didactic reasons,
we opted by elaborating a summary of the safety
assess-ment, in accordance with the previous themes, by drug
class/mechanismofactionand,separately,general consider-ationsonsafety intheuse ofbiologicalsinpregnancyand lactation.
Safetyassessmentbydrugclass/mechanismofaction
Tumornecrosisfactorantagonists(anti-TNF)
Tumor necrosis factor alpha (TNF␣) is a proinflammatory
cytokinethat exertsmultipleeffectsondifferent celltypes andplaysacriticalroleinthepathogenesisofchronic
inflam-matory diseases, such as RA, ankylosing spondylitis (AS),
psoriaticarthritis(PA),andarthritisassociatedwith inflam-matoryboweldiseases(enteropathicarthritis).7TNF␣exerts
cytotoxicactionondifferenttypesoflymphocytes, stimulat-ing their apoptosis andthat ofendothelialcells.Currently, therearefivedifferentanti-TNFbiologicalagents(alsocalled
TNFblockers)marketed:adalimumab(ADA),a100%human
monoclonalantibody;certolizumab(CERT)pegol,aFab
frag-mentofahumanizedanti-TNFantibodywithhighaffinityfor
TNF, conjugatedwithtwo moleculesofpolyethyleneglycol
(5–10% of animal protein); etanercept(ETN), a fusion
pro-teincomposedofTNFsolublereceptorplusFcregionofIgG;
golimumab(GOL),anotherhumanmonoclonalantibody;and
infliximab(IFX),achimericmonoclonalantibody(25–30%of
animalprotein).8WiththeexceptionofIFX,adrugfor
intra-venous (IV)use, the biologicalagentsofanti-TNFclassare drugsforsubcutaneous(SC)use.
Thebiologicalagentsoftheanti-TNFclassareprescribed
where there is no response, or only an incomplete
(par-tial) response was obtained, to basic conventional drugs,
mainly methotrexate(MTX), both inRA9,10 and PA.11,12 On
theotherhand,inASpatientsthesebiologicalsmaybe
pre-scribed after failure with continuous use of non-steroidal
anti-inflammatorydrugs(NSAIDs),incasesofpredominantly
axialdisease,andafterbasicconventionaldrugs,incasesof peripheraldisease.13,14
UsedinthetreatmentofRAforalmosttwodecades, anti-TNFagentsusuallyareusedforatleastfiveyearsin60%ofthe
patients,accordingtotheDutchRheumatoidArthritis
Moni-toringregister.15Itsuseforoveradecadehasnotpresented
serious riskswithrespecttolong-termsafety inRA.16 The
possibilityofsuccessiveexchangesofbiologicalagentsinthe
long-termfollow-upofpatientswithRAcanbringquestions
abouttowhatagenttoimputebeneficialoradverseeffects.17
Ontheotherhand,anti-TNFagentsrepresenttheonlyclass ofbiologicalagentscurrentlyinprovenuseinAS.Thereare recordsofgoodresponsemaintainedinfaceoftheuseofIFX foreightyears,18ETNforfouryears,19ADAforfiveyears20and
GOLfortwoyears.21Thereisnodifferenceinefficacyamong
thevariousanti-TNFdrugsinthetreatmentofAS.The
sud-dendiscontinuationofIFX,afteragoodsustainedresponse
forthreeyears,ledtorelapseinmorethan90%ofthepatients withina1-yearperiod.22Whileanti-TNFmaintenanceis
simi-larinASandRAafteroneyearoffollow-up,thepersistentuse ofanti-TNFinthelongtermissignificantlylongerinpatients withAS.23AlsoinPA,anti-TNFagentsmaintaingoodresponse
totreatmentovertime,withnodeadlinefordiscontinuation ofthesedrugs.24–26
Anti-TNFmedicationsarecontraindicatedinpregnantor
breastfeedingwomen,inpatientswithcongestiveheart fail-ure(CHF)classesIIIandIVaccordingtotheNewYorkHeart
Association (NYHA), in the presence ofactive infection or
lowerlimbs,septicarthritisinthepast12months),recurrent
pulmonary infections,multiple sclerosis, and with current
orpreviousdiagnosisofneoplasia(lessthanfiveyears).The
patient shouldbe carefullymonitored, with assessmentof
possible emergence of signs of infection, that should be
treatedpromptlyandimmediately.7–9
Infections
Inthemaintenanceofanyanti-TNFagent,bothatthe begin-ningoftreatmentandafteryearsofmedication,infectionis
the mostfrequentand importantadverseevent.Generally,
theseareusuallybacterialorviralinfections,mainly affect-ingtherespiratorytract,skin,softtissuesandurinarytract.27
Theriskofhospitalizationduetobacterialinfectionistwiceas highinpatientsusinganti-TNFthaninpatientsin monother-apywithMTX;thisriskincreasesfourtimeswhenconsidering thefirstsixmonthsoftreatment.28
Mostavailabledataontheriskofinfectioninpatientson biologictherapyconcernthefirstanti-TNFagents:IFX,ETN
andADA.Nodefinitivecomparativestudieswerepublished.
Meta-analysesandobservationalstudyassessmentsshowed
nosignificantdifferenceintheincidenceofinfectious
com-plications amongdifferent biological agents. Albeit with a
shorterobservationtime,thecurrentunderstanding isthat theneweranti-TNFagents,e.g.GOLandCERT,areassociated withthesameriskofinfection.29
Althoughclinicaltrialshavenotshownsignificantincrease
versusplacebo,meta-analyses, extensionstudies and
post-marketingregistriesconfirmedahigherriskofinfection in patientswithrheumaticdiseasesusingbiologicalagents.The relativerisk(RR)fordifferentformsofinfectionvariesfrom 1.2to2.8comparedtosyntheticornon-biologicalDMDs,e.g. MTX.29,30Severeinfections –definedasinfectionsrequiring
hospitalizationand/orIVantibiotics–andopportunistic infec-tionssuchastuberculosisandPneumocystiscariniiandfungal infections,alsoincreasedinpatients on biologictherapy.31
Theincidenceofinfectiouscomplicationsdonotincreasewith theprogressionoftreatmentandappearstobegreatestinthe firstmonthsofexposuretobiologicalagents.27,31
Variationsinthespectrumofsignsandsymptoms
asso-ciatedwithinfectionandatypicalclinical presentationsare
common,and this requires a careful monitoring and
clin-icalsuspicion fora correctdiagnosis.30 Skin infections are
amongthe most common adverse effects with the use of
anti-TNF.29Theyaccountforabout20%ofallinfectious
com-plicationsassociatedwithTNFinhibitors,beingsecondonly torespiratorytractinvolvement.30Cellulitisofbacterialorigin
andherpeszostervirusinfectionsareamongthemost
com-moncutaneousinfectiouscomplications.Althoughinfection
byherpeszosterismorecommoninRApatientsthaninthe
generalpopulation,recentstudiesshowanincreasedriskin usersofimmunobiologicaltherapy.32,33
Asinfectious complication,tuberculosisrequires special attention.ConsideringthatTNFplaysacentralroleinthe
for-mationandmaintenanceofgranulomaintegrity,tuberculosis
isanadverseeventthatshouldbepotentiallyveryfrequent,34
haditnotbeenitssystematicprevention,whichshouldnever beneglected.Mostcasesoccurinthefirstmonthsof
treat-mentwithanti-TNFandthefrequenciesofextra-pulmonary
tuberculosisandatypicalpresentationsarehigherinpatients usinganti-TNFagents.35
Observationalstudiesandmeta-analysessoughtto
eval-uatedifferencesintheriskoftuberculosisamongdifferent anti-TNFagents,andtheresultsareconflicting.Thecurrent understandingisthat,ifthereisadifference,thiswouldnot beofclinicalsignificance.36Theriskofreactivationof
tuber-culosisappearstobelowerwithotherbiologicalagents,but therearenodefinitivedata.Thatiswhyascreeningexamfor latenttuberculosisisinorder,aswellasitstreatmentinall patientsthatwilldependontheuseofbiologicalagents.
