Rev. Bras. Reumatol. vol.57 número3

(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

Review

article

Treatment

of

latent

tuberculosis

in

patients

with

juvenile

rheumatic

diseases:

a

systematic

review

José

Cleosmaque

Leite

Júnior

a

_,

_Regina

_Terse

_Trindade

_Ramos

b

_,

Teresa

Cristina

Martins

Vicente

Robazzi

b,∗

a_Universidade_Federal_da_Bahia_(UFBA),_Faculdade_de_Medicina,_Salvador,_BA,_Brazil b_Universidade_Federal_da_Bahia_(UFBA),_Departamento_de_Pediatria,_Salvador,_BA,_Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received2July2016 Accepted24November2016 Availableonline21February2017

Keywords:

Rheumaticdiseases Child

Adolescent Biologicalfactors Latenttuberculosis

a

b

s

t

r

a

c

t

Introduction:ChildrenandadolescentswithrheumaticdiseasesreceivingTNFblockersare atriskfortheactivationoflatentMycobacteriumtuberculosisinfection(LTBI).AlthoughLTBI treatmentisindicatedinthisgroup,therearedifferenttherapeuticregimensinthe litera-ture,withoutadefiniteconsensus.

Objectives: Toreviewintheliteraturetherapeuticschemesusedandindicatedforthe treat-mentofLTBIinthesepatients.

Methods:Systematicreviewoftheliterature,usinghealthdatabases,selectingstudiesthat addressedthetreatmentofLTBIinpatientswithjuvenilerheumaticdiseasesusingTNF blockers,from1990to2015.Allstudydesignswereconsidered.

Results:Atotalof162studieswereidentifiedthroughtheelectronicdatabasesandonewas foundthroughamanualsearchbytheauthor,totaling163articles.Weexcludedstudiesthat didnotmeetthementionedinclusioncriteria,andincludedaretrospectivecohortstudyand twoprospectivecohortstudies.Thethreestudiesaddressedtreatmentwithisoniazid(INH) for9monthsandoneofthemalsoaddressedINHtreatmentassociatedwithrifampicinfor 3months.

Conclusions: OnlyonecaseofLTBIactivationwasobserved;therewasgoodtreatment adher-enceandabsenceofcomplicationsduringfollow-up.Morestudiesarenecessarytoevaluate theresponsetotheotheravailabletherapeuticregimens,withbettertolerabilityassessment andalargersample.However,theresultsshowedthatINHtherapyfor9monthsandINH therapyplusrifampicinfor3monthshadalowrateofLTBIactivationandcomplications.

∗ _{Corresponding}_author_.

E-mail:trobazzi.ufba@gmail.com(T.C.Robazzi).

http://dx.doi.org/10.1016/j.rbre.2017.01.009

(2)

Tratamento

da

tuberculose

latente

em

pacientes

com

doenc¸as

reumáticas

juvenis:

uma

revisão

sistemática

Palavras-chave: Doenc¸asreumáticas Crianc¸a

Adolescente Fatoresbiológicos Tuberculoselatente

r

e

s

u

m

o

Introdução: Criançaseadolescentescomdoençasreumáticasemterapiaanti-TNF-␣são

grupoderiscoparaativac¸ãodainfecc¸ãolatenteporMycobacteriumtuberculosis(ILTB).Embora otratamentodaILTBsejaindicadonessegrupo,existemdiferentesesquemasterapêuticos naliteratura,semumconsensodefinido.

Objetivos:Revisarnaliteraturaesquemasterapêuticosusadoseindicadosparaotratamento daILTBnessespacientes.

Métodos: Revisãosistemáticadaliteratura,nasbasesdedadosemsaúde,selecionaram-se estudosqueabordaramotratamentodaILTBempacientesreumáticosjuvenisemusode anti-TNF-␣,de1990a2015.Todososdesenhosdeestudoforamconsiderados.

Resultados: Foramidentificadosatravésdasbasesdedadoseletrônicas162estudoseumfoi encontradopormeiodebuscamanualdoautor,totalde163.Foramexcluídososestudos quenãoatenderamaoscritériosdeinclusãoreferidos,incluídosumestudodecoorte retro-spectivaedoisdeestudosdecoorteprospectivas.Ostrêsestudosabordaramotratamento comisoniazida(INH)pornovemeseseumdelesabordoutambémotratamentocomINH associadoarifampicinaportrêsmeses.

Conclusões: Foi observado apenas um casode ativação da ILTB; uma boa adesão ao tratamentoe ausênciadecomplicaçõesdurante oacompanhamento.Maisestudossão necessáriosparaavaliararespostaaosoutrosesquemasterapêuticosdisponíveis,com mel-horavaliaçãoda tolerabilidadeemaioramostra.Porém,osresultadosmostraramquea terapiacomINHpornovemeseseaterapiacomINHmaisrifampicinaportrêsmesestêm baixoíndicedeativaçãoecomplicações.

