Rev. Bras. Reumatol. vol.55 número6

(1)

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

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Original

article

Update

on

the

2012

Brazilian

Society

of

Rheumatology

Guidelines

for

the

treatment

of

rheumatoid

arthritis:

position

on

the

use

of

tofacitinib

Licia

Maria

Henrique

da

Mota

a,b,∗

,

Bóris

Afonso

Cruz

c

,

Cleandro

Pires

de

Albuquerque

d

,

Deborah

Pereira

Gonc¸alves

e,f,g

,

Ieda

Maria

Magalhães

Laurindo

h,i

,

Ivanio

Alves

Pereira

j,k

,

Jozélio

Freire

de

Carvalho

l

,

Geraldo

da

Rocha

Castelar

Pinheiro

m

,

Manoel

Barros

Bertolo

n,o

,

Maria

Raquel

da

Costa

Pinto

p,q

,

Paulo

Louzada-Junior

r

,

Ricardo

Machado

Xavier

s,t

,

Rina

Dalva

Neubarth

Giorgi

u

,

Rodrigo

Aires

Corrêa

Lima

v a_Hospital_{Universitário}_de_Brasília,_Universidade_de_Brasília_(UnB),_Brasília,_DF,_Brazil

b_Postgraduate_Program_in_Medical_Sciences,_Medicine_School,_Universidade_de_Brasília_(UnB),_Brasília,_DF,_Brazil

c_Biocor_Instituto,_Nova_Lima,_MG,_Brazil

d_Service_of_{Rheumatology,}_Hospital_{Universitário}_de_Brasília,_Universidade_de_Brasília_(UnB),_Brasília,_DF,_Brazil

e_Service_of_{Rheumatology,}_Hospital_{Universitário}_Walter_Cantídio,_Fortaleza,_CE,_Brazil

f_Service_of_{Rheumatology,}_Hospital_Geral_Dr._César_Cals,_Fortaleza,_CE,_Brazil

g_Program_of_Medical_Residence_in_{Rheumatology,}_Hospital_Geral_Dr._César_Cals,_Fortaleza,_CE,_Brazil

h_Universidade_de_São_Paulo_(USP),_São_Paulo,_SP,_Brazil

i_{BiobadaBrasil,}_Brazil

j_Discipline_of_{Rheumatology,}_Universidade_do_Sul_de_Santa_Catarina_(UNISUL),_{Florianópolis,}_SC,_Brazil

k_Nucleus_of_{Rheumatology,}_Teaching_Hospital,_Universidade_Federal_de_Santa_Catarina_(UFSC),_{Florianópolis,}_SC,_Brazil

l_Hospital_Alianc¸a,_Salvador,_BA,_Brazil

m_Discipline_of_{Rheumatology,}_Medical_Sciences_School,_Universidade_do_Estado_do_Rio_de_Janeiro_(UERJ),_Rio_de_Janeiro,_RJ,_Brazil

n_Discipline_de_{Rheumatology,}_Medical_Sciences_School_(FCM),_Universidade_Estadual_de_Campinas_(UNICAMP),_Campinas,_SP,_Brazil

o_Department_of_Internal_Medicine,_Medical_Sciences_School_(FCM),_Universidade_Estadual_de_Campinas_(UNICAMP),_Campinas,_SP,_Brazil

p_Rheumatoid_Arthritis_Outpatient_Clinic,_Hospital_das_Clínicas,_Universidade_Federal_de_Minas_Gerais_(UFMG),_Belo_Horizonte,_MG,

Brazil

q_Medicine_School,_Universidade_Federal_de_Minas_Gerais_(UFMG),_Belo_Horizonte,_MG,_Brazil

r_Faculdade_de_Medicina_de_Ribeirão_Preto,_Universidade_de_São_Paulo_(USP),_Ribeirão_Preto,_SP,_Brazil

s_Medicine_School,_Universidade_Federal_do_Rio_Grande_do_Sul_(UFRGS),_Porto_Alegre,_RS,_Brazil

t_Service_of_{Rheumatology,}_Hospital_de_Clínicas_de_Porto_Alegre,_Porto_Alegre,_RS,_Brazil

u_Service_of_{Rheumatology,}_Hospital_do_Servidor_Público_Estadual_“Francisco_Morato_de_Oliveira”_(HSPE-FMO),_São_Paulo,_SP,_Brazil

v_Service_of_{Rheumatology,}_Hospital_de_Base_do_Distrito_Federal,_Brasília,_DF,_Brazil

∗ _{Corresponding}_author_.

E-mailaddresses:licia@unb.br,liciamhmota@gmail.com(L.M.H.daMota).

http://dx.doi.org/10.1016/j.rbre.2015.09.003

(2)

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received9August2015 Accepted11August2015 Availableonline21October2015

Keywords:

Rheumatoidarthritis Treatment

Brazil Tofacitinib

a

b

s

t

r

a

c

t

In 2014, tofacitinib, a target-specific, synthetic disease modifying anti rheumatic drug (DMARD)anda selectiveinhibitorofJanuskinase(JAK)wasapprovedforuseinBrazil. This position paper aimsto update the recommendationsof the BrazilianSociety of Rheumatology(SBR)onthetreatmentofrheumatoidarthritis(RA)inBrazil,specifically regarding theuseoftarget-specificsynthetic DMARDs.The methodofthis recommen-dationconsistedofaliteraturereviewofscientificpapersheldontheMedlinedatabase. Afterthisreview,atextwasproduced,answeringquestionsinPicostructure, consider-ing efficacyandsafetyissuesoftofacitinib useforRAtreatment indifferentscenarios (suchasfirst-linetreatmentafterfailurewithmethotrexate[MTX]orotherconventional syntheticDMARDsafterfailurewithbiologicaltherapy).Basedonexistingevidence,and consideringtheavailabledataonefficacy,safetyandcostofmedicationsavailabletotreat thediseaseinBrazil,theRACommissionofSBR,afteraprocessofdiscussionand vot-ingonproposals,establishedthefollowingpositionontheuseoftofacitinibfortreatment ofRAinBrazil:“Tofacitinib,aloneorincombinationwithMTX,isanalternativeforRA patients withmoderateor highactivityafterfailureofatleast twodifferentsynthetic DMARDsandonebiologicalDMARD.”Thelevelofagreementwiththisrecommendation was7.5.

Thispositionmaybereviewedinthecomingyears,inthefaceofagreaterexperience withtheuseofthismedication.

