Incidence of tuberculosis among patients with rheumatoid arthritis using TNF blockers in Brazil: data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil)

Claudia Leiko Yonekura Rene Donizeti Ribeiro Oliveira David C. Titton Roberto Ranza Aline Ranzolin André L. Hayata Ângela Duarte Inês G. Silveira Hellen M. da S. de Carvalho Júlio C. Bertacini de Moraes Mirhelen Mendes de Abreu Valéria Valim Washington Bianchi Claiton Viegas Brenol Ivanio A. Pereira Izaias Costa José C. Macieira José R.S. Miranda Luiz S. Guedes-Barbosa Manoel B. Bertolo Maria Fátima Lobato da C. Sauma Marília B.G. Silva Marlene Freire Morton A. Scheinberg Roberto A. Toledo Sheila K.F. Oliveira Vander Fernandes Marcelo M. Pinheiro Glaucio Castro Walber Pinto Vieira Cesar Emile Baaklini Antonio Ruffino-Netto Geraldo da Rocha Castelar Pinheiro Ieda Maria Magalhães Laurindo Paulo Louzada-Junior About the authors

Abstract

Objectives

To assess the incidence of tuberculosis and to screen for latent tuberculosis infection among Brazilians with rheumatoid arthritis using biologics in clinical practice.

Patients and methods

This cohort study used data from the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil), from 01/2009 to 05/2013, encompassing 1552 treatments, including 415 with only synthetic disease-modifying anti-rheumatic drugs, 942 synthetic DMARDs combined with anti-tumor necrosis factor (etanercept, infliximab, adalimumab) and 195 synthetic DMARDs combined with other biologics (abatacept, rituximab and tocilizumab). The occurrence of tuberculosis and the drug exposure time were assessed, and screening for tuberculosis was performed. Statistical analysis: Unpaired t-test and Fisher's two-tailed test; p < 0.05.

Results

The exposure times were 981 patient-years in the controls, 1744 patient-years in the anti-TNF group (adalimumab = 676, infliximab = 547 and etanercept = 521 patient-years) and 336 patient-years in the other biologics group. The incidence rates of tuberculosis were 1.01/1000 patient-years in the controls and 2.87 patient-years among anti-TNF users (adalimumab = 4.43/1000 patient-years; etanercept = 1.92/1000 patient-years and infliximab = 1.82/1000 patient-years). No cases of tuberculosis occurred in the other biologics group. The mean drug exposure time until the occurrence of tuberculosis was 27(11) months for the anti-TNF group.

Conclusions

The incidence of tuberculosis was higher among users of synthetic DMARDs and anti-TNF than among users of synthetic DMARDs and synthetic DMARDs and non-anti-TNF biologics and also occurred later, suggesting infection during treatment and no screening failure.

Keywords:
Rheumatoid arthritis; Tuberculosis; Biologics; Brazil; Registry

Resumo

Objetivos

Avaliar incidência de tuberculose e triagem para tuberculose latente em brasileiros com artrite reumatoide em uso de agentes biológicos na prática clinica.

Pacientes e métodos

Estudo de coorte com dados do Registro Brasileiro de Monitoração de Terapias Biológicas (BiobadaBrasil), de 01/2009 a 05/2013, abrangeu 1.552 tratamentos, 415 somente com drogas modificadoras do curso da doença (MMCDs) sintéticas, 942 MMCDs sintéticas em associação com anti-TNF (etanercepte, infliximabe, adalimumabe) e 195 MMCDs sintéticas em associação com outros biológicos (abatacepte, rituximabe e tocilizumabe). Avaliaram-se ocorrência de tuberculose, tempo de exposição às drogas e triagem para TB. Análise estatística: teste t não pareado e teste de Fisher bicaudal; p < 0,05.

Resultados

O tempo de exposição dos controles foi de 981 pacientes-ano, do grupo de anti-TNF foi de 1.744 pacientes-ano (adalimumabe = 676, infliximabe = 547 e etanercepte = 521 pacientes-ano) e o de outros biológicos de 336 pacientes-ano. A incidência de TB foi de 1,01/1.000 pacientes-ano nos controles e de 2,87 pacientes-ano nos usuários de anti-TNF (adalimumabe = 4,43/1.000 pacientes-ano; etanercepte = 1,92/1.000 pacientes-ano e infliximabe = 1,82/1.000 pacientes-ano). Não houve casos de tuberculose no grupo de outros biológicos. O tempo médio de exposição até a ocorrência de tuberculose foi de 27(11) meses para o grupo anti-TNF.