Introduction

Even though the overall incidence of tuberculosis (TB) decreasedby18%inrelationtotheyear2000whenthe Mil-lenniumDevelopmentGoalswereestablished,TBisthefifth largestcauseofdeathworldwide,whenoneincludesdeaths fromTBinindividualsinfectedwiththehuman immunode-ficiencyvirus(HIV).However,thepossibilityofcureishigh whenearlydiagnosisandtreatmentoccur.1

Itisestimatedthat9.6millionpeoplehadthediseasein 2014,withonemillionchildren,although37%ofcaseswere notdiagnosedorreported.Additionally,TBwasresponsiblefor thedeathsof1.5millionindividualsin2014,ofwhich140,000 werechildren.2

InBrazil,theaimofreducingTBincidence,prevalence,and mortalitybyhalfin2015comparedto1990,asdefinedbythe WorldHealthOrganization(WHO)1_has_been_met._However, thecountryremainsinthegroupof22countrieswiththe high-estratesofthedisease.BrazilhasanincidenceofTBof33.83 andamortalityof2.6per100,000inhabitants.4,5

InthestateofBahia,theincidenceofTBwas30.5newcases per100,000inhabitantsandmortalityof2.1per100,000 inha-bitantsin2014.SãoPaulo,RiodeJaneiroandBahiaarethe threestateswiththehighestnumberofTBcasesinthe coun-tryandtogethertheywereresponsiblefor44.5%ofnewcases in2013.6

TheWHO defineslatentMycobacterium tuberculosis infec-tion (LTBI)asa stateofpersistentimmune responsetoM.

tuberculosisantigenstimulationwithnoevidenceofclinical manifestations of activeTB. It is estimatedthat one-third of the world’s population isinfected by this bacterium. In Brazil,theincidenceis46per100,000individuals.Despitethe absenceofsymptoms,thereisariskthatthesepatientswill developTBdisease,especiallyinthefirsttwoyearsafterthe primaryinfection.Activationoccursin5–10%ofcases.7

RiskfactorsforthedevelopmentofactiveTBinclude:HIV infection,contactwithacaseofpulmonaryTB,therapywith TNFblockers,dialysis,organtransplantationorblood trans-fusion,andsilicosis.8

TheevaluationofcontactwithTBcasesisimportantfor thescreeningofLTBI.TheMinistryofHealthconsidersas con-tacteverypersonlivinginthesameenvironmentastheindex caseatthetimeofTBdiagnosis,andtheassessmentofthe degreeofcontactexposureshouldbeindividualized, consid-eringtheformofthedisease,theenvironment,andthetime ofexposure.Contactsundertheageoffive,peoplewith HIV-AIDSandthoseathighriskshouldbeconsideredaspriorities intheprocessofcontactevaluationandLTBItreatment.9

Thus,adequatescreeninganddiagnosisareveryimportant topreventLTBIactivation.Themostwidelyuseddiagnostic methods includethe tuberculin skintest(TST), Interferon-Gamma Release Assays (IGRAs),10 _and _chest _X-rays.11 _TST isthemostoftenusedmethod,althoughthepositiveresult can alsooccurdue toactivediseaseor previouslyresolved infection.12,13

(3)

Table1–Keywordsusedinarticlesearch.

Palavras-chave Keywords

Adolescentes Adolescents

Crianc¸as Children

TuberculoseLatente LatentTuberculosis Doenc¸asreumáticas RheumaticDiseases

to illness or immunosuppressive treatment, patients with inflammatory/autoimmunediseasesusing immunosuppress-ivemedication need toundergo LTBI screening.13 _Of_these drugs,TNFblockersstandsout.TNF-␣isanessentialcytokine

formacrophageactivation,leukocyterecruitmenttothesite ofinfection andgranulomaformationandismore concen-tratedinorgansaffectedbyrheumaticdiseases.TNFblockers inhibitthiscytokineand,consequently,inhibitits inflamma-toryeffects.Thisactionofthesedrugsisveryimportantin thetreatmentofrheumaticdiseases;however,theinhibition ofTNF-␣-mediatedinflammatorypathwaysmayleaveusers

susceptibletoinfections.12,13

The Brazilian Registry of Biological Therapy Monitoring inRheumaticDiseases– BiobadaBrazil–inits 2014report, showed that the most important adverse events found in rheumatic patients submitted to biological therapies were infections and infestations. There were 19 cases of TB in the2464patientsusing biologicalagentsand controls,and only one patient was in the control group (patients with rheumatoidarthritis,juvenileidiopathicarthritis,or ankylos-ingspondylitis,nottakingbiologicalagents).Theanalysisof thereportalsoshowsthattheincidenceofTBwas101/100,000 patient-years,higherthanthatfoundintheBrazilian popula-tion,whichis37.2cases/100,000person-years.14

Additionally,itisknownthatthefrequencyofTBishigher inrheumaticpatientsthaninthegeneralpopulation,andthis riskincreaseswiththeuseofTNFblockers.13,15

Therefore,thepresentarticleaimstoreviewinthe litera-turethetherapeuticregimensusedtotreatlatenttuberculosis inpediatricpatientswithrheumaticdiseasesandtoidentify themostappropriatetherapeuticregimensforthesepatients.