Posicionamento

sobre

o

uso

de

tofacitinibe

no

algoritmo

do

Consenso

2012

da

Sociedade

Brasileira

de

Reumatologia

para

o

tratamento

da

artrite

reumatoide

Palavras-chave:

Artritereumatoide Tratamento Brasil Tofacitinibe

r

e

s

u

m

o

Em2014,otofacitinibe,ummedicamentomodificadordocursoda doença(MMCD) sin-tético,alvo-específico,inibidorseletivodasJanusquinases(JAK),foiaprovadoparausono Brasil.Estedocumentodeposicionamentotemoobjetivodeatualizarasrecomendações daSociedadeBrasileiradeReumatologia(SBR)sobreotratamentodaartritereumatoide (AR)noBrasil,especificamentecomrelaçãoaousodeMMCDsintéticosalvo-específicos. O métododessa recomendaçãoincluiu revisão bibliográficade artigoscientíficos, feita na base de dados Medline. Após a revisão, foi produzido um texto, que responde a perguntas na estrutura Pico, e considera questões de eficácia e segurança do usodo tofacitinibeparatratamentodeARemdiferentessituações(comoprimeiralinhade trata-mento,apósfalhaaometotrexato[MTX]ououtrosMMCDsintéticosconvencionais,após falhadaterapiabiológica).Combasenasevidênciasexistentes,econsiderandoosdados disponíveissobreeficácia,segurançaecustodasmedicaçõesdisponíveisparatratamento da doençano Brasil,a Comissão deARda SBR,apósprocesso de discussãoevotação de propostas,estabeleceuoseguinteposicionamentosobreousode tofacitinibeparao tratamento da ARno Brasil:“Tofacitinibe, em monoterapiaouem associaçãoao MTX, é umaopçãoparaospacientescomARematividademoderadaoualta,apósfalhade pelo menos doisesquemascomdiferentesMMCDsintéticos eum esquemade MMCD biológico”.Ograudeconcordânciacomessarecomendaçãofoi7,5.Esseposicionamento poderáserrevistonospróximosanos,comamaiorexperiênciaadquiridacomousodo medicamento.

(3)

Introduction

Rheumatoidarthritis(RA)isasystemic,autoimmune inflam-matorydiseasecharacterizedbyinvolvementofthesynovial membraneofperipheraljoints.Itisestimatedthatthe preva-lenceofRAis0.5–1%ofthepopulation,mainlyinwomenand inpeopleagedfrom30to50years.1

ThetreatmentofRAhasprogressedsubstantiallyinrecent decades,duetoamajorbreakthroughinunderstandingthe pathophysiologicalmechanismsofthedisease,development ofnewtherapeuticclassesandimplementationofdifferent strategiesoftreatmentandfollow-upofpatients,forinstance, intensivediseasecontrolandinterventionintheearlyphase ofsymptoms.1

In2012and 2013, the RACommissionofthe Sociedade BrasileiradeReumatologia(SBR)publishedaseriesofpapers aimedatproducingrecommendationsonthediagnosisand treatmentofRAinBrazil.Thepurposeofthesedocuments wastoestablish consensusguidelines forthe treatmentof RAinBrazilandtosupportBrazilianrheumatologists,using evidencefromscientificstudiesandtheexperienceofa com-mitteeofexpertsonthesubjectinordertostandardizethe therapeuticapproachofRAinthe Braziliansocioeconomic context,maintainingtheautonomyofthe physicianinthe indication/choiceoftreatmentoptionsavailable.2–5

Atthattime,thedocumentspredictedthat,duetotherapid advancesofknowledgeinthisfieldofscience,itwouldbe nec-essarytomakeperiodicupdatesofsuchrecommendations.

Sincethen,adrugbelongingtoadifferent classof pre-viouslyexistingdrugs,tofacitinib,asynthetic,target-specific disease-modifyinganti-rheumaticdrug(DMARD)and selec-tiveinhibitorofJanuskinase(JAK)hasbeenapprovedforusein Brazil.6_Tofacitinib_was_submitted_for_approval_to_the_National HealthSurveillanceAgency(ANVISA) onApril18,2012and approvedonDecember8,2014.7

Thus,acontingentupdateoftheTreatmentGuideline pre-viouslyreportedbySBRwasinordertoestablishtheposition oftheRACommissionontheuseoftarget-specific,synthetic DMARDsinBrazil.

Objective

ThispositionpaperaimstoupdateSBRrecommendationson thetreatmentofRAinBrazil,specificallyregardingtheuseof target-specific,syntheticDMARDs.

Methods

Theliterature reviewof scientificarticles of this guideline wasconductedonMEDLINEdatabase.Thesearchforevidence camefrom actualclinicalsettings,usingthefollowing key-words(MeSH terms): Arthritis, Rheumatoid, Therapy, Efficacy,

Safety, Prognosis, Remission, Tofacitinib, Herpes zoster vaccine. StudiespublisheduptoMay2015wereevaluated.

Afteraliteraturereview,atextwasproduced,answering questionsinthePICOstructure(Population/patient, Interven-tion/indicator, Comparator/control, Outcome),8 _taking _into account efficacy and safety issues of tofacitinib use for

treatment of RA in different scenarios (such as first-line treatment after failure with methotrexate [MTX] or other conventionalsyntheticDMARDs,afterfailurewithbiological therapy).

Basedonthereviewconductedandonexpertopinion, pro-posals ofrecommendations on the use oftofacitinib were drawn up, subjectedto successiveroundsofvotingamong membersoftheCommitteegatheredinpersonforthis pur-pose, pending approval of positioning (recommendations). The degree of agreement with the text of the approved recommendationonanumericalscalefrom0(strongly dis-agree)to10(completelyagree)wasalsoestablished,withthe finaldegreeofagreementcalculatedbyaveragingthevalues assignedindividuallybyeachofthemembersofthe Commis-sion.Dependingontheapprovedrecommendation,anupdate oftheflowchartforthetreatmentofRAinBrazilwas devel-oped,consideringascenariooftofacitinibinsertion.

