r e v b r a s r e u m a t o l . 2015;55(4):390–393
w w w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Letter
to
the
Editor
Preliminary
guidelines
of
the
Brazilian
Society
of
Rheumatology
for
evaluation
and
treatment
of
tuberculosis
latent
infection
in
patients
with
rheumatoid
arthritis,
in
face
of
unavailability
of
the
tuberculin
skin
test
Orientac¸ões
preliminares
da
Sociedade
Brasileira
de
Reumatologia
para
avaliac¸ão
e
tratamento
da
tuberculose
infecc¸ão
latente
em
pacientes
com
artrite
reumatoide
na
indisponibilidade
do
teste
tuberculínico
Introduction
Thedetectionandtreatmentoftuberculosislatentinfection
(TBLI) in individuals with increased risk of progression to
tuberculosis(TB)diseasearestrategiesrecommendedbythe
WorldHealthOrganizationtocontrolthisdisease.The
tuber-culintest,which usesPPD(purifiedproteinderivative),isa
procedurewidelyincorporatedtotheclinicalpracticeforthe
diagnosisofTBLI. Patientswithrheumatoidarthritisare in
increasedriskforthedevelopmentofactiveTB,particularly
whentreatedwithbiologicalagentsofTNF-␣inhibitorclass.
The2012ConsensusofTheBrazilianSocietyofRheumatology
(BSR)fortreatingrheumatoidarthritisrecommendstheuseof
screeningproceduresand,whereindicated,thetreatmentof
TBLIineverypatientcandidatetousesomebiologicalagent.
Inadditiontotheevaluationoftheepidemiologicalrisk,
thisscreeningincludesperformingchestradiography anda
tuberculintest.AftertheexclusionofTBdisease,the
treat-mentofTBLIconsistsofisoniazidatadoseof5–10mg/kg/day
(withamaximumof300mg/day)for6months.Thistreatment
isindicatedinpatientswithtuberculintest≥5mm,positivity
forIGRA (interferon-␥release assays),radiographicfindings
consistentwithpriorTB,orclosecontactwithaTBcase.The
treatmentofTBLI(chemoprophylaxis)shouldbeestablished
atleast onemonthbeforeintroducing thebiologicalagent;
however,exceptionallyandwhenthesymptomaticurgency
ofthesituationdemandsit,bothdrugsmaybeinitiated
con-comitantly.
In September 2014, the Ministry of Health, through
the General Coordination of the National Program for
Tuberculosis Control, published a note informing on the
difficulties to acquire PPD, thanks to its unavailability in
the international market,whichshould resultinshortages
of the Brazilian health system, still without any
predic-tion for resumption of its distribution (information note
n◦ 8/CGPNCT/DEVEP/SVS/MS, of September 10, 2014). The
unavailabilityofthetuberculin testhasalreadybeen
effec-tively feltinourhealthcarenetwork. Consideringthat the
current situation requirea quickattitude inorder toguide
clinicalpractice,theArthritisRheumatoidCommitteeofBSR
decided to disclose the following preliminary guidelines,
whichweredevelopedbyexpertconsensus.TheCommittee
suggestsaconsultationofselectedreferences,whichextend
thediscussionsheredeveloped.1–12
Therecommendationsforanevaluationandtreatmentof TBLIinpatientswithrheumatoidarthritisaredifferent whenusingTNF-˛inhibitorsandbiologicalagentswith othermechanismsofaction?
There is a difference in the risk of TB reactivation when
using TNF-␣ inhibitors, which represent an increased risk
– especiallyin the caseofmonoclonalantibodies, in
com-parisonwithothernot-TNF-␣-inhibitorbiologicals.However,
the 2012 BSR Consensus for the treatment of rheumatoid
rev bras reumatol.2015;55(4):390–393
391
alsoconsidering reports ofdisease reactivation during the
immunosuppressivetreatment,recommendedTBLIscreening
whenusinganybiologicalDMARDs.
Insertsofsomeofthenot-TNF-␣inhibitorbiologicals,such
astocilizumabandabatacept,alsorecommendcarryingouta
TBLIscreeningpriortotheuseofthedrug.Thus,considering
alsopossiblemedico-legalimplications,atpresentBSRprefer
tokeepthesamerecommendationsforevaluationand
treat-mentofTBLI,inthecaseofuseofanybiologicalDMARDsfor
treatmentofrheumatoid arthritis.Theserecommendations
alsoapplytotheuseofcorticosteroidsatadoseequivalentto
prednisone≥15mg/dayformorethan30daysinindividuals
olderthan65years.