Methods

Literaturesearch

This is a systematic review. The sources of information used for the literature search were health databases such as Medline (Pubmed) (www.ncbi.nlm.nih.gov/pubmed), Scopus (Elsevier) (www.scopus.com), The Cochrane Library (www.cochranelibrary.com), Web of Sci-ence (ISI) (webofknowledge.com), LILACS (Bireme) (www.bireme.br), Scielo (www.scielo.org) and CAPES Portal (www.periodicos.capes.gov.br).

ThekeywordsinPortugueseareDescriptorsinHealth Sci-ences(DeCS),aswellasthecorrespondingtermsinEnglish (Table1).English-languageanalogswereselectedfromMeSH. ThesearchwasperformedinDecember2015.

In Medline (Pubmed),the keywords and the equivalent termsintheEnglishlanguagewere cross-referencedinthe advancedsearchusingtheBooleanoperators“AND”and“OR”,

asfollows:((Latenttuberculosis)[AllFields]ANDRheumatic diseases[AllFields])AND(Children[AllFields]ORAdolescents [AllFields]).Combinedsearcheswereperformedusing(#)prior toeachsetnumberinthequery.

In the Cochrane Library database, keywords, equivalent terms,andtermswidelyusedintheEnglishlanguagewere cross-referencedintheadvancedsearchusingBoolean oper-ators“AND”and“OR”asfollows:LatentTuberculosis(Search all text) AND [Rheumatic Diseases (Search All Text)] AND [children (Search all text)OR adolescents(Search all text)]. Combinedsearcheswereperformedusing(#)priortoeachset numberinthequery.

IntheLILACSdatabase,keywords,equivalentterms,and terms widely used in the English language were cross-referencedintheadvancedsearch usingBooleanoperators “AND”and“OR”asfollows:[Latenttuberculosis(Words)]and [Rheumaticdiseases(Words)]and[children(Words)OR ado-lescents(Words)].Inthesearchsettings,theEnglishlanguage wasselectedasthe“Interfacelanguage”.

AsfortheadvancedsearchintheCAPESPortal,asthereare onlytwofieldstobefilledoutforthesearch,itwascarriedout asfollows:{[LatentTuberculosis(any/contains)]AND [Rheu-maticdiseases(any/contains)]}.Torefinethesearch,thedate ofpublicationdeterminedincludedthelast20years;forthe topic“typeofmaterial”,weselectedarticlesandthechosen languagewasEnglish.

IntheScielosite,keywords,equivalentterms,andterms widelyusedintheEnglishlanguagewerecross-referencedin theadvancedsearchusingBooleanoperators“AND”and“OR” asfollows:(LatentTuberculosis)[allindices]AND(Rheumatic diseases)[allindices]AND(Children[allindices]OR Adoles-cents[allindices]).

In the WebofSciencesite, keywords, equivalentterms, and termswidelyusedintheEnglishlanguagewere cross-referencedintheadvancedsearch usingBooleanoperators “AND”and“OR”andthe“TS”fieldlabel,whichrepresentsthe topic,andcomprisesallrecordsthatcontainthesearchterms inthefieldsofthetitle,abstract,orauthor’skeywords.The searchwascarriedoutasfollows:[TS=(LatentTuberculosis)] AND[TS=(Rheumaticdiseases)]AND[TS=(childrenOR ado-lescents)].Combinedsearcheswereperformedusing(#)prior toeachsetnumberinthequery.Sincetherewasapossibilityin thissitetorefinethesearch,studiesweresearchedbetween 1990and2015andtheselectedlanguagewasEnglish,since therewereonlytwooptions,EnglishandKoreanlanguages.

In the Scopus (Elsevier) database, keywords, equivalent terms, and terms widely used in the English language werecross-referencedintheadvancedsearchusingBoolean operators “AND” and “OR” as follows: [Latent Tuber-culosis (Article Title/Abstract/Keywords)] AND [Rheumatic Diseases (Article Title/Abstract/Keywords)] AND [children (Article Title/Abstract/Keywords) OR adolescents (Article Title/Abstract/Keywords)]. Combined searches were per-formedusing(#)priortoeachsetnumberinthequery.Studies publishedbetween1990and2015wereassessed.