Tofacitinib–generalaspects

Tofacitinib is a preferential inhibitor of JAK1/JAK3 (mem-bersofthetyrosinekinasefamily,intracellularJanuskinase thattransducecytokine-mediatedsignalsthroughJAK-STAT signalingpathway).Thisagentisindicatedforpatientswith activeRAwhohaveexperiencedtreatmentfailurewith syn-thetic DMARDs, or with TNF inhibitors (TNFi). Tofacitinib can be usedin combination withsynthetic DMARDsor as monotherapy.6_The_approved_dosage_for_tofacitinib_is₁_tablet (5mg)twicedaily.7

Regarding its main adverse effects, the safety profileis similar tobiological immunomodulatorydrugs withhigher incidenceofseriousinfections,tuberculosisandherpeszoster compared to the controlgroup. Theobserved incidenceof herpeszosterhasbeen higherthanthat reportedforother immunobiological agents, mostly milder cases. Laboratory abnormalitiesobservedincludeincreasesintotalcholesterol, fractionsoflow-densitylipoprotein–LDL andhigh-density lipoprotein–HDL,allreversiblewithspecifictreatment; neu-tropeniaandlymphopenia,increasedliverenzymes,creatine phosphokinase(CPK)andaslightincreaseincreatinine(not associated with increased incidence of renal failure). The increasedincidenceofmalignancies,nonmelanomaskin can-cersandlymphoproliferativediseaseshasnotbeenobserved sofar,butonemustkeepstrictsurveillance,consideringthat this isapotentimmunosuppressiveagent. Briefly,patients with RA who will be treated with tofacitinib should be assessedpriortotreatmentwithrespecttopotentiallatent TB(tuberculinskintest,chestX-rayandpriorhistoryof con-tactwithpeopleinfectedwithtuberculosis)andperiodically monitoredwithcompletebloodcounts,assessmentofrenal function,liverenzymesandlipidogram.9–15

Tofacitinibisanexpensivedrug,generallysimilarto bio-logicalDMARDs.

Istofacitinibasafeandeffectivedrugforthetreatmentof RApatients,asfirstlinetherapy?

(4)

intherapeuticdoses,wererandomizedtotakeadoseof tofac-itinib5mgtwiceaday,tofacitinib10mgtwiceaday,orMTX.14

Effectiveness

Inthis study,tofacitinibwassuperiortoMTXincontrolling signsandsymptoms(ACR70responsesat6months:25.5%in thegroupreceivingtofacitinib5mgtwiceaday,37.7%inthe groupoftofacitinib10mgtwiceaday, and12% ofpatients receivingMTX,p<0.001.ACR70=animprovementof70%of theAmericanCollegeofRheumatologyscore–ACR).There wasalsoasignificantlygreaterreductionofstructural dam-age in patients receiving tofacitinib compared to patients receivingMTX(progressionofSharpindex[modified]insix months=0.2pointsinthegrouptreatedwithtofacitinib5mg and<0.1pointsinthe10-mggroup,comparedto0.8inthe groupreceivingMTX,p<0.001forbothcomparisons).14

Safety

Fivecasesofneoplasm,including3casesoflymphoma,have beenreportedinthegrouptreatedwithtofacitinib,compared to1caseinthe groupreceiving MTX.Infections,including herpeszoster,weremorecommoninpatientsreceiving tofac-itinib,whichalsowasassociatedwithincreasesofcreatinine, LDLandHDL.14

Thisstudysuggeststhattofacitinibiseffectivein control-lingsignsandsymptomsandinreducingstructuraldamageas afirst-linetreatmentinpatientswithRA.Theuseoftofacitinib incombinationwithotherDMARDshasnotbeenevaluatedin thispopulation.Thebenefitoftofacitinibshouldbeevaluated inthecontextoftheadverseeffectsdescribed.

Istofacitinibasafeandeffectivedrugforthetreatmentof RApatientsafterfailurewithMTXorothersynthetic DMARDs?

Effectiveness

Sixsystematicreviewswithameta-analysisevaluatedthe effi-cacyoftofacitinibversusplacebointhetreatmentofpatients withRA,followinganinadequateresponsetoaDMARD.16–21 Zhangetal.16_evaluated₁₀_randomized_studies_totaling_4,929 patients. Tofacitinib was superior to placebo in the evalu-ation byACR20response(20%improvementin ACRscore), HAQ-DI(HealthAssessmentQuestionnaire–DisabilityIndex) score,andDAS28(28-jointDiseaseActivityScore)inweek12 (asmonotherapyorincombinationwithMTX)andinweek 24 (combined with MTX; monotherapy data not available). Song et al.17 _included _five _randomized _trials _totaling ₁₅₉₀ patients.Tofacitinibatdosesof5mgand10mg(twicedaily) wassuperiortoplaceboonallevaluatedefficacyendpoints: ACR20 response, painful and swollen joint counts, visual scales ofpainand ofthe overall assessmentbythe physi-cianandpatient,HAQ-DIscoreandC-reactiveprotein(CRP) levels.

Berhan18_conducted_a_{meta-analysis}_of₈_randomized tri-alstotaling4,283patientswithRA,followinganinadequate responseto a DMARDor a biological agent. Theodds ratio

for ACR20 response was 4 times greater with tofacitinib

versus placebo (OR=4.15;95% CI: 3.23–5.32). Theresults of tofacitinibcombined withMTX or asmonotherapydid not differsignificantlyfromeachother.Therewasadecreasein

HAQ-DIscoreinpatientstreatedwithtofacitinibversus con-trols (meanstandardizeddifference=−0.62,95%CI=−0.735

to −0.506). He et al.19 analyzed eightrandomized studies,

totaling 3,791 patients with RA, following an inadequate response to MTX. Higher ACR20 response rates at week 12 occurred with the use of tofacitinib 5mg (relative risk [RR]=2.20; 95% CI=1.58–3.07) and 10mg (RR=2.38; 95% CI: 1.81–3.14)versusplacebo.Theresponsesweremaintainedat week24.

Kawalecetal.20_compiled_eight_randomized_studies com-paringtofacitinibversusplacebointhetreatmentofRA,after aninadequateresponsetoasyntheticorbiologicalDMARD. Tofacitinib was superior to placebo in ACR20, ACR50 and ACR70responseratesafter12weeksoftreatment(p<0.0001 forallcomparisons).Tofacitinibalsoresultedinan improve-ment in HAQ-DIversus placebo. Kaur et al.21 _conducted _a systematicreview(withoutmeta-analysis)of8phaseIIand IIIrandomizedtrials,comparingtofacitinibversusplaceboin patientswithRA,followinganinadequateresponsetoa syn-theticorbiologicalDMARD.Tofacitinibwassuperiortoplacebo after12weeksoftreatmentinACR20andACR50responses andindecreasesinHAQ-DIscore.Together,thesixsystematic reviewsincluded 12publications,related to11randomized clinicaltrials.9–13,22–28_The_findings_corroborate_the effective-nessoftofacitinibcombinedtoMTXorasmonotherapyinthe treatmentofRA.