Likeotherspecialtysocieties,SBRrecommendsascreening
forlatenttuberculosisthroughepidemiology,chestimaging
andtuberculinskintest(PPD).37Whenavailable,␥-interferon
releaseinvitroassays(IGRA–interferongammareleaseassay), e.g.Quantiferon® or Elispot®, canenhance the accuracyof
a latenttuberculosisdiagnosis.38 Patients withevidenceof
latenttuberculosisshouldreceiveisoniazidforsixmonths.
During pregnancythere isaphysiologicalstateofimmune
suppression,whichisimportantforthemother’srelationship withfetalallogenicimmunogenicity.Atthispoint,thelevelsof
progesteroneincrease,withconsequentTh1toTh2-response
shift.Quantiferon®testdependsontheintegrityofthe
cellu-larimmuneresponseofTh1,andthustheperformanceofthis testmaybepoorerduringpregnancy.Whilepossiblywith clin-icalimportance,todatetherearenotestsavailableforusein clinicalpracticeallowingmonitoringtheonsetandintensity ofantibodiesagainstanti-TNFdrugsandotherbiologicals.
RegardingtheevaluationofLatentTuberculosisInfection (LTBI)inpatientswhoarealreadyinuseofsomeTNFblocker,
the epidemiological investigation ofcontactants and/or
re-exposuretomycobacteria shouldbedone actively atevery
outpatientvisit,inordertoensureanadequatesurveillanceof newcases.Inthepresenceofapositiveepidemiology, includ-ing personal,familyand professionaldata,arevaluationof LTBIisindicated.
InthecaseofPPDgreaterthanorequalto5mminpatients
withno priortreatmentofLTBI beforetheuse ofanti-TNF
agents, isoniazid must be initiatedand maintained forsix
months. There isno needto discontinue TNF antagonists
inasymptomaticpatients.Inthosesymptomaticpatients,a
properexpertevaluationiscritical.
Assuming the lack of consistent scientific data on the
necessityofrepeatingthetuberculinskintest(PPD),abooster test(PPD-Booster)andchestradiographyinthissetting,wedo
notrecommendthepracticeofroutineand/orannual
inves-tigation inasymptomaticpatientsand/orintheabsenceof
convincingepidemiologicaldata.
However, the rheumatologist may request a LTBI
re-investigation in doubtful cases of clinical management,
consideringthelocalprevalenceoftuberculosis,clinicaldata (alcoholismandmalnutritionandotherconditionsassociated
with immunosuppression,forexample)and socioeconomic
conditions. Thistopicwillbediscussedinmoredetailina
specificdocumentonthemanagementofendemicdiseases
inpatientswithRA,nowinproductionphasebySBR. InthepresenceofhepatitisBandCinfection,theuseof
anti-TNFshouldbeavoided.Inexceptionalcasesof
hepati-tis C virusinfection, anti-TNFdrugs canbeused, withthe
The treatment of other infectious diseases, including endemic/epidemicdiseasesinBrazil,suchasleprosy,malaria, Chagas disease, esquistosomiasis, leishmaniasis, filariasis, dengue,yellowfever,fungalinfections(blastomycosis, para-coccidioidomycosis,etc.),amongothers,willbediscussedin aspecificdocumentbySBR.
Infusionreactions
Most skin reactions related to the administration of TNF
inhibitorshavemildtomoderateintensityanddonotrequire
discontinuationofthedrug.39 Themostcommonreactions
are:erythema,urticaria,eczemaorrash,whichmay,inturn,
beaccompaniedbypainoredema.39Whiletheappearanceof
rashhasbeendescribedinapproximately6.9%ofthepatients onuseofIFX,40injectionsitereactionswerereportedin40%
ofthecaseswithETN41andin15%ofthecaseswithADA.42
Withrespecttothenewanti-TNFs,theincidenceofreactions attheinjectionsiteappearstobelower:2.3%withCERT43and
2.4%withGOL.44
Hematologicalreactions
Changes suchasthrombocytopenia, anemia (aplastic type)
andpancytopeniaarerarelyreportedduringanti-TNFtherapy,
althoughsomerecommendations,suchastheUKguidelines
andthe2012ConsensusoftheBrazilianSocietyof
Rheuma-tologyonTreatmentofRheumatoidArthritis,suggestblood
seriesmonitoring.37,45Todate,19casesofthrombocytopenia
weredescribedintheliteratureinassociationwithanti-TNF.46
Noneofthecaseswasassociatedwithsignificantclinical
con-ditionsor major bleeding. Moreover,leukopenia isa blood
seriesabnormalitythatmaybeseenalittlemorecommonly
insomepatientsunderanti-TNFtherapy.47 Inthissense, a
studyinvolving130patientsusingIFXreportedleucopeniain about12%ofthecases.48Thepossibilityofmarrowblockage
orperipherallysishasbeenevaluated,anditissuggestedthat thislatterpossibilityisthemostfrequent.49
The occurrence of neutropenia is defined as a
neu-trophilcount below1500/mm3 and the risk ofinfection is
increasedwithneutropenia<1000/mm3.Sofar,neutropenia
was reported in 111 patients using anti-TNF agents, most
ofthemdiagnosedwithRA,and96%werenotintreatment
withotherimmunosuppressivemedicationwithpotentialto
generateneutropenia.MostcaseswereusingESV(72.8%),
fol-lowedbyIFX(18.5%)andADA(9%).Onestudyshowedthat
twoimportantriskfactorsareaneutrophilcount<4000mm3
beforetheuseofanti-TNFandahistoryofneutropeniadue
tosyntheticDMDs.Thepresenceofsevereevents
accompa-niedbyneutropeniahasbeenreportedin6%ofthecases,with nodeathsassociated.46Consideringthedatacurrently
avail-able,theconclusionisthattheuseofanti-TNFseemstobe associatedwithlowerriskofhematologicalchanges,
throm-bocytopeniabeingaveryrareevent,andleucopeniadueto
neutropeniabeingthemostfrequentmanifestation.Asa
rou-tine,acellblood countcouldbeusefulimmediately before
startingandduringfollow-upofpatientsinuseof immunobi-ologicals.