Inclusionandexclusioncriteria

(4)

Medline n=20

Scopus n=15

Web of science n=5

The cochrane library n=5

CAPES portal n=117

163 articles identified

136 excluded articles (duplicated or did not meet the inclusion criteria)

24 excluded articles

Eligibility

Screening

Identification

Main reasons for exclusion • Not addressing the age range of interest

• Not addressing LBTI treatment • Language

27 selected articles

3 included articles Title and abstract reading

Full-text reading

Manual search n=1

Fig.1–Flowchartofarticleidentificationandeligibilityinthesystematicreview.

adolescentsbetween1and 18years ofage withrheumatic diseases, within a publication period of 25 years (1990 to 2015) and studiespublished inEnglish and Portuguese.All studydesignswereconsidered relevant.Weexcluded stud-ies that didnot meet the previously establishedinclusion criteria.

Methodsofanalysis

Initially,all theresults,exceptduplicateswereanalyzedby readingthetitleand abstract,toselectthepossiblearticles thatwouldbeincludedinthestudy.

Afterthis previous study selection,based on the analy-sisofthe title andthe abstract,the textswere readinfull and only after that, the studies were definitivelyincluded inthe systematicreview,if they metthe previously estab-lishedinclusioncriteria.Atthismoment,whenstudieswere readinfulltodefineeligibility,theauthoralsoperformeda manualsearch ofthereferences includedin thesestudies, aimingattheidentification ofarticlesthatwere notfound duringthedatabase search,but thatcould befoundinthe references.

Asthearticlesinthereferenceswerenotidentifiedinthe resultsofthisstudy,theywereselectedforoverallreadingto determineiftheywouldbeincludedinthestudy.

Table 2 shows the authors, titles, year of publication, database, inclusion,or exclusion justificationofall studies selectedforfullreading.Furthermore,itcontainsthearticle selectedbymanualsearchperformedbytheauthor.

Results

Atotalof162studieswereinitiallyidentifiedthroughsearchin theelectronicdatabases(Medline20,Scopus15,TheCochrane Library5,WebofScience5,LILACS0,Scielo0andCAPES Por-tal117)and1wasidentifiedbymanualsearchperformedby theauthor,totaling163studies.Ofthese,136wereexcluded becausetheywereidenticalarticles,i.e.,thesamepublication wasfoundindifferentdatabases,andbecausetheydidnot meettheobjectivesand/orinclusioncriteriaofthesystematic review,basedonthereadingofthetitleandtheabstract.

The27 articlesthat were notexcluded atthescreening basedonthereadingoftitlesandabstracts,werefully eval-uatedtodetermineiftheymettheeligibilitycriteria.Ofthese, 3wereincludedinthisstudy.Fig.1showstheflowchartthat representstheselectionandeligibilityofthestudies.Table3

indicatesthearticlesincludedinthestudy highlightingthe author, year of publication,study design,sample size, age groupandLTBItreatmentused.

Studycharacteristics

(5)

Table2–Studiesselectedforfull-textreading.

Authors Title Year Inclusionor

justificationfor exclusion

Database

Tandon,VR;Mahajan,A; Khajuria,V

TNFblockersandtuberculosis:anIndian concern

2006 Doesnotaddressthe agerangeofinterest ofthestudy

CAPESPortal

Vanhoof,J;Landewe,S;Van Wijngaerden,E;Geusens,P

Highincidenceofhepatotoxicityof isoniazidtreatmentfortuberculosis chemoprophylaxisinpatientswith rheumatoidarthritistreatedwith methotrexateorsulfasalazineand anti-tumournecrosisfactorinhibitors

CAPESPortal

DianaMariadeAlmeidaLopes; ValériaGoesFerreira Pinheiro;HelenaSerraAzul Monteiro;JoséAjaxNogueira Queiroz;LucivaldoDos SantosMadeira;Mônica MariadeAlmeidaLopes

Diagnosisandtreatmentoflatent tuberculosisinpatientswithchronic inflammatorydiseases:useof

TNF-alpha-targetingbiologicalproducts

2011 Agerange:≥11years CAPESPortal

Trajman,A.;Steffen,R.E.; Menzies,D.