Two randomized studies evaluated tofacitinib and adal-imumab in parallel groups versus placebo.10,27 _No _direct comparisonbetweentofacitinibandadalimumabwasheld.In thefirststudy(n=384),ACR20responseratesatweek12were 59.2%and 70.5%fortofacitinibatdoses of5mgand 10mg, respectively, and 22%in theplacebo group(p<0.0001). Dif-ferencesfavoringtofacitinibwerealsofoundinACR50(50% improvement in ACR score) and ACR70 responses, and in DAS28,HAQ-DIandSF-36(MedicalOutcomesStudy36-Item– Short-FormHealthSurvey)scores,andalsointheevaluationof fatiguebyFACIT-F(FunctionalAssessmentofChronicIllness Therapy–Fatigue).Inthisstudy,adalimumabdidnotdiffer significantlyfromplacebowithrespecttomostoutcomes.27_In anotherstudy(n=717),ACR20responseratesafter6months oftreatmentwere51.5%and52.6%ingroupswithtofacitinib 5mg and 10mg respectively; 47.2% in groups treated with adalimumab;and28.3%intheplacebogroup(p<0.001forall comparisonsvs.placebo).Alsoahighernumberofsubjectsin remission(DAS28≤2.6)wereobservedafter6monthsinthe

activetreatmentgroups.Theresponsesweremaintaineduntil the12thmonthoffollow-up.10

vanderHeijdeet al.11_conducted_a_randomized, double-blind, placebo-controlled trial to assess the prevention of structuraldamagebytofacitinibin797RApatients. After6 months of treatment (interimanalysis of data), tofacitinib 10mg(twicedaily)significantlyreducedtheprogressionofthe totalmodifiedSharp/vanderHeijdescoreversusplacebo.

Thedataavailablefrom phaseIIandIIIstudies indicate thattofacitinibiseffectiveinthetreatmentofRAafterfailure withaDMARD.

Safety

(5)

patientsfromphaseI,29,30_II,22,23,25,27_and_III9–13,28,31 random-izedclinicaltrials.Overall,discontinuationoftreatmentwas observed in 842 patients (20.8%), and 437 patients (10.7%) werediscontinuedduetoadverseevents.Themainadverse eventsassociatedwithdiscontinuationwere infectionsand laboratoryabnormalities(anemia,neutropenia,lymphopenia, changes inliverenzymes, and serum cholesterol,LDL and creatinineincreases).32

Themostcommoninfectionswerenasopharyngitis,upper respiratorytractinfectionandurinarytractinfection. Infec-tionsofparticularinterestasherpeszosterandtuberculosis weremoreoftenobservedinAsianpatients, forwhomthe riskofdevelopingherpeszosterwashigher(6.7 eventsper 100patient-years)comparedtoCaucasianpatients(3.7events per 100 patient-years).32 _The _risk _of _developing tubercu-losis was evaluated in a model by Maiga et al.33 _These authors showed that tofacitinib can induce reactivation of latenttuberculosisinfection(LTBI),becausethedruginduces increasesinmycobacteria replication. Long-termextension studies reported the occurrence of 10 cases of tuberculo-sisin 4,102 patients, reinforcing the recommendation of a LTBIsurveybeforestartingtreatmentwithtofacitinib.32_The mostcommongastrointestinalmanifestationswerediarrhea (4.4%),nausea(3.3%)and gastritis(2.5%). Despitereportsof gastrointestinalperforation,theoccurrenceoftheseadverse eventsdidnotdifferfromthoseoccurringwithbiologicaland non-biologicalDMARDusers(0.05–0.17eventsper100 patient-years).34,35

Regarding laboratory changes, these effects were char-acterized as mild to moderate, not being, in most cases, required a permanent discontinuation of treatment with tofacitinib.32 _As_to_anemia,_a_hemoglobin_drop_below₇_g/dL or a decrease greater than 3g/dL was observed in 1% of patients, with the majority of patients presenting anemia haddecreasesinhemoglobinvaluesintheorderof1–2g/dL (12.7%). The incidence of neutropenia was 4.9%, and no patientshadneutrophilcountsunder500cells/mm3_;_3.9%_had neutrophilcountsof1500–1999cells/mm3_._Liver_enzyme ele-vationsoccurredin35%ofpatients,andthemostcommon findingwasaonefoldincreaseofnormalvalue(29.7%).These changesweretransientanddidnotresultintreatment discon-tinuation.Athreefoldincreaseofthenormalvalueoccurred in1.2%ofpatients,whose valuesreturned tonormalafter discontinuation oftofacitinib. An increase of creatinewas observedin3.3%ofpatients;thisfindingwasreversibleand transient,anddoesnotseemtoberelatedtoacuterenal fail-ureorprogressiveworseningofrenalfunction.32,36 _The_use oftofacitinibincreasesserumcholesterol,LDLandHDL,with ameanelevationofcholesterolof13mg/dL,avaluesimilar tothatobservedwithHDLelevation.Itwasnotyetproperly establishedtherealmeaningofthesemoderateelevationsin lipidprofile.37

Regardingtheoccurrenceofmalignancies,Curtisetal. ana-lyzed5,671tofacitinibusersin6phaseIIstudies,6phaseIII studiesandtwolong-termextensionstudies.Theyobserved theoccurrenceof107malignancies(excludingnon-melanoma skincancer).Themostcommonneoplasmwaslungcancer (n=24),followedbybreastcancer(n=19),lymphoma(n=10) andgastriccancer(n=5).Themalignancyratebysix-month intervalsofexposuretotofacitinibremainedstableduringthe

periodoftime analyzed.Theincidenceratesofthese neo-plasms wereasexpectedforRApatients withmoderate or severeactivity.38

IstofacitinibasafeandeffectivedrugfortreatmentofRA patientsafterfailurewithbiologicaldrugs?

Effectiveness

AphaseIII, double-blind,placebo-controlled,parallelgroup trialwithsixmonths’durationwasconductedinpatientswith moderatetosevereRAwhohadnotrespondedorwere intol-eranttooneormoreTNFis.12_All_patients_involved_in_the_study wereusing,andremainedinuse,ofMTX.399patientswere included(133intofacitinib5mgtwicedailygroup,134in tofac-itinib10mgtwicedailygroup,and132intheplacebogroup). Afterthreemonths,patientsintheplacebogroupwere dis-tributed bytofacitinib 5mgor10mggroups. Mostpatients were female(80.3%),white (84.8%)andwithameanageof 54.4–55.4yearsandameandiseasedurationof11.3–13years. ThemeannumberofpriortreatmentswithTNFiwas1.4–1.5 (64%hadbeenpreviouslytreatedwithaTNFi:26%withtwo and8%withthreeormoretreatments).TNFihadbeen dis-continued forlack ofefficacy in 65.2%,for lackof efficacy andintolerance in19.8%,andforintoleranceonlyin13.8%. BaselinemeanvaluesofHAQ-DIandDAS28-ESR(erythrocyte sedimentationrate)rangedfrom1.5–1.6and6.4–6.5, respec-tively.Theprimaryobjectivesofthestudyweretoevaluatethe ACR20responserate,meanHAQ-DIchangefromtheonsetof treatment,anddiseaseactivityindex(DAS28-VHS)rates<2.6 attheendofthreemonths.12