Neurologicalreactions
Todiagnosetheneurologicaleventassociatedwiththeuseof
biologictherapy,thefollowingphenomenashouldbetaken
intoaccount:thecausallinkbetweentheuseandtheevent,
observation ofpartialor complete improvementafterdrug
withdrawal,relapseofsymptomsafterpossiblereintroduction ofthebiologicalagent,evidenceofneurologicalinvolvement and,ifpossible,comparisonwiththeexpectedincidencefor thepopulation.50
Various neurological disorders have been described in
patients on biologic therapy. Among them are: onset or
exacerbation of multiple sclerosis, optic neuritis and
var-ious forms of demyelinating peripheral neuropathy. The
prevalenceofdemyelinatingdisease induced bythe useof
biologicals, reportedinrandomizedcontrolledtrials andin
post-marketingstudiesonautoimmunediseases(RA,juvenile
idiopathicarthritis,spondyloarthritidesandCrohn’sdisease)
isestimatedtobebetween0.02%and0.20%.Ameta-analysis
ofthesestudiesshowedaprevalenceof0.05–0.20%.Thecases
are described mainly with the use of TNF␣ blockers (IFX,
ETNandADA)andwiththegreatestnumberofcases
occur-ring withmonoclonalantibodies.51 Themean elapsedtime
betweenthebeginningofabiologicalDMDandtheonsetof
symptomswas7.5months(range,2–18months)andwitha
favorableoutcomeafterdrugdiscontinuationandtreatment
in66%ofthecases.51
Demyelinating diseases of the central nervous
sys-tem (CNS) showed less favorable outcomes. Multifocal
leukoencephalopathy(MLE)exhibitedgreatercorrelationwith
natalizumab(takenawayfromthemarketduetothisevent)
and,toalesserextent,withalemtuzumabandalfalizumab,
allnotapprovedforuseinthetreatmentofRA.52Bythetime
ofpreparationofthismanuscript,MLEhadbeenconfirmedin acaseofapatientdiagnosedwithRAinuseofIFX.53
Guillain–Barrésyndromeisalsodescribedinpatientswith RAbeingtreatedwithanti-TNFsand,asoneofitscauses,viral infectionpriortotheeventmustberemembered,sincetherisk ofvirusinfectionisincreasedwhenusingtheseagents.54
Two studies which evaluated the use of anti-TNF for
multiplesclerosistreatmentwerediscontinueddueto
exac-erbationofthedisease,suggestingthedeleteriouseffectof theseagentsforthiscondition.55,56Ananalysisby
Fernández-Esparteroetal.,inSpain,comparingasystematicliterature review(SLR)ofcasereportsinthemedicalliteraturewiththe
Spanish register ofbiological agents BIOBADASER(Spanish
RegistryofBiologicalTherapiesinRheumaticDiseases)and
thepharmacosurveillancesystemofSpain,FEDRA(Spanish
Pharmacosurveillance DatabaseofAdverseDrugReactions)
failed to establish a clear association between the use of
anti-TNF(IFX,ETNandADA)forthetreatmentofrheumatic
disordersandtheoccurrenceofdemyelinatingdisease.57
Data from BIOBADASER, with an exposition of
13,075patients/yearwithadiagnosis ofRA,confirmed nine
casesofdemyelinatingdisease(22suspected,unconfirmed,
cases),withanincidencerateof0.69per1000patient-years
(95% CI: 0.36–1.32). The incidence of multiple sclerosis in
theSpanishpopulation(0.022–0.038)wassimilartotherate observedinpatientswhoreceivedanti-TNF(0.01–0.33).57Data
from FEDRA described 10 cases of demyelinating diseases
inRApatientstreatedwithanti-TNF,andSLRfound31case
reports.Themorefrequenttypesofdemyelinationwere: mul-tiple sclerosis,optic neuritisand peripheraldemyelinating
disease.Amongtherheumaticdiseasesstudied,RAaccounted
distributionbetweengenderandageandwithanincidence
ratelower than inPA (1.04/1000,95% CI:0,34–3.24) and AS
(0.70/1000,95%CI:0.17–2.79).InBIOBADASERregister,alonger
timeofanti-TNFexposition(mean,1.44years) andalower
recoveryrateofdemyelinatingdisease(43%)wereobserved.57
Thedifferencesbetweenthesedataandtheapparentlack
ofassociation betweentheuseofDMDforbiological
treat-mentofRAandtheoccurrenceofdemyelinatingdiseasecan
beexplainedbyamethodbiasforregistrationofcasesineach ofthesestudies,andbythedifficultyofanalysisofan appro-priatecontrolgroup.
Incontrast,a study witha case–control design,using a databasefromacohortofover10,000RApatients,suggested
thatanti-TNFagentswereassociatedwithanincreasedrisk
ofapproximately30%fordemyelinatingevents.58
Regarding the measuresemployed for the treatment of
neurologicalmanifestationsassociatedwithanti-TNF,
espe-cially in cases of CNS manifestations and mononeuritis
multiplex,thefollowingconductshavebeendescribed(alone
or in combination): high doses of oral- or pulse therapy
corticosteroids, IV Ig, plasmapheresis, cyclophosphamide,
azathioprineand cyclosporineA.Igandpulsetherapywith
corticosteroidshavebeenthemostusedmethods.The exclu-sivepracticeofwithdrawalofthebiologicalagentusedwas alsoperformed,insomecaseswithreversionornormalization oftheclinicalpicture.52
Beforestartingananti-TNF,oneshouldevaluatethe possi-bilityofpreviousneurologicalimpairmentthroughthehistory
and physicalexaminationinorder todetect andtreat
pre-viousneuropathyconditions.Neurologicalmanifestationsin
RAaremorefrequentinelderlypatients,inthediseasewith worseprognosticfactors,andinthepresenceofcomorbidities andotherconditionspotentiallycausing,orassociatedwith,
neuropathies.Theuseofanti-TNFagentsiscontraindicated
inpatientswithdemyelinatingdisease–especiallyinthose withcurrentorpriordiagnosisofopticneuritis, demyelinat-ingperipheralneuropathyandmultiplesclerosis.Infaceof
asuspicionofdemyelinatingdisease,the anti-TNF
medica-tionshouldbeimmediatelydiscontinued,seekingtoestablish
whether thereisacausal relationshipbetweenmedication
use andonset ofsymptoms.Itissuggestedthat
investiga-tionsbecarriedoutandtherightdocumentationbecollected, dependingonthetypeofneurologicalmanifestation,inorder toexcludethepossibilityofneurologicaldisordersunrelated tothebiologicalagent.
Thetreatmentshouldbeindividualizedforeachpatient,
dependingontheseverityandneurologicalmanifestations,
and pulseor high-dose corticosteroids, Ig, plasmapheresis,
cyclophosphamide,azathioprineand cyclosporineAcanbe
used.Ifre-introductionofabiologicalagentforcontrolofRA activityisneeded,thepreferenceshouldbeforanon-anti-TNF agent,suchasrituximab(RTX)orabatecept(ABAT).
Gastrointestinalreactions
Gastrointestinalandhepaticmanifestationsassociatedwith
anti-TNFareuncommon.