Whatshouldberegardedasapositiveepidemiologyfor tuberculosis?
Contactwithabacilliferouscaseofpulmonaryorrespiratory
TBis the key epidemiologicalfactor. The riskof acquiring
TBLIbycontactingabacilliferouspatientisincreasedby
con-ditionssuchashouseholdcontact(especiallyamongthose
whosharethesamebedroom);longerexposuretime;
expo-sure inplaceswith poorventilation; cavitation revealed in
a chest X-ray from the index case; positive direct
bacil-loscopy, and greater amount of bacilli in the index case
sputum. Patients exposed to coexistencesituations with a
high disease burden, namely, health professionals, prison
inmates,residentsofnursinghomesorhostels,andinjectable
drugusers,aredefinedaspeopleingreaterepidemiological
risk.
Therisk of developing TBdisease is higher in the first
twoyearsafterinfection.Contactsofbacilliferous
individu-alsare atincreasedriskofdevelopingTBdisease,whenin
situationsofextremeage(≤10yearsor>60years),
immuno-suppression,householdexposure,andexposuretopatients
withpositivebacilloscopyorsputumculture.Tuberculintest
≥5mm is also a risk factor for developing TB disease in
contacts. Themain clinical condition associatedwith
pro-gression from TBLI to TBdisease isco-infection with HIV,
particularly when CD4+ T cells ≤200/mm3. Other medical
conditionsmeaningriskforprogressionfromTBLItoTB
dis-easeare:useofaTNF-␣inhibitor,diabetesmellitus,chronic
renalfailureondialysis,malignantneoplasms,
immunosup-pressionassociatedwithorgantransplantation,malnutrition,
changesinchestX-ray–especiallyfibroticlesionsinupper
areas(withorwithoutcalcifiednodulesorpleuralthickening)
–suggestiveofsequelofapreviouslyuntreatedpulmonary
TB.
Patientswithrheumatoidarthritis,wheninuseof biopharmaceuticalsandwithapositivehistoryofcontact withapulmonaryTBcase,shouldbetreatedforTBLI withoutatuberculintest?
Yes.TherecommendationistoproceedwiththeTBLI
treat-mentwithoutthetuberculintestincontactsofpulmonaryTB
cases,whenusingTNF-␣inhibitors.TNF-␣inhibitoruserswith
asuggestiveX-rayofuntreatedpulmonaryTBsequelshould
alsobetreatedforTBLI,regardlessofthetuberculin test.It
isbelievedthat,inthesecases,thebenefitofpreventingTB
overcomestherisksofapreventivetreatment.
Whenusingbiopharmaceuticals,patientswith rheumatoidarthritiswithnohistoryofcontactwitha caseofpulmonaryTBshouldreceivetreatmentforTBLI withoutatuberculintest?
A negative history of contact does not exclude TBLI. In
these cases, and inthe absence of atuberculin test, IGRA
is recommended for obtaining a diagnosis oflatent
infec-tion.Inthecaseofunavailabilityofbothtests,thedecision
about TBLI treatment should be individualized, and the
physicianwilltakeintoconsiderationitsrisksandbenefits.
When assessingthepotential benefitofthis treatment,we
mustconsiderthe factorsdiscussed(above)withrespectto
the questionofapositiveepidemiologyfortuberculosis.In
particular, the increasedepidemiological risk (high disease
burdenintheconvivialenvironment)and thesynergismof
risk factors forprogressiontoTB disease shouldbe
evalu-ated.
Intheassessmentofriskassociatedwithtreatment,we
must considerthe hepatotoxic potentialofisoniazid,
espe-ciallyinindividualsaged>35years,frequentalcoholusers,
patients withpreviouslyabnormalliverfunctiontests, and
inthoseindividualsonconcomitantuseofotherhepatotoxic
drugs.However,generallyspeaking,liverdiseasedueto
isoni-azidisanuncommonoccurrence,andtheconcomitantuseof
hepatotoxicdrugsisnotanabsolutecontraindicationto
isoni-aziduse.However,theuseofthisagentrequiresliverfunction
testmonitoring.
Finally,onemustconsiderthepotentialformicrobial
resis-tanceinduction,thankstotheindiscriminateuseofisoniazid.
Aftertheevaluation,ifthetreatmentofTBLIisdeemed
unnec-essary, amonthlyclinical monitoringforearlydetectionof
activeTBisrecommended,withspecialattentiontosignssuch
ascough,fever,sweatingandweightloss.Theinvestigation
ofsymptomaticpatientsshouldberefinedtoincludeatleast
aradiographicstudyofchest,inadditiontobacilloscopyand
sputumculture;andanexpertevaluation(byapulmonologist,
phthisiologistorinfectologist)shouldalsobeconsidered.