Afterthreemonths,theACR20responseoftofacitinib 5-mggroupwas41.7%(55of132;95%CI:6.06–28.41;p=0.0024)

versusplacebo24.4%(32of131).Alsoafterthreemonths,the ACR50responsetotofacitinib 5-mggroupwas 26.5%(35of 132;[9.21–27.02];p<0.0001)versusplacebo(8.4%;11of131)and theACR70responsetotofacitinib5-mggroupwas13.6%(18of 132;[5.89–18.32];p<0.0001)versusplacebo,1.5%(2of131).Still, afterthreemonths,themean variationofleastmeanleast squares(LMS)versusbaselineforHAQ-DIwas−0.43([95%CI: −0.36to−0.15]; p<0.0001) fortofacitinib 5-mggroupversus

placebo(−0.18).ImprovementinHAQ-DI≥0.22wasobserved

in54.2%(71of131;[1.76–25.71];p=0.0245) fortofacitinib 5-mggroupversusplacebo,40.5%(53of131).Improvementin HAQ-DI≥0.5wasobservedin35.9%(47of131;[4.52–26.01];

p=0.0053)fortofacitinib5-mggroupversusplacebo,20.6%(27 of131).TheproportionofpatientswithDAS28<2.6afterthree monthswas6.7%(8of119;[0–10.10];p=0.0496)fortofacitinib 5-mggroupversusplacebo(1.7%,2of120).Aftersixmonths, thisfigureincreasedto8.2%(10of122)withtofacitinib5mg

versusplacebo,5.0%(6of120).Inthethirdandsixthmonths, remission(definedbyBooleancriteria)wasreachedby6.1%(8 of132;[1.99–10.13];p=0.0035)fortofacitinib5-mggroupversus

0%intheplacebogroup.12

Regardingtheoutcomesreportedbypatients(PRO–Patient ReportedOutcomes)afterthreemonths,the proportionsof patients with greater than or equal answers to minimum clinicallyimportantdifference(MCDI)were:1.Overall assess-mentofdiseaseactivity–41.88%intheplacebogroupversus

(6)

Monotherapy (preferably MTX)

First line

Failed after 3 months

Partial response to MTX Intolerance to MTX

In all stages:

Prednisone or equivalent (use the shortest time/needed

dose possible)

Intra-articular corticosteroid and/or NSAID and/or analgesics

Exchange between synthetic DMARDs

Synthetic DMARD (preferably MTX)

+

Biological DMARD

(TNFi as first choice or ABAT or TOCI)

Active disease:

Consider DAS, aiming remission or at least low disease activity Failure or intolerance to biological DMARD:

Keep synthetic DMARD (preferably MTX) and switch biological DMARD to other TNFI or ABAT or RTX or TOCI or TOFA

Failed after 3 months

Failed after 3 months Second

line

Third line

ABAT, abatacept; NSAID, nonsteroidal anti-inflammatory agent; DMARD, disease modifying antirheumatic drug; MTX, methotrexate; RTX, rituximab; TNFi, tumor necrosis factor inhibitors; TOFA, tofacitinib; TOCI, tocilizumab.

Combination of synthetic DMARDs

(7)

(p<0.0001);3.Fatigue(FACIT)–38.60%inthe placebogroup

versus61.54%intofacitinib5-mggroup(p<0.0001);4.SF-36v2 –physicalcomponent–49.14%intheplacebogroupversus

67.80%intofacitinib5-mg group(p<0.05), and 5.SF-36v2– mentalcomponent–37.07%intheplacebogroupversus54.24% intofacitinib5-mggroup(p<0.05).39

InanotherphaseIII,double-blind,placebo-controlledtrial, 611patientswithactiveRArefractoryorintoleranttoatleast onesyntheticorbiologicalDMARDwererandomizedingroups of monotherapy with tofacitinib 5mg twice daily (n=243), tofacitinib10mgtwicedaily(n=245)andplacebo(n=122).13_A sub-analysiswithpatientswhohadalreadymadeuseofTNFi orotherbiologicalagentrevealedthat18of46(42.9%)patients inthetofacitinib5-mggroupand6of34(17.7%)patientsin theplacebogroupachievedACR20responsecriteriaatthree months.

Safety

Inthefirst threemonthsofthephaseIIItrial, 145adverse eventswere reported in71 of133 patientsintofacitinib 5-mg group (53.4%) versus 167 adverse events in 75 of 132 patients in the placebo group (56.8%). During this period, themostcommon adverseeventswerediarrhea(13of267; 4.9%),nasopharyngitis(11of267;4.1%),headache(11of267; 4.1%) and urinary tract infection (8 of267; 3.0%) in tofaci-tinib(5mgand10mg)groups;andnausea(9of132;6.8%)in the placebogroup. Seriousadverse events occurred in4of 267patients(1.5%)treatedwithtofacitinib(2in5-mggroup and 2in10-mggroup), and 6in132 patients(4.5%) inthe placebogroup.Noseriousinfectiouseventwasreported.Eight patients(6.0%)discontinuedtheprotocolbecauseofadverse eventsintofacitinib5-mggroupversus7(5.3%)intheplacebo group.12,13

Isthereevidenceforindicationoftheuseofherpeszoster vaccineintofacitinibusers?

Thepreventionofherpeszoster(HZ)isofgreatinteresttoRA patients,sincetheyareingreaterriskofinfectioncompared tothegeneralpopulation.40,41

InBrazil,the vaccineforHZprevention(andits compli-cations)contains liveattenuatedvirus,with14 timesmore antigensthanthevaricellavaccinecanhavefromthesame manufacturer.HZvaccineislicensed foruseinpeopleover 50yearsold.AccordingtotheImmunizationGuideprepared in2014bytheBrazilianSocietyofImmunizations(BSIm)and theBrazilianSocietyofRheumatology(SBR),its useshould beavoidedinpatientswithseveredrugimmunosuppression orwithimmunosuppressioncausedbydisease;however,this vaccinemaybeindicatedinpatientswithmild immunosup-pression.Patients withchronicdiseasescan bevaccinated, exceptincaseofsevereimmunosuppressionandifin treat-mentwithbiologicalagents.42

Atthemoment,however,thereislimitedinformationon thesafetyandefficacyofthisvaccineinRApatients.There are few studies evaluating its value inpatients being sub-mittedtodifferentimmunosuppressiveregimens,including tofacitinib.40

Takingintoaccountthatvaccinationisapreventive mea-surewiththegreatestimpactonreducing theincidenceof

infectioninanyagegroup,theSBRConsensusof2012on vac-cinationinRApatientsrecommendsareviewandupdatingof theimmunizationcardbeforetheuseofsyntheticor biolog-icalDMARDs,includingthevaccineagainstherpeszosterin patientsover50yearsold.43

Likewise, ACR recommends vaccination prior to the onset of treatment with synthetic or biological DMARDs in RA patients over 50 years old. During the use of syn-thetic DMARDs, the vaccine may also be applied, but this is not recommended during the use of biological DMARDs.1,3,4_The_use_of_tofacitinib_was_not_addressed_in_these recommendations.40,44,45

Importantly, the vaccine is not available on the public HealthServiceandisnotcoveredbymosthealthplansand healthinsurancecompanies.