Cardiovascularreactions
Rheumaticdiseases of inflammatorynature are associated
withhighmortality,mostlyfromcardiovascularmortality.59,60
Severalstudieshavefoundanincreasedoccurrenceof
cardio-vasculareventsinRAandAS,andthisfindingcanbejustified
bythe increaseininflammatorycytokinessuchasTNF,an
accelerated atherosclerosis,endothelial dysfunction,use of
other medications thatcause cardiovascular morbidityand
mortality,presenceoftraditionalcardiovascularriskfactors, andthegeneticheritageoftheindividual.61
Diseases suchasRA, ASand CHF have incommon the
presenceofhighlevelsofinflammatorycytokines,particularly TNF.62Inthissense,theattempttotreatCHFwithanti-TNF
appearedtobeanalternative.However,theuseofanti-TNFfor thetreatmentofpatientswithheartfailure(functionalclasses IIIandIV–NYHA)didnotshowbenefit,63 beingassociated
withalargenumberofadverseeventsanddeaths,leadingto prematureterminationoftheseclinicalstudies.64Inaddition,
someindividuals withnoprevious historyofheart disease
developedCHFwiththistreatment;acompletereversionof
thiscomplicationoccurredwithdiscontinuationofthe anti-TNFagent.65Thisfactledtotheterminationofstudiesandput
severeCHFasacontraindicationtoanti-TNFtherapy.Thus,
wehadadilemma:anti-TNFagentscouldimprove,or
pos-sibly trigger or aggravate cardiovascular events in patients withRA?Ononehand,itwouldbebiologicallyplausiblethat thereductionintheinflammatoryprocessthroughtheuseof anti-TNFagentswouldtheoreticallyreducetheriskofheart failure.Ontheotherhand,theanti-TNFagentcouldincrease theriskofheartfailureinpatientswithRA,justasoccurred inthegeneralpopulation.66 Totrytosolvethisdilemma,in
this topic we willanalyze studies evaluating anti-TNF and
cardiovasculareventsinRA,andnotinotherinflammatory
rheumatic diseases, because, in addition of being strongly
associatedwithcardiovascularevents,RAisfavoredwiththe mostrobustpublishedevidence.Aglobalandindividual anal-ysisofthecardiovascularriskwillbeperformed,takinginto accountmyocardialinfarction(MI),strokeandCHF.
Theriskoftheuseofanti-TNFandcardiovasculareventsas awholewasassessedinsevenstudiesinvolvingRApatients,
including a randomized controlled trial, four cohorts, one
case–control study and onecross-sectionalstudy.The
gen-eralconclusionisthatanti-TNFtherapyreducestheincidence ofcardiovasculareventsasawhole,withadeclineofRRto 0.46 (95%CI:0.25–0.85).67–71 Sevenstudies(one cohort, five
case–controlstudiesandonecross-sectionalstudy)evaluated
theriskofMIinpatientswithRAandfoundnodifferences
between subjectsreceiving anti-TNFand the controlgroup
(treatedwithsyntheticDMDs),althoughinthosepatientswho
had a good to moderate EULAR (European League Against
Rheumatism)responseaftersixmonthsoftreatment, aRR
reductionof64% (95%CI:0.19–0.69%)wasnoted,compared
withnon-EULARresponders.72–78
Theriskofstrokewiththeuseofanti-TNFwasassessed inRApatientsinfourstudies(onecohort,onecase–control studyandtwocross-sectionalstudies).Theconclusionofmost ofthesestudiesisthatTNFantagonistswerenotassociated withariskofstroke,andapparentlyinthoseindividualswho respondedtoanti-TNFandtothecontinueduseofthesedrugs formorethansixmonths,theriskofstrokewasreduced.79
TheoccurrenceofCHFduringtheuseofanti-TNFinRA
patients was assessed insix studies (fivecohorts and one
case–control study).80–85 The results of these studies were
maybeassociatedwithanincreasedriskofCHF,84 inthose
patientsagedlessthan50yearstheconclusionstillisnotfinal.
Thegeneral conclusionon this topic isthat the use of
anti-TNFinRApatientsappearstobeassociatedwithless
cardiovascular morbidity when the changes are evaluated
together.However,theindividualriskassessmentofstroke, MIandCHFstillhasnodefinitiveconclusions.
Solidneoplasms
It is speculated if the long-term use of biological DMDs
could contributetoan increasedriskofcancer inpatients withinflammatorydiseases.Itisnotyetclearwhetherthe
malignancy is a consequence of chronic inflammation, or
of therapies used to treat inflammatory diseases such as
RA.86 Studies show that, in RA, there is a greater risk of
certainmalignancies,includinglymphoma,lungcancer,
non-melanomaskincancerandpossiblymelanomaandleukemia.
Currentevidencesuggeststhatthisoccursduetouncontrolled inflammationandpossiblytosmoking.86
BeforetheadventofbiologicalDMDs,theincidenceofsolid
cancersin patients diagnosedwith RAmirrored whatwas
seeninthegeneralpopulation,includinglung,colorectal,skin, breast,prostate,bladder,ovaryandpancreasneoplasms,and thisscenariohasnotchangedsignificantlysincethe
intro-ductionofnewtherapies.87WolfeandMichaudobservedin
13,001patients from the National Databank forRheumatic
Diseasesthattheuseofbiologicalswasnotassociatedwith anincreasedriskofsolidtumors.88
Skin tumors are among the possible manifestations
associatedwiththe useofanti-TNFagents.Evidence ofan
increasedriskofnon-melanomacarcinomataamongpatients
treatedwithanti-TNFincludeoneregistrydatameta-analysis, prospectiveobservationalstudiesandrandomizedtrials.88–91
The most common neoplasms are non-melanoma skin
cancers, mainly basal cell carcinoma and, less frequently,
squamouscellcarcinoma.89–94Casesofmalignantmelanoma,
however,havealsobeendescribedinpatientsusinganti-TNF therapy.95–104 Althoughtheexact role ofthesedrugsinthe
development of melanomas is not well established, one
shouldpaycloseattention tothe appearanceofpigmented
lesionsorchangesinthecharacteristicsofpreexistingnevi.39
When in doubt, in order to obtain a correct explanation
of the picture, an histopathologic study of the lesion is
recommended.
Regardingtherecurrenceofsolidcancerafteruseofa bio-logicalagent, little isknowndue tothe exclusionofthese patientsintheirparticipationinclinicaltrials.10 Inpatients
treatedforsolidcancerduringmorethanfiveyears,wecan recommendtheuseofanybiologicalagent.Inpatientsunder fiveyearsoftreatment,RTXshouldbethebiologicalchoice.
Thus,although noincreased riskwas observedfor cancer,
exceptfornon-melanomaskincancer88–91inpatientsusing
anti-TNFagents,surveillancefortheoccurrenceof malignan-cies(includingrecurrenceofsolidtumors)inpatientstreated withTNFinhibitorsremainsappropriate.