Interferon-gammareleaseassaysversus tuberculinskintestingforthediagnosis oflatenttuberculosisinfection:an overviewoftheevidence

CAPESPortal

Winthrop,KL Updateontuberculosisandother opportunisticinfectionsassociatedwith drugsblockingtumournecrosisfactor␣

CAPESPortal

Keane,Joseph;Bresnihan,Barry Tuberculosisreactivationduring immunosuppressivetherapyin rheumaticdiseases:diagnosticand therapeuticstrategies

CAPESPortal

Kurt,OzlemKar;Kurt,Bahar; Talay,Fahrettin;Tug,Tuncer; Soy,Mehmet;Bes,Cemal; Hayran,Mutlu

Intermediatetolong-termfollow-up resultsofINHchemoprophylaxispriorto anti-TNF-alphatherapyinahigh-risk areafortuberculosis

CAPESPortal

Haroon,Muhammad;Martin, Una;Devlin,Joe

Highincidenceofintoleranceto tuberculosischemoprophylaxis

CAPESPortal

Carmona,Loreto; Gómez-Reino,JuanJ; Rodríguez-Valverde,Vicente; Montero,Dolores;

Pascual-Gómez,Eliseo;Mola, EmilioMartin;Carre ˜no,Luis; Figueroa,Manuel

Effectivenessofrecommendationsto preventreactivationoflatenttuberculosis infectioninpatientstreatedwithtumor necrosisfactorantagonists

CAPESPortal

Moosig,F.;Dalhoff,K. Infectiouspulmonarycomplicationsof rheumaticdiseases

2009 Articlewrittenin German

CAPESPortal

Nobre,Christiane;Callado, Maria;Lima,José;Gomes, Kirla;Martiniano,Germana; Vieira,Walber

Tuberculosisinfectioninrheumatic patientswithinfliximabtherapy: experiencewith157patients

CAPESPortal

Kilic,Omer;Kasapcopur, Ozgur;Camcioglu,Yildiz; Cokugras,Haluk;Arisoy,Nil; Akcakaya,Necla

Isitsafetouseanti-TNF-␣ agentsfor

tuberculosisinchildrensufferingwith chronicrheumaticdisease?

2012 Included CAPESPortal, Medline (Pubmed), Scopus,Webof Science Diel,R.;Hauer,B.;

Loddenkemper,R.;Manger, B.;Krüger,K.

Recommendationsfortuberculosis screeningbeforeinitiationof

TNF-␣-inhibitortreatmentinrheumatic

diseases

CAPESPortal

Valls,Victoria;Ena,Javier Short-coursetreatmentoflatent tuberculosisinfectioninpatientswith rheumaticconditionsproposedfor anti-TNFtherapy

(6)

Table2–(Continued₎

Database

Bray,Marie-Gaëlle;Poulain, Cécile;Dougados,Maxime; Gossec,Laure

Frequencyandtoleranceof

antituberculosistreatmentaccordingto nationalguidelinesforpreventionofrisk oftuberculosisduetotumornecrosis factorblockertreatment

CAPESPortal

Chu,AlvinaD;Polesky,Andrea H;Bhatia,Gulshan;Bush, ThomasM

Activeandlatenttuberculosisinpatients withsystemiclupuserythematosusliving intheUnitedStates

CAPESPortal

Dinser,R;Fousse,M;Sester,U; Albrecht,K;Singh,M;Köhler, H;Müller-Ladner,U;Sester,M

Evaluationoflatenttuberculosisinfection inpatientswithinflammatory

arthropathiesbeforetreatmentwith TNF-alphablockingdrugsusinganovel flow-cytometricinterferon-gamma releaseassay

CAPESPortal

Xie,Xi;Li,Fen;Chen,Jin-Wei; Wang,Jia

Riskoftuberculosisinfectionin anti-TNF-␣ biologicaltherapy:From

benchtobedside

2014 Doesnotaddressthe agerangeofinterest ofthestudy;limited approachforLTBI treatment

CAPESPortal

He,Dongyi;Bai,Fengmin; Zhang,Shu;Jiang,Ting; Shen,Jie;Zhu,Qi;Yue,Tao; Shao,Lingyun;Gao,Yan; Feng,Yun;Weng,Xinhua; Zou,Hejian;Zhang,Ying; Zhang,Wenhong

Highincidenceoftuberculosisinfection inrheumaticdiseasesandimpactfor chemoprophylacticpreventionof tuberculosisactivationduringbiologics therapy

CAPESPortal, Medline (Pubmed), Scopus,Webof Science

Bieber,Jeffry;Kavanaugh, Arthur

Considerationoftheriskandtreatment oftuberculosisinpatientswhohave rheumatoidarthritisandreceivebiologic treatments

CAPESPortal

Mariette,X;Salmon,D Frenchguidelinesfordiagnosisand treatinglatentandactivetuberculosisin patientswithRAtreatedwithTNF blockers

CAPESPortal

Abud-Mendoza,Carlos; Martínez-Martínez,Marco Ulises;DeJesús

Macías-Mendoza,José; Maga ˜na-Aquino,Martín

Shouldtuberculinskintestbepositiveto givelatenttuberculosistreatmentbefore tumornecrosisfactor-alphainhibitorsin selectedpatientsindevelopingcountries?