RACommissionofSBRpositionontheuseoftofacitinib forthetreatmentofRAinBrazil

Basedonpreviousevidenceandconsideringtheavailabledata onefficacy,safetyandcostofmedicationsavailabletotreatthe diseaseinBrazil,theRACommissionofSBR,afteraprocessof discussionandvotingonproposals,establishedthefollowing positionontheuseoftofacitinibfortreatmentofRAinBrazil: “Tofacitinib,aloneorincombinationwithMTX,isan alterna-tiveforRApatientswithmoderateorhighactivityafterfailure ofatleasttwodifferentsyntheticDMARDsandonebiological DMARD.”Thelevelofagreementwiththisrecommendation was7.5.

TheRACommissionconsidersitnecessarytoestablisha timelyandobjectiverecommendation,whichwouldhelpthe rheumatologistinhis/herdecisionmakingabouttheuseof thisnewmedicationinRAtreatmentflowchart.Butwealso considered–andthiswasquiteclearonthebasisofafairly debatedvotinganddiscussionprocess–that,undercertain conditionsandinveryspecificclinicalscenarios,theearlier useoftofacitinibcouldbeindicated,atthephysician’s discre-tion,since,asshown,thereisevidenceofefficacyofthisdrug atdifferenttimesinthetreatmentofRA.

ThedecisionofthisCommissionofexperts,toindicatethe useoftofacitinibafterfailureofatleasttwodifferentsynthetic DMARDsandonebiologicalDMARD,tookintoaccountmainly the stillrestrictedperiodofpost-marketingexperience.We believe that this aspect limits the informationrelevant on safety,comparedtoothermedicationsalreadyinuseforRA treatment.Thispositionmaybereviewedincomingyears,in thefaceoftheacquisitionofagreaterexperiencewiththeuse ofthisdrug.

RAtreatmentflowchartupdateinBrazil

Fig.1summarizestheupdatedflowchartofdrugtreatmentfor RAinBrazil,asproposedbytheRACommitteeofSBR.

Conclusion

(8)

issuggestedthatitsuseisconsideredinascenariooffailure inatleasttwosyntheticDMARDandatleastonebiological DMARD,thankstoalesserlong-termclinicalexperiencewith thisdruginclinicalpractice.

Thispositioningmayberevisedovertime,inthefaceofthe acquisitionofagreaterexperiencewiththeuseofthisdrug.

Conflicts

of

interest

Licia Maria Henrique da Mota is a consultant/speaker for Abbvie, Bristol-Myers Squib, Janssen, Hospira, Lilly, Pfizer, RocheandUCB.CleandroPiresdeAlbuquerquereportsgrants, personalfeesandnon-financialsupportfromPfizer,grants, personalfeesandnon-financialsupportfromAbbvie,grants, personalfeesand non-financialsupportfrom AstraZeneca, grantsandnon-financialsupportfromJanssen,non-financial support from Bristol-Myers-Squibb, outside the submitted work.RodrigoAiresCorrêaLimaworksasspeakerforAbvvie, PfizerJanssenandUCB.GeraldodaRochaCastelarPinheiro worksasconsultantforAstra-Zeneca,BristolMyersSquibb, Janssen,Novartis,Pfizer,Roche,RuiYiandSanofi.IedaMaria MagalhãesLaurindo works asa speaker and/orconsultant forAbbvie, Astra-Zenica, Bristol, GSK, Lilly, Janssen, Pfizer, RocheandUCB.ManoelBarrosBertololecturesforPfizer, Abb-vie,Roche,JanssenandAventis.Theauthorconductsclinical researchforMSD,Bristol,AventisandRoche.PauloLouzada JúniorheldservicesforUCBandRoche.RinaDalvaNeubarth Giorgi is a honorary member in clinical research for UCB, HGS(GSK),Sanofi-AventisandRoche;andworksas consult-ant and lecturesfor BMS,Pfizer, Janssen and Lilly.Ricardo Machado Xavier works as a speaker and consultant; and reportsresearchgrantsornon-financialsupportfor partici-pationinscientificeventsforAbbvie,Hospira,Janssen,Lilly, Pfizer,Roche.Theotherauthorsdeclarenoconflictsof inter-est.

r

e

f

e

r

e

n

c

e

s

1. SmolenJS,LandewéR,BreedveldFC,BuchM,BurmesterG,

DougadosM,etal.EULARrecommendationsforthe

managementofrheumatoidarthritiswithsyntheticand

biologicaldisease-modifyingantirheumaticdrugs:2013

update.AnnRheumDis.2014;73:492–509.

2. daMotaLM,CruzBA,BrenolCV,PereiraIA,FronzaLS,Bertolo

MB,etal.2011ConsensusoftheBrazilianSocietyof

Rheumatologyfordiagnosisandearlyassessmentof

rheumatoidarthritis.RevBrasReumatol.2011;51:

199–219.

3. daMotaLM,CruzBA,BrenolCV,PereiraIA,Rezende-Fronza

LS,BertoloMB,etal.2012BrazilianSocietyofRheumatology

Consensusforthetreatmentofrheumatoidarthritis.Rev

BrasReumatol.2012;52:152–74.

4. PereiraIA,MotaLM,CruzBA,BrenolCV,FronzaLS,Bertolo

MB,etal.2012BrazilianSocietyofRheumatologyConsensus

onthemanagementofcomorbiditiesinpatientswith

rheumatoidarthritis.RevBrasReumatol.2012;52:

474–95.

5. MotaLM,CruzBA,BrenolCV,PereiraIA,Rezende-FronzaLS,

BertoloMB,etal.Guidelinesforthedrugtreatmentof

rheumatoidarthritis.RevBrasReumatol.2013;53:158–83.

6.O’SheaJJ,KontziasA,YamaokaK,TanakaY,LaurenceA.

Januskinaseinhibitorsinautoimmunediseases.AnnRheum

Dis.2013;72Suppl.2:ii111–5.

7.DiárioOficialdaUnião-SuplementoAnvisa–DOU1–Edic¸ão nr237de08/12/2014Pag.13.Availableat:http://pesquisa.in. gov.br/imprensa/jsp/visualiza/index.jsp?jornal=1010&pagina

=13&data=08/12/2014[accessed19.06.15].