Lymphomas
Sincepre-biologicaltimesitisknownthattheestimatedrisk
ofapatientwithRAdevelopinglymphoma(especially
non-Hodgkin’s)isabout twotimes higherthan that forgeneral
population.105–107ASwedishcase–controlstudyshowedthat
thisriskisdirectlyrelatedtotheintensityanddurationofthe inflammatoryprocess.108,109
TNF isknowntohavea roleinsurveillance againstthe
developmentofneoplasia;therefore,itsinhibitionhasbeen
seen as a possible riskfactor forthe onset oftumors. On
the other hand, coincidingwith thebeginning ofanti-TNF
therapy,thegeneralwaytotreatthisdiseasechangedalot.
Overthe past15 years,muchemphasiswas giventoearly
diagnosis and to a strict control of disease activity. This
changecouldpotentiallyreduce,forexample,theriskforthe onsetoflymphoma.Nevertheless,oneshouldnotforgetthat, untilrecently,theanti-TNFtherapywasrestrictedtopatients refractorytotraditionaltreatment,i.e.,oflongdurationand
withhighinflammatoryburden.Notsurprisingly,therefore,
thatthedatarelatedtotheriskoflymphomaassociatedwith theuseofanti-TNFtherapyareconflicting.
Inarecentmeta-analysisinvolving63randomizedclinical trials (RCTs)with29,423patients withRA,the riskof
lym-phomaamongusersofanti-TNF,comparedwiththeriskof
controlsubjects, wasdoubled (oddsratio[OR]=2,1;95%CI: 0.55–8.4);however,thisdifferencewasnotstatistically signifi-cant.Theauthorsofthismeta-analysispointoutthatthe lim-itednumberofpatientsandthereducedfollow-uptimeofthe RCTslimittheextrapolationofthesedatatotheprolongeduse ofthesedrugs.110Intheanalysisofthefirstcasesoflymphoma
amonganti-TNFtherapyusers,halfofthemwerediagnosed
inthefirsteightweeksoftreatment.111Todate,thereisno
evidenceoftheemergenceofanincreasingriskoflymphoma
relatedtotheprolongeduseofanti-TNFagents.86,112
One SLR and a meta-analysis of observational studies
andregistries,alsorecentlypublished,confirmedthat, com-paredwiththegeneralpopulation,patientstreatedwithTNF
inhibitorshaveanincreasedriskoflymphoma(standardized
incidence ratio=2.55, 95% CI: 1.93–3.17).89,113–115 But when
comparedwithRApatientstreatedwithsyntheticdrugs,this increaseintheriskforlymphomawasnotobserved(estimated risk=1.11,95%CI:0.70–1.51).88,116,117
Immunogenicity
Anti-human chimeric antibodies (HACA) and human
anti-humanantibodies(HAHA)mayoccurwiththeuseofanyofthe drugsinthisclass,buttheireffectontheeffectivenessof ther-apyisunclear.Theinductionofantibodiesagainstanti-TNF agentsdependsmainlyontheirstructure.Chimericmolecules
haveagreatercapacitytoinduceimmunogenicity,compared
withfully humandrugs.Amonganti-TNFagents,this
phe-nomenon hasbeen studiedmainly inIFX users,especially
inthosewithRAorCrohn’sdisease.Theprevalenceof
anti-IFXantibodiesinRArangesfrom12%to44%andappearsto
beinversely relatedtoserum levelsand tothetherapeutic
responsetomedication.TheuseofETNwasassociatedwith
thedevelopmentofanti-ETNantibodiesin0–18%ofpatients, withoutanyapparentimpactontheefficacyoronthe occur-renceofadverseevents.StudiesinpatientswithRAandwith
Crohn’s disease show the presenceof anti-ADA antibodies
in1–87%ofpatients.In25childrenwithjuvenileidiopathic arthritis,8%hadanti-ETNantibodies.118,119
ThemethodsmoreoftenusedforthedetectionofHACA
andradioimmunoassay.Thepresenceofanti-IFXantibodies inRApatientsmaysuggestapoorertherapeuticresponseand anincreasedriskofinfusionreaction.However,perhapsthese sameconclusionsmaynotbeobservedinrelationtoanti-ADA andanti-ETNantibodies.ImmunologicaltolerancetoADAand
IFXmaybeincreasedwithaconcomitantuseof
immunomod-ulatorssuchasMTXandazathioprine.Thereisnoevidence
intheliteratureofcross-reactivityofHACAandHAHAforthe differentanti-TNFagents.119
Otherreactions
Amongthemanifestationsnotpreviouslymentioned,those
ofdermatologicalorigin areofspecialinterest.Skin condi-tionsdescribedinanti-TNFinhibitorusersmaydidactically bedividedinto:skinreactionsrelatedtotheiradministration,
skininfections,skinneoplasms(previouslymentioned)and
immune-mediateddiseases.
Amongtheimmune-mediateddiseases,theonsetof
pso-riasishasbeendescribedfollowingtheuseofseveraldrugs
such as anti-malarials, anti-inflammatory drugs and
beta-blockers.97 In the caseof association ofpsoriasis withthe
use ofanti-TNF, the aspect that seems paradoxical is the
onsetofpsoriaticskin lesionswiththe useofadrug indi-catedfortheirtreatment.Theprevalenceofthisphenomenon
is varied, but according to some studies, it lies between
0.6%and 5.3%.98,99,120 Themean latencytime betweenthe
start ofthe TNF inhibitor and the onset ofskin lesions is
10months; however,this timemay varyfrom several days
toseveral years.97,101–103 Thethree maintypesof psoriatic
lesionsobservedare:pustular,about 56%;en plaque, inhalf ofthe cases; and guttate in about 12% ofthe cases.104 In
approximately 15% ofthe patients, morethan one typeof
lesion is present.104 The most characteristic clinical form
associated with the use of TNF inhibitors is pustulosis
palmoplantaris.104
Initially, theselesions were considered asa hypersensi-tivityreaction tothedrug. Subsequenthistologicalstudies,
however, showed that the lesions were identical to those
occurringinpeoplewithidiopathicpsoriasis.102,120Ingeneral,
patientswhodevelopthistypeofadverseeffecthaddisplayed agoodresponsetoanti-TNF,suchthattheappearanceofthe skinlesionaffectsnegativelytheeffectivenessofthe treat-ment.
Considering that most of the described cases of this
associationoccurred inRApatients,wecannotforget that,
from the beginning, it may be a case of PA, since in up
to 15% of the patients with this illness the joint
condi-tionemerges beforetheskincondition.Ontheother hand,
maybe this could be only the case of an association of
twoconditionsthatarenotrare.104Thecoexistenceof
pso-riasis and RA, however, is infrequent (about 2%), while
the onset ofpsoriasis induced byTNF inhibitors occurs in
about 3% of the patients with spondyloarthritides and in
2–5% of those with RA, an incidence much higher than
expected.98,102,120
Reportsofcutaneouslupus,121–124alopeciaareata,99,125–133
cutaneous vasculitis,134–138 vitiligo,135,139,140 relapsing
polychondritis,141polymyositis/dermatomyositis,142,143
local-izedscleroderma(morphea),144–146granulomaannulare,135,147
lichen or lichenoid reaction,120,135,148 and pemphigus149–151
weredescribedwiththeuseofTNFinhibitors.Thecauseand
effect relationship of these associations, however, are not
wellestablished.