CAPESPortal

Scrivo,Rossana;Armignacco, Orlando

Tuberculosisriskandanti-tumour necrosisfactoragentsinrheumatoid arthritis:acriticalappraisalofnational registrydata

CAPESPortal

Calzada-HernándezJ(1), Anton-LópezJ(2), Bou-TorrentR(3), Iglesias-JiménezE(4), Ricart-CamposS(5),Martín deCarpiJ(6);CarmenGarcía deVicu ˜naMu ˜nozdelaNava, Torrente-SegarraV(7), Sánchez-ManubensJ(8), Giménez-RocaC(9), Rozas-QuesadaL(10), Juncosa-MorrosMT(11), FortunyC(12),Noguera-Julian A(13)

Tuberculosisinpediatricpatientstreated withanti-TNF␣ drugs:acohortstudy

2015 Included Medline (Pubmed)

SantosMJ(1),FonsecaJE, CanhãoH,CondeM,José VieiraM,CostaL,CostaM, SalgadoM,MeloGomesJÁ

Guidelinesforprescribingandmonitoring biologictherapiesinjuvenileidiopathic arthritis

2007 Verylimited approachofLTBI treatment

(7)

Table2–(Continued₎

Database

Demir,S.a,SadiAykan,F.a, Öztuna,D.b

Latenttuberculosistreatmentresultsin patientsthattakenTNF-alphablockersat AnkaraNumunetrainingandresearch hospitalchestdiseasesclinicforlast8 years(2006–2013)

Scopus

NurayAktayAyaz,Erkan Demirkaya,YeldaBilginer,U ˘g urÖzc¸elik,NazanC¸obano ˘glu, NuralKiper,NesrinBesbas, AysinBakkalo, ˘gluSezaÖzen

Preventingtuberculosisinchildren receivinganti-TNFtreatment

2010 Included Author’smanual search

andchesttomography.AnTST≥10mmwasconsidered pos-itive.Atthepre-anti-TNF-␣ therapyassessment,21patients weredetectedwithLTBIandtreatedwithINH(isoniazid)at 10mg/kg/day(maximum,300mg/day)for9monthsstarting1 monthbeforeanti-TNF-␣ therapy.NoTBdiseasewasdetected inthese patientsafter 9months. During follow-up, 7 chil-drenhadpositiveTSTandreceivedtreatmentforLTBIwith INHat 10mg/kg/day (maximum, 300mg/day)for9 months duringanti-TNF-␣ therapy.A13-year-oldfemalepatientwith juvenileidiopathicarthritisandsecondaryuveitisdeveloped positiveIGRAduringtreatmentwithINH.Anti-TBtreatment was started and, after 18 months, TB-related signs disap-peared.

Calzada-Hernándezetal.,17_in_a_prospective_cohort_study, assessed221childrenandadolescents withrheumatic dis-eases using TNF blockers. Before treatment, patients were submittedtoTSTorQuantiFERONGold-InTube(QTF-G)test and chest X-ray, and an TST ≥5mm was considered posi-tive.Duringtreatment,patientswereassessedevery6months throughclinicalhistoryandphysicalexamination.TST/QTF-G

andchestX-rayswereperformedonlywhennecessary.LTBI wasdiagnosedin3patientswithjuvenileidiopathicarthritis. TheyweretreatedforLTBIandthentheanti-TNF-␣treatment

wasreintroduced.OnepatientreceivedtreatmentwithINH for9monthsand,intwo,thetreatmentconsistedofINHand Rifampicinfor3months.Treatmentadherencewasobserved inallthreecases,andtherewerenoproblemsrelatedto tol-eranceandevidenceofTBactivation.Therewerenochanges inliverenzymelevelsaspartateaminotransferase(AST)and alanineaminotransferase(ALT).

Ayaz et al.,18 _in _a_prospective _cohort_study, _followed ₃₆ patients diagnosedwith juvenileidiopathic arthritistaking etanercept.Allchildrenandfamilymemberswerescreened forLTBIandactiveTBpriortoetanercepttherapy.Screening consistedofclinicalhistory,physicalexamination,TST,and chestX-ray.Thechildrenwerere-evaluatedevery3months. SevenpatientshadTST>10mmandwere treatedwithfull doseofINHfor4–8weeks,plus9monthsafterthestartof theanti-TNF-␣therapy.TherewasnoTBactivationinthese

patientsorothercomplicationsduringfollow-up.

Table3–Characteristicsofincludedstudies.

Author(year) Studytype Sampletreated Screeningmethod Treatmentused Observedoutcomes

Kilic(2012)16 _{Retrospective}_cohort

study

28patients Historyandphysical examination,TST (≥10mm),chest X-rayand,when necessary,gastric aspirateculture every6months

10mg/kg/day

(maximum,300mg/day) ofINHfor9months.