Conclusões

A incidência de tuberculose foi maior nos usuários de MMCDs sintéticas e anti-TNF do que nos usuários de MMCDs sintéticas e de MMCDs sintéticas e biológicos não anti-TNF, e também mais tardia, sugerindo infecção durante o tratamento, e não falha na triagem.

Palavras-chave
Artrite reumatoide; Tuberculose; Biológicos; Brasil; Registro

Introduction

The introduction of tumor necrosis factor blockers (anti-TNF) started the era of biological therapies for rheumatoid arthritis (RA), unquestionably benefiting the share of patients unresponsive to disease-modifying anti-rheumatic drugs (DMARDs),11 Chen YF, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess. 2006;10:iii-iv. thereby resulting in reduced radiographic progression, fewer joint deformities and improved overall health of individuals.22 Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443-50.,33 Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26-37. In Brazil, the following biological DMARDs were available in the Unified Health System (Sistema Único de Saúde - SUS) until 2012: etanercept (ETN), infliximab (IFX), adalimumab (ADA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ). In addition to therapeutic failure, the main reason for treatment discontinuation is the occurrence of adverse events, among which infections are the most worrying based on either the relative frequency or the severity.44 Hyrich KL, Watson KD, Silman AJ, Symmons DP. Predictors of response to anti-TNF-a therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology. 2006;45:1558-65.,55 Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55. The increased incidence of tuberculosis (TB) among anti-TNF users is a worldwide concern, with strong evidence suggesting a causal relationship.66 Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med. 2001;345:1098-104.

7 Mohan AK, Cote TR, Block JA, Manadan AM, Siegel JN, Braun MM. Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis. 2004;39:295-9.
-88 Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Biobadaser Group Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48:2122-7.

TB is a disease with a high worldwide incidence and prevalence, inclusively in Brazil. The World Health Organization (WHO) estimates that the worldwide incidence of TB was 9.4 million cases (equivalent to 137 cases per 100,000 inhabitants) and that the prevalence was 14 million cases (equivalent to 200 cases per 100,000 inhabitants) in 2009.99 Global tuberculosis control: WHO report 2010. Available at: http://whqlibdoc.who.int/publications/2010/9789241564069_eng.pdf.
http://whqlibdoc.who.int/publications/20...
In Brazil in 2010, the estimated incidence was 37.2 cases per 100,000 inhabitants.1010 Ministério da Saúde - Programa Nacional de Controle da tuberculose. Available at: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/741-secretaria-svs/vigilancia-de-a-a-z/tuberculose/11485-situacao-epidemiologica-dados.
http://portalsaude.saude.gov.br/index.ph...
Brazil is among the 22 countries prioritized by WHO, encompassing 80% of the global tuberculosis burden, and ranks 19th in number of cases. The risk for TB among patients with RA is two to four times higher than among the general population, ranging according to the study region or country.1111 Baronnet L, Barnetche T, Kahn V, Lacoin C, Richez C, Schaeverbeke T. Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. Joint Bone Spine. 2011;78:279-84. No study on the incidence of TB among patients with RA in the Brazilian population has been published.

TNF plays a key role in the effective immune response against Mycobacterium tuberculosis, increasing the phagocytic capacity of macrophages and contributing to destroying the pathogen, forming granulomas and preventing the systemic spread of the infection.55 Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55. Therefore, using anti-TNF in patients with RA further increases the risk for TB, which is extrapulmonary in 60% of the cases and disseminated in 26%.1111 Baronnet L, Barnetche T, Kahn V, Lacoin C, Richez C, Schaeverbeke T. Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. Joint Bone Spine. 2011;78:279-84. Among anti-TNF drugs, monoclonal antibodies (IFX and ADA) are associated with a higher risk for developing TB than soluble TNF receptors (ETN).77 Mohan AK, Cote TR, Block JA, Manadan AM, Siegel JN, Braun MM. Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis. 2004;39:295-9.,88 Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Biobadaser Group Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48:2122-7. According to a systematic literature review, the incidence of TB in patients who used ETN ranged from 9 to 39/100,000 patient-years. Conversely, the incidence of TB among those who used IFX and ADA ranged from 95 to 215/100,000 patient-years.1111 Baronnet L, Barnetche T, Kahn V, Lacoin C, Richez C, Schaeverbeke T. Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. Joint Bone Spine. 2011;78:279-84. Gardam et al. suggest that functional and structural differences between monoclonal antibodies and soluble receptors may explain that difference.55 Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55. The increased incidence of TB among patients with RA using non-anti-TNF biologics has not been undisputedly described thus far in either pre- or post-marketing clinical studies.1212 Campbell L, Chen C, Bhagat SS, Parker RA, Östör AJ. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology. 2011;50:552-62.