Vaccinationresponse
Regardingvaccination,theresponsetoinfluenzavaccinedoes
notseemtobeimpairedinpatientsusinganti-TNFagents,
even whencombined withMTX.152–154 However,an author
showedareducedresponsetothisvaccine,whenevaluating
patientsusingIFXassociatedwithMTXorETN.155Similarly,
astudy conductedinBrazil,evaluatingthe H1N1influenza
vaccine,found,besidesagoodsafetyprofile,areducedserum protectioninRApatients,regardlessofdiseaseactivity.MTX
wastheonlyDMDassociatedwithreducedresponsetothe
vaccine.156Asforthepneumococcalvaccine,theuseofMTXin
isolation,oritsusecombinedwithsomeanti-TNFs(ADA,ETN andIFX),maydecreasetheeffectivenessofthevaccine,while theuseofthesebiologicalsinisolationdoesnotinfluencethe vaccineresponse.153,155Additionally,theuseofanti-TNFcould
significantlyreducetheresponsetohepatitisBvaccine.157
Vaccineswithliveattenuatedcomponentsshould
prefer-ablybeadministeredthreetofourweeksbeforeinitiationof
immunosuppressivetherapy,toensurethatviralreplication
finishedbeforethealterationoftheimmunecompetenceof
thepatient(intermsofdruguse).Otherwise,undertreatment, thevaccinationshouldbedelayedforatleasttheequivalent timeoffourhalf-livesofeachanti-TNFdrug.158
T-cellco-stimulationblocker–ABAT
ABATisahumanfusionproteinconsistingoftheextracellular
domainofhumanCTLA-4linkedtothemodifiedFcportion
ofhumanimmunoglobulin (Ig)G1.ThisdruginhibitsT-cell
activationforbindingtoCD80andCD86,therebyblockingits interactionwithCD28(theco-stimulationreceptor).159ABAT
wasapprovedinDecember2005bytheFoodandDrug
Admin-istration(FDA) forRA patients,both fortherapeuticfailure withsynthetic,asbiological,DMDs.InBrazil,theSBR
Consen-sus(2012)ontreatmentofRAsuggestthatABATcanbeused
inpatientswithactiveRAthatfailedwithsyntheticDMDs,
preferably whenthese drugswere usedin combination,or
aftertheuseofananti-TNF.ABATcanbeusedpreferablyas
monotherapy,orcombinedwithasyntheticDMD.37
ASLRontheuseABATinRApatientspooledseven
stud-iesand2908patients.InthisSLR,totaladverseeventswere
slightly more common with ABAT compared with placebo
(RR=1.05, 95% CI: 1.01–1.08) and severe infections in 12
monthsweremorecommonwithABATversuscontrolgroup
(OR=1.91,95%CI:1.07–3.42).160Pooleddatafrom4149patients
enrolledinseveralpivotalstudiesdemonstratedthatthe inci-denceofseriousadverseevents(95%CI)withABATisverylow, withgradualdecreaseateachyear.161,162
RegardingsecurityofABATinteractionwithMTXorother
DMDs, the extension ofthe AIM (Abatacept in Inadequate
responderstoMethotrexate)studyshowedefficacyandsafety
ofABATcombinedwithMTX.163TheASSURE(AbataceptStudy
ofSafetyinUsewithOtherRATherapies)studyalsoshowed
safetyofcombiningABATwithMTXandwith
Infections
ABATis contraindicated inpatients with active infections,
including skin ulcers, infected prostheses,and in catheter
users.165Theriskofseriousinfectionisreportedin2.9%with
ABATversus1.9%forplacebo.164Thecombinationwithother
biologicalsincreasesthe risk(serious infection5.8%versus 1.6%).164 ABAT does notincrease Mycobacterium tuberculosis
infection,andonlyninecasesoftuberculosisin4149patients treatedovertime(12,132patient-years)havebeenreported.162
Astudy withmicedemonstrated thesafety ofthisdrug in
relationtotuberculosisinfection.166Inthisstudy,chronicM.
tuberculosisinfectionwascausedinC57BL/6mice.Afterfour monthsofinducedinfection,miceweretreatedwithdifferent biologicalagentsforupto16weeksinthreedifferentgroups
(one groupwithABATand the other twowithanti-TNF or
placebo).InmicetreatedwithplaceboandABAT,tuberculosis controlwasmaintained,with100%ofsurvivalafter16weeks oftreatment.Micetreatedwithanti-TNFhad100%of mortal-ityatnineweeks,withweightlossandincreasedbacterialload inthelungs,lymphnodesandspleen.Thus,itwasconcluded thatABATdidnotexacerbatetheinfectionwithM.tuberculosis
inmice.166
Asforthosepatientswho initiatedtheirtreatmentwith otherbiologicalagents,screeningtestsforhepatitisBandC mustbeperformedbeforethestartofABAT.161
Infusionreactions
The infusion reactions with ABAT are rare, with 3.9/100
patient-years in six studies reviewed involving 3755
patients.162 The most common symptoms are dizziness,
nausea,headacheandhypertension.Severehypersensitivity
reactionsarerare(0.4%versus0.2%withplacebo).162,167
Hematologicalreactions
To date, no studies evaluating hematological changes and
ABATinrheumaticdiseaseswerepublished.
Neurologicalreactions
Todate,noreportsofperipheralneuropathyorCNS involve-mentassociatedwiththeuseofABATwerepublished.
Gastrointestinalreactions
Liverenzymechangesaremildandrareinpatientstreated
withABAT(0.1–1%ofpatients)and thushave littleclinical value.ItappearsthatthecombinationwithMTX,NSAIDs, cor-ticosteroids,sulfasalazineandleflunomidedoesnotincrease theoccurrenceofhepatotoxicity.161
Cardiovascularreactions
Regarding the increased cardiovascular risk in patients
with RA, studies have shown that the use of ABAT
deter-minesnogreaterrisk.161,162Cardiovasculardiseasedoesnot
contraindicatetheuseofABATandthisdrugdoesnot
inter-act with cardiovascular drugs, nor with the use of oral
anticoagulants.162
Neoplasms
Solidneoplasmsandlymphomas
Therisk ofmalignancies, e.g.,non-melanoma skin cancer,
lung cancer,colorectal cancer and breast cancer,for ABAT
usersiscomparablewiththeriskforRApatientsinuseof syn-theticDMDs.162Onestudyanalyzedsevenclinicaltrialswith
4134patientsversusRApatientsfromfivecohorts(41,529RA patients,withameanfollow-upbetween1.8and9.3years).In thepopulationtreatedwithABAT,alymphomaratesimilarto thatindifferentcohortsofRAwasfound,withastandardized incidencerate=0.89(95%CI:0.36–2.15).168
Regarding the riskof lymphomaand other
hematologi-cal diseases,double-blindand openstudies involving 4149
patients treated with ABAT (11,658 patient-years) showed
hematologicmalignancyoccurringonlyin0.13/100
patient-years(similartoRA),butjustaswithanti-TNFbiologicals,the
useofABATshouldbeavoidedinpatientswhohadlymphoma
overthepastfiveyears.161
Immunogenicity
Unlikewhatwasobservedwiththeuseofanti-TNF
biologi-calDMDs,antinuclearantibodies(ANA)andanti-DNAdidnot
becomepositiveovertimeinpatientstreatedwithABAT.162
ThereappearsthattheformationofHACAandHAHAusing
ABATdoesnotoccur.