8.SchardtC,AdamsMB,OwensT,KeitzS,FonteloP.Utilization

ofthePICOframeworktoimprovesearchingPubMedfor

clinicalquestions.BMCMedInformDecisMak.2007;7:16.

9.KremerJ,LiZG,HallS,FleischmannR,GenoveseM,

Martin-MolaE,etal.Tofacitinibincombinationwith

nonbiologicdisease-modifyingantirheumaticdrugsin

patientswithactiverheumatoidarthritis:arandomizedtrial.

AnnInternMed.2013;159:253–61.

10.vanVollenhovenRF,FleischmannR,CohenS,LeeEB,Garcia

MeijideJA,WagnerS,etal.Tofacitiniboradalimumabversus

placeboinrheumatoidarthritis.NEnglJMed.

2012;367:508–19.

11.vanderHeijdeD,TanakaY,FleischmannR,KeystoneE,

KremerJ,ZerbiniC,etal.Tofacitinib(CP-690,550)inpatients

withrheumatoidarthritisreceivingmethotrexate:

twelve-monthdatafromatwenty-four-monthphaseIII

randomizedradiographicstudy.ArthritisRheum.

2013;65:559–70.

12.BurmesterGR,BlancoR,Charles-SchoemanC,WollenhauptJ,

ZerbiniC,BendaB,etal.Tofacitinib(CP-690,550)in

combinationwithmethotrexateinpatientswithactive

rheumatoidarthritiswithaninadequateresponsetotumour

necrosisfactorinhibitors:arandomisedphase3trial.Lancet.

2013;381:451–60.

13.FleischmannR,KremerJ,CushJ,Schulze-KoopsH,Connell

CA,BradleyJD,etal.Placebo-controlledtrialoftofacitinib

monotherapyinrheumatoidarthritis.NEnglJMed.

2012;367:495–507.

14.LeeEB,FleischmannR,HallS,WilkinsonB,BradleyJD,

GrubenD,etal.Tofacitinibversusmethotrexatein

rheumatoidarthritis.NEnglJMed.2014;370:2377–86.

15.BulaXELJANZ,CitratodeTofacitinibe;2014.

16.ZhangX,LiangF,YinX,XiaoX,ShiP,WeiD,etal.Tofacitinib foracuterheumatoidarthritispatientswhohavehadan inadequateresponsetodisease-modifyingantirheumatic drug(MMCD):asystematicreviewandmeta-analysis.Clin Rheumatol.2014;33:165–73.Availablefrom:

http://www.ncbi.nlm.nih.gov/pubmed/24389749[accessed

10.06.15;cited25.04.15].

17.SongGG,BaeS-C,LeeYH.Efficacyandsafetyoftofacitinibfor activerheumatoidarthritiswithaninadequateresponseto methotrexateordisease-modifyingantirheumaticdrugs:a meta-analysisofrandomizedcontrolledtrials.KoreanJ InternMed.2014;29:656–63.Availablefrom:http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=4164730

&tool=pmcentrez&rendertype=abstract[accessed08.06.15;

cited31.03.15].

18.BerhanA.Efficacy,safetyandtolerabilityoftofacitinibin patientswithaninadequateresponsetodiseasemodifying anti-rheumaticdrugs:ameta-analysisofrandomized double-blindcontrolledstudies.BMCMusculoskeletDisord. 2013;14:332.Availablefrom:http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=4222887&tool=pmcentrez

&rendertype=abstract[accessed12.06.2015;cited29.03.15].

19.HeY,WongAYS,ChanEW,LauWCY,ManKKC,ChuiCSL, etal.Efficacyandsafetyoftofacitinibinthetreatmentof rheumatoidarthritis:asystematicreviewandmeta-analysis. BMCMusculoskeletDisord.2013;14:298.Availablefrom:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=

3819708&tool=pmcentrez&rendertype=abstract[accessed

(9)

20.KawalecP,MikrutA,Wi´sniewskaN,PilcA.Theeffectiveness oftofacitinib,anovelJanuskinaseinhibitor,inthetreatment ofrheumatoidarthritis:asystematicreviewand

meta-analysis.ClinRheumatol.2013;32:1415–24.Available from:http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=3778229&tool=pmcentrez&rendertype=abstract

[accessed10.06.15;cited03.03.15].

21.KaurK,KalraS,KaushalS.Systematicreviewoftofacitinib:a newdrugforthemanagementofrheumatoidarthritis.Clin Ther.2014;36:1074–86.Availablefrom:

16.06.15;cited23.04.15].

22.KremerJM,BloomBJ,BreedveldFC,CoombsJH,FletcherMP, GrubenD,etal.ThesafetyandefficacyofaJAKinhibitorin patientswithactiverheumatoidarthritis:resultsofa double-blind,placebo-controlledphaseIIatrialofthree dosagelevelsofCP-690,550versusplacebo.ArthritisRheum. 2009;60:1895–905.Availablefrom:

30.05.15;cited28.02.15].

23.KremerJM,CohenS,WilkinsonBE,ConnellCA,FrenchJL, Gomez-ReinoJ,etal.AphaseIIbdose-rangingstudyofthe oralJAKinhibitortofacitinib(CP-690,550)versusplaceboin combinationwithbackgroundmethotrexateinpatientswith activerheumatoidarthritisandaninadequateresponseto methotrexatealone.ArthritisRheum.2012;64:970–81. Availablefrom:

11.06.15;cited19.04.15].

24.TanakaY,TakeuchiT,YamanakaH.Tofacitinib(CP-690,550),

anoralJanuskinaseinhibitor,asmonotherapyinJapanese

patientswithactiverheumatoidarthritis:a12-weekphase2b

study[abstract].ArthritisRheum.2011;63Suppl.10:2192

[accessed09.06.15].

25.TanakaY,SuzukiM,NakamuraH,ToyoizumiS,ZwillichSH. PhaseIIstudyoftofacitinib(CP-690,550)combinedwith methotrexateinpatientswithrheumatoidarthritisandan inadequateresponsetomethotrexate.ArthritisCareRes (Hoboken).2011;63:1150–8.Availablefrom:

02.06.15;cited01.04.15].

26.TanakaY,TakeuchiT,YamanakaH,NakamuraH,Toyoizumi S,ZwillichS.Efficacyandsafetyoftofacitinibas

monotherapyinJapanesepatientswithactiverheumatoid arthritis:a12-week,randomized,phase2study.Mod Rheumatol.2014:1–25.Availablefrom:

05.06.15;cited03.05.15].