TheperformanceofIGRAfordiagnosingTBLIis comparabletothetuberculintest?
TheaccuracyofIGRAissimilarorsuperiortothetuberculin
skintestfordiagnosisofTBLI.Thereisapotentialadvantageof
IGRAinBCG-vaccinatedindividualsandinimmunodepressed
patientsduetodiseaseand/ortreatment–situationswhere
thetuberculintestaccuracydecreasesduetofalsepositives
and falsenegatives,respectively.There isdebateabout the
performanceofIGRAinpopulationswithhighprevalenceof
TB.Thereisalsothepossibilityofindeterminateresults,which
shouldbeevaluatedwithcaution;withsuchanoccurrence,a
conductofTBLItreatmentshouldbeconsidered.Despitesuch
considerations,giventhecurrentunavailabilityofthe
tuber-culinskintest,theBSRadvocatestheincorporationofIGRAin
thelistofproceduresoftheBrazilianUnifiedHealthSystem
392
rev bras reumatol.2015;55(4):390–393IntheabsenceofTST,andwithavailabilityofIGRA,this lattertestissuitablefortheestablishmentofaTBLI diagnosticinallpatientswithrheumatoidarthritisusing immunobiologicals?
Yes. IGRAisindicatedin thesame situations inwhichthe
tuberculin skin testwould apply, replacing it.Therefore, if
IGRAisavailable,itsuseisrecommendedforTBLIscreening
inallpatientswithrheumatoidarthritis,wheninuseofan
TNF-␣inhibitor,intheabsenceofthetuberculintest.Ifthere
islimitedavailability,weshouldprioritizeIGRAforpatients
withanegativeoruncertainhistoryofcontactwithacaseof
pulmonaryTB.
WiththeprolongeduseofaTNF-˛inhibitor,orwithan exchangeofbiologicalsinpatientswhocompleted treatmentforTBLIinthepast,thereisneedtorepeatthe treatmentwithisoniazid?
Asa rule, oncetreated fully and effectively,TBLI does not
requireretreatment.Exceptionsoccurwhenthereisaknown
re-exposure to M. tuberculosis; in this case, retreatment is
indicated.Basedonexpertopinion,wecanconsidera
peri-odic retreatment every 2 or 3 years in areas of high TB
prevalence, when a persistent state of immunodepression
prevails.11However,aBrazilianstudyevaluatedtheefficacyof
long-termTBLIscreeningandtreatmentin202patientswith
rheumatoidarthritisinuseofdifferentTNF-␣inhibitors.13In
thisprotocol,noregularretreatmentforTBLInorrepetition
ofthetuberculinskintestwerecarriedoutinasymptomatic
patients,andthisconductwascontinuedforover3yearsof
follow-up.
ShouldbetreatedforTBLIthosepatientswithrespiratory symptomatologyandwithapositivehistoryofcontact withapulmonaryTBcase,whenintheuseofaTNF-˛ inhibitor?
The prophylactic schemes are contraindicated, thanks to
the likelihood of TB disease emergence through
ineffi-ciencyand/or potentialmicrobial resistanceinduction.The
treatment of TBLI involves an active TB exclusion in all
instances.Contactswithrespiratorysymptomatologydeserve
anextendedinvestigation.Insuchcases,anassessmentbya
TBspecialist(pulmonologist,phthisiologistorinfectologist),
withfulltreatment,whenindicated,priortotheuseofTNF-␣,
isrecommended.
OncethepossibilityofTBdiseasewasruledout,patients withahistoryofcontactwithacaseof
multidrug-resistantTBshouldreceivetreatmentforTBLI, whenusingbiologicalDMARDs?
The treatment of TBLI in multidrug-resistant TB contacts
isnotrecommended.Insymptomaticcontacts,tuberculosis
shouldbeinvestigated.Inasymptomaticsubjects, after
rul-ing outTB,a monthlyclinical and half-yearlyradiographic
follow-up isrecommendedinthe first twoyears.Isoniazid
prophylaxisshouldnotbeattempted.Insuchcases,theuseof
anot-TNF-␣inhibitorbiologicalagentshouldbeconsidered,
independentlyofthetuberculinskintestorIGRA.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
r
e
f
e
r
e
n
c
e
s
1.Brasil.MinistériodaSaúde.SecretariadeVigilânciaem Saúde.DepartamentodeVigilânciaEpidemiológica.Manual derecomendac¸õesparaocontroledatuberculosenoBrasil. Brasília:MinistériodaSaúde;2011.