Otherevents
The use of ABATis contraindicatedin patients with signs
ofchronicobstructivepulmonarydisease(COPD),becauseof
the exacerbation of dyspnea and an increased occurrence
ofinfections.37Studieswerepublishedontheoccurrenceof
psoriasiformrash,169aswellaslupus-likesyndromeand
Sjö-gren syndrome,170 possibly in association with the use of
ABAT.
Theriskofdevelopmentofautoimmuneeventswiththe
use of ABAT, based on pooled data of 4149 patients and
12,132patient-years,showedrarecasesofcutaneous
psori-asis(OR=0.60),Sjögren’ssyndrome(OR=0.26)andvasculitis (OR=0.34).162
Vaccinationresponse
RegardingvaccinationinRApatientsinuseofABAT,a
sub-analysisoftheARRIVE(AbataceptResearchedinRAPatients
withanInadequateanti-TNFresponsetoValidate
Effective-ness) study evaluated the efficacy and safety of influenza
vaccinationin20patients.171Atotalof55%,50%and35%of
thepatientsdevelopedvaccineresponsetoH1N1,H3N2and
influenzaBvirusstrains,respectively.AstudyinBrazil
inves-tigated the humoral response tovaccination against H1N1
fluvirusin11RApatientstreatedwithMTXincombination
withABAT.172Only9%ofthepatientstreatedwiththe
combi-nationofMTXandABATachievedseroprotection,compared
with 58%ofpatients treatedonlywith MTX andwith 70%
ofhealthyindividuals.Schiffetal.investigatedtheresponse
toanti-pneumococcalvaccinein21patientswithRAtreated
withABATinasub-analysisoftheARRIVEstudy.173Ofthese
21patients,81%exhibitedimmuneresponsetoatleastone
serotype.173
B-cell
depletion
drug
–
RTX
RTX is a monoclonal antibody directed against
activity, with treatment failure to an anti-TNF agent.37,174
RTX is used preferably in combination with MTX, and
may be prescribed in association with other DMDs. RTX
hasabettertherapeuticresponse inpatientswithpositive serology for rheumatoid factor (RF) and/or anti-cyclic cit-rullinatedpeptide(anti-CCP)antibodies.175 Individualswith
good response to treatment may be subjected to a new
courseofRTXifthediseaseisreactivatedinatimeinterval <6months.176
Inameta-analysisthatincluded938patientstreatedwith RTXandunresponsiveorintoleranttosyntheticDMDsor anti-TNFagentsfollowedduring24–48weeks,itwasobservedthat theincidenceofadverseeffectsinallsystemswasnothigher thaninthosepatientstreatedwithplacebo(RR:1.062,95%CI: 0.912–1.236,p=0.438).Withregardtothenumberofpatients whoexperiencedatleastoneseriousadverseevent,no signif-icantdifferencebetweenthosetreatedwithRTXandplacebo wasobserved(RR:0.855,95%CI:0.622–1.174,p=0.333).177The
long-termsafetyaftermultipleinfusionsofRTXwasalso ana-lyzedinarecentpublication.178 Submitteddataare pooled
fromeightRCTsandtwoopen-labelextensionstudies,
includ-ing atotal of3194patientswho received up to17 courses
ofRTXover9.5years(4418patient-years).Thepercentageof
infectionsand seriousadverse eventsremainedstableover
timeandaftermultipleinfusions.178
RTXiscontraindicatedinpatientswithhypersensitivityto thisdrugortoothermurineproteins,withactiveinfectionand severeheartfailure.179
Infections
Withregardtoinfections,ameta-analysisthatincluded745
patients treated with RTX in three RCTs found that there
wasnoincreasedriskforserious infectionscomparedwith
placebo.180
IntheaforementionedstudybyvanVollenhovenetal.178
the percentage ofserious infections was 3.94/100
patient-years(3.26/100 patient-years inpatients observedformore
than five years) and was comparable to that for the
placebogroupassociatedwithMTX(3.79/100patient-years). AdecreaseinIglevelswasobservedfromfourmonths,after atleast onecourse ofRTX, but the clinical significanceof thisisuncertain.ThesubgroupofpatientswithlowIgG
lev-elsshowed ahigherrisk ofserious infections comparedto
patientswhoneverpresentedthisfinding,buttheriskof infec-tionwasalreadyincreasedinthesepatients,evenbeforethe onsetofIgGleveldecrease.IgGlevelsmustbemeasuredprior totreatmentwithRTXandmonitoredovertime.179Lowlevels
ofIgMwerenotassociatedwithanincreasedriskofinfection. Regardingtuberculosis,RTXisapprovedforpatientswho
do not respond or are intolerant to anti-TNF. Thus, most
patientswhousedRTXhavebeenpre-selectedforlatent tuber-culosisinclinical trials and in dailypractice.With that in mind,reactivationoftuberculosiswasnotobserved,despite thepackageinsertrecommendingasearchforlatent tubercu-losisbeforestartingthemedication.36,181
RegardinghepatitisBandC,expertsrecommendthat sero-logyforhepatitisBshouldbeperformedpriortoinitiationof
treatmentwithRTX.179Reactivationhasbeendocumentedin
bothnegativeandpositivepatientstohepatitisBvirussurface antigen(HBsAg),182,183 emphasizing the needtoinvestigate
notonlyHBsAg,butalsootherantibodiesagainstcore anti-gen(HbcAg–hepatitisBcoreantigen)toidentifyapositive stateofcarrier.ThenegativityforHBsAg(alsowith negativ-ity foranti-HBsantibodies) identifies the groupofpatients
requiring vaccination prior toimmunosuppressive therapy.
A search forhepatitis Bvirus DNA (HBV-DNA) is not
indi-cated as screening tool, but for investigation ofviral load
and response in chronic infection established byhepatitis
B.Althoughthereisvariationamongcurrentlyexisting
rec-ommendations,itisgenerallyconsideredthatthose
HbsAg-and/oranti-HBc-positivepatientsshouldbetreated
prophy-lactically. The treatment of occult infection by hepatitisB virus withanti-HBc-positiveinisolationremainsuncertain:
insuchpatients, HBV DNAcould bedetermined,and then
prophylaxis could be considered, with close patient
mon-itoring. Routine evaluation for hepatitis C should also be
considered.184–189
Infusionreactions
The most frequent adverse events are infusion reactions,
whichoccurin30–40%ofthepatientsduringthefirst infu-sionandaboutin10%atsecondinfusion.190Inmostcases,
thereactionsareofmildtomoderateintensity.Severecases requiringdrugdiscontinuationoccurinlessthan1%oftreated
patients.179 Sixty minutes before each RTX infusion, the
patientmustbetreatedwithIVmethylprednisolone100mg,
acetaminophen1gandantihistamines,toreduceseverityand frequencyofinfusionreactions.190
Hematologicalreactions
TheeffectonBlymphocyteswithdepletionofthesecellsis
expected,andispartoftheactionmechanismofthisdrug.