27.FleischmannR,CutoloM,GenoveseMC,LeeEB,KanikKS, SadisS,etal.PhaseIIbdose-rangingstudyoftheoralJAK inhibitortofacitinib(CP-690,550)oradalimumab

monotherapyversusplaceboinpatientswithactive rheumatoidarthritiswithaninadequateresponseto disease-modifyingantirheumaticdrugs.ArthritisRheum. 2012;64:617–29.Availablefrom:

05.06.15;cited19.04.15].

28.CoombsJH,BloomBJ,BreedveldFC,FletcherMP,GrubenD, KremerJM,etal.Improvedpain,physicalfunctioningand healthstatusinpatientswithrheumatoidarthritistreated withCP-690,550,anorallyactiveJanuskinase(JAK)inhibitor: resultsfromarandomised,double-blind,placebo-controlled trial.AnnRheumDis.2010;69:413–6.Availablefrom:

12.06.15;cited19.04.15].

29.KrishnaswamiS,KudlaczE,WangR,ChanG.A supratherapeuticdoseoftheJanuskinaseinhibitor tasocitinib(CP-690,550)doesnotprolongQTcintervalin

healthyparticipants.JClinPharmacol.2011;51:1256–63. Availablefrom:

04.06.15;cited05.05.15].

30.CohenS,ZwillichSH,ChowV,LabadieRR,WilkinsonB. Co-administrationoftheJAKinhibitorCP-690,550and methotrexateiswelltoleratedinpatientswithrheumatoid arthritiswithoutneedfordoseadjustment.BrJClin Pharmacol.2010;69:143–51.Availablefrom:http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=2824475

&tool=pmcentrez&rendertype=abstract[accessed25.05.15;

cited03.05.15].

31.LeeEB,FleishmannRM,HallS,vanVollenhovenRF,BradleyJ,

GrubenD,etal.Radiographic,clinicalandfunctional

comparisonoftofacitinibmonotherapyversusmethotrexate

inmethotrexate-naïvepatientswithrheumatoidarthritis

[abstract].ArthritisRheum.2012;64Suppl.:S1049[accessed

05.06.15].

32.WollenhauptJ,SilverfieldJ,LeeEB,CurtisJR,WoodSP,Soma K,etal.Safetyandefficacyoftofacitinib,anoralJanuskinase inhibitor,forthetreatmentofrheumatoidarthritisin open-label,longtermextensionstudies.JRheumatol. 2014;41:837–52.Availablefrom:http://www.ncbi.nlm.nih.gov/

pubmed/24692527[accessed17.06.15;cited03.05.15].

33.MaigaM,LunS,GuoH,WingleeK,AmmermanNC,Bishai WR.Riskoftuberculosisreactivationwithtofacitinib (CP-690550).JInfectDis.2012;205:1705–8.Availablefrom:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=

3415851&tool=pmcentrez&rendertype=abstract[accessed

02.06.15;cited05.05.15].

34.CurtisJR,XieF,ChenL,SpettellC,McMahanRM,FernandesJ, etal.Theincidenceofgastrointestinalperforationsamong rheumatoidarthritispatients.ArthritisRheum.

2011;63:346–51.Availablefrom:http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=3031757&tool=pmcentrez

&rendertype=abstract[accessed03.06.15;cited05.05.15].

35.CurtisJR,LanasA,JohnA,JohnsonDA,SchulmanKL.Factors associatedwithgastrointestinalperforationinacohortof patientswithrheumatoidarthritis.ArthritisCareRes (Hoboken).2012;64:1819–28.Availablefrom:http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=3508293&tool

=pmcentrez&rendertype=abstract[accessed06.06.15;cited

05.05.15].

36.LundquistLM,ColeSW,SikesML.Efficacyandsafetyof tofacitinibfortreatmentofrheumatoidarthritis.WorldJ Orthop.2014;5:504–11.Availablefrom:http://www.

pubmedcentral.nih.gov/articlerender.fcgi?artid=4133456&tool

=pmcentrez&rendertype=abstract[accessed28.05.15;cited

29.03.15].

37.SoutoA,SalgadoE,ManeiroJR,MeraA,CarmonaL,

Gómez-ReinoJJ.Lipidprofilechangesinpatientswithchronic inflammatoryarthritistreatedwithbiologicagentsand tofacitinibinrandomizedclinicaltrials:asystematicreview andmeta-analysis.ArthritisRheumatol(HobokenNJ). 2015;67:117–27.Availablefrom:

29.05.15;cited25.04.15].

38.CurtisJR,LeeEB,KaplanIV,KwokK,GeierJ,BendaB,etal. Tofacitinib,anoralJanuskinaseinhibitor:analysisof malignanciesacrosstherheumatoidarthritisclinical developmentprogramme.AnnRheumDis.2015,

http://dx.doi.org/10.1136/annrheumdis-2014-205847,

pii:annrheumdis-2014-205847[accessed05.06.15].

39.StrandV,BurmesterGR,ZerbiniCAF,MebusCA,ZwillichSH,

GrubenD.Tofacitinibwithmethotrexateinthird-line

treatmentofpatientswithactiverheumatoidarthritis:

patient-reportedoutcomesfromaphaseIIItrial.Arthritis

(10)

40.WinthropKL,YamanakaH,ValdezH,MortensenE,ChewR,

KrishnaswamiS,etal.Herpeszosterandtofacitinibtherapy

inpatientswithrheumatoidarthritis.ArthritisRheumatol.

2014;66:2675–84.

41.SmittenAL,ChoiHK,HochbergMC,SuissaS,SimonTA,Testa

MA,etal.Theriskofherpeszosterinpatientswith

rheumatoidarthritisintheUnitedStatesandtheUnited

Kingdom.ArthritisRheum.2007;57:1431–8.

42.PileggiGS,BallalaiI,BrenolC,SaadCGS,TittonD,KlumbEM,

etal.GuiadeImunizac¸ãoSBIm/SBR.Reumatologia.2014/15.

43.BrenolCV,daMotaLM,CruzBA,PileggiGS,PereiraIA,

RezendeLS,etal.2012BrazilianSocietyofRheumatology

Consensusonvaccinationofpatientswithrheumatoid

arthritis.RevBrasReumatol.2013;53:4–23.

44.SinghJA,FurstDE,BharatA,CurtisJR,KavanaughAF,Kremer

JM,etal.2012updateofthe2008AmericanCollegeof

Rheumatologyrecommendationsfortheuseof

disease-modifyingantirheumaticdrugsandbiologicagents

inthetreatmentofrheumatoidarthritis.ArthritisCareRes

(Hoboken).2012;64:625–39.

45.HarpazR,Ortega-SanchezIR,SewardJF.Preventionofherpes

zoster:recommendationsoftheAdvisoryCommitteeon

ImmunizationPractices(ACIP).MMWRRecommRep.