2.CantiniF,NiccoliL,GolettiD.Tuberculosisriskinpatients treatedwithnon-anti-tumornecrosisfactor-␣(TNF-␣)
targetedbiologicsandrecentlylicensedTNF-␣inhibitors:
datafromclinicaltrialsandnationalregistries.JRheumatol Suppl.2014;91:56–64.
3.GolettiD,SanduzziA,DeloguG.Performanceofthe tuberculinskintestandinterferon–releaseassays:an updateontheaccuracy,cutoffstratification,andnew potentialimmune-basedapproaches.JRheumatolSuppl. 2014;91:24–31.
4.HatemiG,YaziciH.Tuberculosisscreeningbeforeandduring treatmentwithtumornecrosisfactorantagonists:something old,somethingnew.JRheumatol.2013;40:1938–40.
5.IannoneF,CantiniF,LapadulaG.Diagnosisoflatent tuberculosisandpreventionofreactivationinrheumatic patientsreceivingbiologictherapy:international recommendations.JRheumatolSuppl.2014;91:41–6.
6.MancusoJD,BernardoJ,MazurekGH.Theelusivegold standardfordetectingMycobacteriumtuberculosisinfection. AmJRespirCritCareMed.2013;187:122–4.
7.ManginiC,DeMeloFAF.Artritereumatoide,terapia imunossupressoraetuberculose.RevBrasReumatol. 2003;43:xi–v.
8.MarquesCDL,DuarteALBP,CavalcantiFdeS,CarvalhoEMF de,GomesYdeM.Abordagemdiagnósticadatuberculose latentenaartritereumatoide.RevBrasReumatol. 2007;47:424–30.
9.PiccazzoR,PaparoF,GarlaschiG.Diagnosticaccuracyofchest radiographyforthediagnosisoftuberculosis(TB)anditsrole inthedetectionoflatentTBinfection:asystematicreview.J RheumatolSuppl.2014;91:32–40.
10.SociedadeBrasileiradePneumologiaeTisiologia.Sociedade
BrasileiradeInfectologia.SociedadeBrasileirade
Reumatologia.Diretrizesclínicasnasaúdesuplementar.
Tuberculoseinfecc¸ãolatente:tratamento;2011.Available
from:http://www.projetodiretrizes.org.br/ans/diretrizes/
tuberculoseinfeccaolatente-tratamento.pdf[accessed 27.10.14].
11.SociedadeBrasileiradePneumologiaeTisiologia.Sociedade
BrasileiradeInfectologia.SociedadeBrasileirade
Reumatologia.Diretrizesclínicasnasaúdesuplementar.
Tuberculoseinfecc¸ãolatente:diagnóstico;2011.Available
from:http://www.projetodiretrizes.org.br/ans/diretrizes/
tuberculoseinfeccaolatente-diagnostico.pdf[accessed 27.10.14].
12.SoutoA,ManeiroJR,SalgadoE,CarmonaL,Gomez-ReinoJJ. Riskoftuberculosisinpatientswithchronic
immune-mediatedinflammatorydiseasestreatedwith biologicsandtofacitinib:asystematicreviewand
rev bras reumatol.2015;55(4):390–393
393
13.BonfiglioliKR,RibeiroACM,MoraesJCB,SaadCGS,Souza FHC,CalichAL,etal.LTBIscreeninginrheumatoidarthritis patientspriortoanti-TNFtreatmentinanendemicarea.IntJ TubercLungDis.2014;18:905–11.
LiciaMariaHenriquedaMota∗,BórisAfonsoCruz,Cleandro
PiresdeAlbuquerque,DeborahGonc¸alves,IedaMaria
MagalhãesLaurindo,IvanioAlvesPereira,JozélioFreirede
Carvalho,GeraldodaRochaCastelarPinheiro,ManoelBarros
Bertolo,NilzioAntôniodaSilva,PauloLouzadaJúnior,
RicardoMachadoXavier,RinaDalvaNeubarthGiorgi,
RodrigoAiresCorrêaLima
SociedadeBrasileiradeReumatologia,SãoPaulo,SP,Brazil
∗Correspondingauthor.
E-mails: [email protected], [email protected] (L.M.H. da
Mota).
2255-5021/©2015ElsevierEditoraLtda.Allrightsreserved.