However, asignificant reductionintotal lymphocytecount
isnotexpected.ThesafetyofB-celldepletionaftermultiple infusionsofRTX,especiallyrelatedtothecumulativeriskof seriousinfectionsandmalignancies,isnotfullyestablished inpatientswithRA.178Hematologicadverseeventshavenot
beenshowntoberelevantinlong-termstudies.178,191
Neurologicalreactions
Todate,sixcasesofMLEwerereportedinpatientswithRA
treated with RTX.178,179 Most cases had long-term RA and
were users ofmultiple immunosuppressants. The number
ofreported casesofMLEinpatients diagnosedwithRAin
useofRTXconfersariskof0.4/100,000patient-years,slightly
increasedcompared tothe generalpopulation(0.2/100,000)
andlowerthanthatobservedinpatientswithsystemiclupus erythematosus(4/100,000).53Thus,althoughtheoccurrenceis
consideredrare(1:20,000)duetothehighmorbidityand mor-talityofthecondition,clinicalsurveillanceforthisdiagnosis isrecommendedinthispatientpopulation.
To date,no reportsof peripheralneuropathyassociated
withtheuseofRTXwerepublished.
Gastrointestinalreactions
Cardiovascularreactions
IncreasedriskofacuteMIovertimeinpatientstreatedwith RTXhasnotbeenobserved.178
Neoplasms
Solidneoplasmsandlymphomas
Increasedrisk of solid or hematological malignancies over
timeinpatientstreatedwithRTXwithanobservationalperiod ofapproximately10yearshasnotbeenobserved.178
Immunogenicity
Safety data from long-term RCTs on RA patients indicate
that11%(273/2578)ofthepatientsexposedtoRTXdevelop
HACA.191HACA-positivepatientsdidnotshowahigher
num-berofinfusionreactions duringthesecond courseofRTX,
comparedwithHACA-negativepatients.
Otherevents
Fewcasesofpsoriasiformconditionshavebeenreportedafter RTXinfusionforthetreatmentofrheumaticdiseasesorother
indications. A series of three cases was described in two
patientswithRAandinonewithSLE,requiringspecific treat-mentforpsoriasisandRTXdiscontinuation.192
Pulmonary manifestations were identified in a
system-aticreviewstudywith121casesofinterstitiallungdisease. OnlynineofthesepatientshadindicationofRTXfor
treat-ment of rheumatic diseases, including three cases of RA,
oneoftheminassociationwithCastleman’sdisease.Inthis review,theinterstitiallungdiseasewasconsideredasarare event,butwithpotentialformorbidityandmortality.Allcases
hadimaging(radiographsand/orcomputedtomography)
find-ings. Pulmonary function tests, when performed, showed
a deficit of diffusion capacity and a restrictive respiratory pattern.193
In a series of 43 patients with autoimmune diseases,
in two casesof patients with systemic lupus
erythemato-sus, and in one caseof primary Sjögren’ssyndrome, mild
fevertypereactions,arthralgia,rash,andurticaria-likelesions
were observed; and in one casethe medication had to be
discontinued.194Wedidnotfindsimilarreportsinpatients
with RA or spondyloarthritides. There are case reports of
serumsickness,withtheappearanceofmildtomoderate dis-easeafterinfusionofRTX.195
Vaccinationresponse
The use of RTX is associatedwith a reduced response to
both T-cell independent and T-cell dependent vaccines.158
There is evidence to suggest a compromised response to
anti-pneumococcal and influenza vaccines,when
adminis-tered to patients receiving RTX.179,196,197 The response to
influenzavaccine(alsoincludingAandH1N1vaccines)isalso
particularlycompromisedwhenthevaccineisadministered
early,fourtoeightweeksafteradministrationofRTX.Thus,
influenzaandpneumococcalvaccinesmustbeappliedbefore
startingRTX,orsixmonthsafterthe1st infusionand four weeksbeforethenextdose.158,179High-riskpatientsfor
con-tractingtetanusandtreatedwithRTXwithinthelast24weeks shouldusepassiveimmunizationwithtetanusIg.HepatitisB
isanothervaccinethatshouldbeadministeredbeforetheuse ofRTX.179
Interleukin-6
(IL-6)
receptor
blocker
–
tocilizumab
(TOCI)
TOCIisahumanizedmonoclonalantibodydirectedagainst
thereceptorofIL-6,includingsolubleandplasma membrane-bound fractions,and abletoblockingtheircellularactions.
TOCI is not only used in the treatment of RA activity in
combinationwithMTXorotherDMD,butalsoas
monother-apy and in patients with an inadequate response toMTX
or other DMDs, or to TNF blockers.37 In general,
monitor-ing should becontinuous for all adverse events related to
TOCI.However,someofthemaremorerelatedtothe
initia-tionoftreatmentandtendtopresentasubsequentreduction
in the frequency of occurrence, such as infusion
reac-tions andchangesinlipidand livertransaminases’plasma
concentrations.
The data on TOCI safety profile were pooled from
24-weekrandomized,placebo-controlledclinicaltrials(RPCCTs)
considered pivotal for registration and approval of this
drug,butalsofromlonger-termstudies,includingresultsof registry trialsandpost-marketingsurveillance studies,
par-ticularlyofFDAand EMEA(European MedicinesEvaluation
Agency).
Infections
Likeotherimmunobiologicalagents,TOCIshouldnotbeused
in patients with active infection by any pathogen,
includ-ingbacteria,viruses,fungiandparasites.198,199Traditionally,
C-reactive protein(CRP)isusedasabiomarkerfortracking infections.However,CRPisnotusefulforTOCIusers,sincea
significantreductioninplasmaconcentrationofCRPoccurs
afterusingthat agent.Sofar, thereisnoevidence
demon-strating theabilityofTOCIinsuppressingfebrileresponse.
RecentCochranemeta-analysis,including8RPCCTs,showed
aninfection risk1.2timesgreater forpatientstreatedwith TOCIversusthoseusingsyntheticDMDs,36,200inaccordance
with datapreviously publishedby the Nishimotogroup.201
However,thisriskdoesnotincreasewithtimeofexposure,
showing a major event rate ranging from four to six per
100,000 patient-years,202 even ifcombined with other
syn-theticDMDs.203
UnlikeTNFblockers,TOCIdidnotincreasetheriskofTbL reactivation.204However,ascreeningforLTBIisstill
recom-mendedbeforeandduringuseofimmunobiologicalagents,
especiallyinendemicareas.InJapan,therewasnoincrease inthenumberofcasesofdiseasecausedbynon-tuberculous mycobacteria.205
Recentevidencerevealednoincreaseintherateofsurgical woundinfectioninpatientswithRAinuseofTOCIafter under-goingtotalkneeorhiparthroplasty.206ThesuspensionofTOCI
atleastforfourweeksbeforetheprocedureisrecommended. Afterpoolingretrospectivelyinformationoninfectious condi-tionsoccurringafterorthopedicsurgery(arthroplasty)inthe
period1999–2010,Momoharaetal.observedmoredelayfor