1caseofTB activationduring treatmentwithINH. ResolvedwithTB treatment.There werenoother complications regardingTB activation Calzada-Hernández

(2015)17

Prospectivecohort study

3patients TSTandQuantiferon Gold-InTube®test (QTF-G),historyand physical

examination

INHfor9monthsand INH+rifampicinfor3 months

Therewerenocases ofTBdiseaseor othercomplications

Ayaz(2010)18 _{Retrospective}_cohort

study

7patients History,physical examination,TST (>10mm)andchest X-rayevery3 months

Initialtreatmentfor4–8 weekswithfull-dose INHandtreatment continuationfora further9monthsafter thestartoftreatment withTNFblocker

(8)

Discussion

Intheliterature,itispossibletoidentifydifferenttherapeutic regimens forthe treatmentofLTBI.TheMinistry ofHealth recommendsINHatthedoseof5mg/kgto10mg/kgofweight uptoamaximumdoseof300mg/dayforaminimumperiodof 6months.However,thereare4optionsrecommendedbythe WHO:INHfor6or9months;Rifapentineweeklyfor3months plusINH;INHfor3–4monthsplusRifampicin;3–4monthsof rifampicin.8

Duetothegreatersusceptibilityoftheat-riskpopulationto developtheactivedisease,thecorrecttreatmentisvery impor-tant. Inthe caseofnewbornscohabiting withthe infected indexcase,newbornsshouldnotbevaccinatedatbirth.INHis administeredforaperiodofthreemonths,afterwhichtheTST isperformed.Chemoprophylaxisismaintainedforanother3 monthsiftheTSTis≥5mm.Otherwise,INHisdiscontinued andtheindividualisvaccinatedwithBCG.9

For children who are contact with infected individuals, treatmentisindicatedwhen theTST is≥5mminchildren notvaccinatedwithBCG,inchildrenvaccinatedformorethan twoyearsorinthepresenceofanyimmunosuppressive con-dition.ItisalsoindicatedwhentheTST≥10mminchildren vaccinatedwithBCG forlessthan twoyears.Childrenthat acquiredLTBIuptotheageof5areconsideredprioritiesfor LTBItreatment.9

However,the number ofstudies included in the review showsthescarcityofstudiesevaluatingthetreatmentofLTBI inchildrenwithrheumaticdiseases.Thepresenceofthese childreninthe riskgroup,aswell asthedisease mortality, makeitimportanttocarryoutstudiescomparingthe differ-entavailabletherapies.Itisobservedthat,duetothisfact,the besttherapyforthesepatientsisyettobedefined.Onlythe studybyKilicetal.16_showed_a_case_of_TB_activation._The_low incidenceofTBdiseaseinthesepatientsisprobablyduetothe continuousfollow-upandscreeningofthesechildrenduring thechronicdiseasetreatment.

Onthe otherhand,onlyonestudy showeddatarelated toliverenzymealterations duringtreatment. Althoughnot frequentandreversible,INH-inducedhepatotoxicityin chil-drenwithLTBIhasbeendescribedintheliterature.19_However, thebehaviorofthehepaticprofileinchildrenwithrheumatic diseases receivingthis medication has notbeen described. Because this is a group of childrenwith chronic systemic diseasesreceivingothermedications,informationabout tol-erabilitymaybevaluableinclinicalpractice.

Goodadherencetotreatmentinallthreestudiesmayalso haveoccurred duetothemedicalmonitoringthesechronic patientsneedtoundergo.Silvaetal.20_showed_that,_in_children withoutcomorbidities,8.9%didnotreturnfortheTSTreading and12.65%didnotadheretotreatment.

OfthetherapeuticregimensrecommendedbytheWHO, thefollowingwerenotobserved:INHfor6months;Rifampicin for 3 months weekly plus INH; 3–4 months of rifampicin. The use to these schemes would be important for the comparison.

Thus,thebest therapeuticregimenforthe treatmentof LTBI in pediatric patients with rheumatic diseases cannot yetbedetermined.Morestudiesarerequiredtoevaluatethe

response tothe other available therapeuticregimens,with bettertolerabilityassessmentandlargersamplesize.

Finally, theresultsofthestudies showedthatINH ther-apyfor6–9monthsandINHtherapyplusrifampicinforthree monthsmayhavealowactivation rate;however,the dura-tioniscontroversial,whichemphasizestheneedtoperform furtherstudies.12

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1.WorldHealthOrganization.GlobalHealthObservatorydata repository.Availableat:http://apps.who.int/gho/data/ node.main.GHECOD[accessed22.11.15].

2.WorldHealthOrganization.Globaltuberculosisreport2015. Availableat:http://apps.who.int/iris/bitstream/10665/ 191102/1/9789241565059eng.pdf?ua=1[accessed22.11.15]. 3.SistemadeInformac¸ãodeAgravoseNotificac¸ão.Série

históricadacoeficientedeincidênciadatuberculose. SINAN/SES2015.Availableat:http://portalsaude.saude. gov.br/images/pdf/2015/setembro/24/taxa-incid–ncia-tuberculose-1999-2014-base-JUN-2015.pdf[accessed22.11.15]. 4.SistemadeInformac¸õessobreMortalidade–SIM.Série

HistóricadoCoeficientedeMortalidadedeTuberculose. Brasil,RegiõeseUnidadesFederadasderesidênciaporano dediagnóstico.MS/SVS/DASIS.Availableat:http://portalsaude. saude.gov.br/images/pdf/2015/setembro/24/taxa-mortalidade-tuberculose-1999-2014-base-JUN-2015.pdf[accessed22.11.15]. 5.MinistériodaSaúde,SecretariadeVigilânciaemSaúde.

Situac¸ãoepidemiológicadatuberculosenosestadospartese associadosdoMercosul2009a2013–Brasília:MS;2015. Availableat:http://portalsaude.saude.gov.br/images/pdf/ 2015/outubro/07/tuberculose-mercosul-6out15-web.pdf

[accessed22.11.15].

6.DiretoriadeVigilânciaEpidemiológica/SESAB,Boletim epidemiológicoJan/2015.DIVEP2015.Availableat:http:// www.suvisa.ba.gov.br/sites/default/files/BOLETIM%202014 %20editado.pdf[accessed22.11.15].

7.ErnstJD.Theimmunologicallifecycleoftuberculosis.Nat RevImmunol.2012;12:581–91.

8.WorldHealthOrganization.Guidelinesonthemanagement oflatenttuberculosisinfection;2015.Availableat:http://apps. who.int/iris/bitstream/10665/136471/1/9789241548908eng. pdf?ua=1&ua=1[accessed22.11.15].

9.MinistériodaSaúdeSecretariadeVigilânciaemSaúde. DepartamentodeVigilânciaEpidemiológica.Manualde recomendac¸õesparaocontroledatuberculosenoBrasil– Brasília:MS;2011.

10.SociedadeBrasileiradeReumatologia.Preliminaryguidelines oftheBrazilianSocietyofRheumatologyforevaluationand treatmentoftuberculosislatentinfectioninpatientswith rheumatoidarthritis,infaceofunavailabilityofthe tuberculinskintest.RevBrasReumatol.2015;55:390–3.

11.MarquesCDL,DuarteALBP,CavalcantiFS,CarvalhoEMF, GomesYM.Abordagemdiagnósticadatuberculoselatentena artritereumatoide.RevBrasReumatol.2007;47:424–30.

12.CostaAF,LazariCS,LeiteOHM.Tuberculoselatente: rastreamento,métodosdiagnósticosetratamento.RevPaul Reumatol.2014;13:11–6.

(9)

sobreastaxasdeinfecc¸ãoempacientescomartrite reumatoide.RevBrasReumatol.2013;53:501–15.

14.TittonDC,RanzolinA,HayataAL,DuarteA,BrenolC,Pinheiro GC,etal.RelatóriodoBiobadaBrasilde30/06/2014.Available at:biobadaser.ser.es/biobadamerica/Brasil[accessed22.11.15]. 15.TittonDC.RegistroBrasileirodeMonetarizac¸ãodeTerapias

BiológicasemDoenc¸asReumáticas–BiobadaBrasil.RevPaul Reumatol.2014;13:17–20.

16.KilicO,KasapcopurO,CamciogluY,CokugrasH,ArisoyN, AkcakayaN.Isitsafetouseanti-TNF-␣agentsfor tuberculosisinchildrensufferingwithchronicrheumatic disease.ReumatolInt.2012;32:2675–9.

17.Calzada-HernándezJ,Anton-LópezJ,Bou-TorrentR, Iglesias-JiménezE,Ricart-CamposS,MartíndeCarpiJ,etal.

Tuberculosisinpediatricpatientstreatedwithanti-TNF␣ drugs:acohortstudy.PediatrReumatol.2015;13:54.

18.AyazNA,DemirkayaE,BilginerY,Özc¸elikU,C¸obano ˘gluN, KiperN,etal.Preventingtuberculosisinchildrenreceiving anti-TNFtreatment.ClinRheumatol.2010;29:

389–92.

19.ChangSH,NahidP,EitzmanSR.Hepatotoxicityinchildren receivingisoniazidtherapyforlatenttuberculosisinfection.J PediatrInfectDis.2014;3:221–7.