13 Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et al. Safety of abatacept administered intravenously in treatment of rheumatoid arthritis: integrated analyses of up to 8 years of treatment from the abatacept clinical trial program. J Rheumatol. 2013;40:787-97.
-1414 Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Dev Ther. 2013;8:87-100.

All patients receiving biological therapy should be tested for latent tuberculosis infection (LTBI). In Brazil, the screening is performed by chest radiography and intradermal test with the purified protein derivative (PPD) of M. tuberculosis. Chemoprophylaxis with isoniazid, 300 mg/day for six months, should be performed when the PPD value is higher than or equal to 5 mm, when changes indicating TB are detected by radiography or when the clinical and epidemiological data suggest contact (or history of contact) with tuberculosis, according to recommendations from the Brazilian Department of Health (Ministério da Saúde do Brasil) and the Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia - SBR).1515 Sociedade Brasileira de Pneumologia e Tisiologia, Sociedade Brasileira de Infectologia e Sociedade Brasileira de Reumatologia. Projeto Diretrizes da Associação Médica Brasileira e Conselho Federal de Medicina. Tuberculose infecção latente: diagnóstico. Available at: http://www.projetodiretrizes.org.br/ans/diretrizes/77.pdf.
http://www.projetodiretrizes.org.br/ans/...
,1616 Da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo MB, et al. 2012 Brazilian Society of Rheumatology Consensus for the treatment of rheumatoid arthritis. Rev Bras Reumatol. 2012;52:152-74.

Assessing the risk for TB among patients using biologics throughout the country and for each disease separately is crucial. Only one Brazilian study showed an increase in the incidence of TB among individuals using anti-TNF for various rheumatic diseases.1717 Nobre CA, Callado MR, Lima JR, Gomes KW, Martiniano GV, Vieira WP. Tuberculosis infection in rheumatic patients with infliximab therapy: experience with 157 patients. Rheumatol Int. 2012;32:2769-75. No previous study has evaluated how the LTBI screening and treatment would be performed among patients with RA using the drugs.

We aimed to assess the incidence of TB among patients with RA using various classes of biologics. Furthermore, we assessed the incidences of TB among patients using each anti-TNF separately, comparing them with the incidence rates of tuberculosis in patients using synthetic DMARDs and in individuals from the general population.

Patients and methods

A cohort study was conducted in patients with RA who were registered in the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil),1818 Titton D, Louzada-Junior P, Guimaraes I, Hayata AL, Carvalho HM, Ranza R, et al. Brazilian biologic registry: BiobadaBrasil implementation process and preliminary results. Rev Bras Reumatol. 2011;51:152-60. established by the Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia - SBR) toward monitoring the use of all biological medications indefinitely licensed for use in rheumatology in the country. The study period extended from January 01, 2009 to May 31, 2013 by online registration, including patient demographic and clinical data and information on the treatments and adverse events from 35 hospital centers from all Brazilian regions. In addition to regular medical visits, patients were followed-up via semiannual telephone contact and annual, on-site reviews of medical records.

Inclusion criteria: RA diagnosis (according to the 1987 American College of Rheumatology classification criteria)1919 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315-24. and inclusion in the BiobadaBrasil from January 01, 2009 to May 31, 2013.

Exclusion criteria: diagnosis other than RA or having RA and using only antimalarials.

We divided the participants into three study groups: Anti-TNF group, represented by patients with RA using synthetic DMARDs and anti-TNF (IFX, ETN or ADA); Other biologics group, represented by patients with RA using synthetic DMARDs and a non-anti-TNF biologic (ABT, RTX or TCZ); and Control group, represented by patients with RA using synthetic DMARDs (methotrexate, leflunomide, sulfasalazine and chloroquine). The patients in this group had never been treated with biologics. No patient migrated from the control to the biologics group. Each anti-TNF was also evaluated separately.

The study variables were the number of treatment courses with each drug, regardless of the number of patients because several patients received more than one biologic during the study period; sex; age; disease time; TB occurrence; drug exposure time; performing screening for TB (PPD skin test and chest radiography) and performing chemoprophylaxis when suspecting LTBI. Patients with PPD ≥ 5 mm or those with chest radiographic changes compatible with TB were considered patients with suspected LTBI, regardless of the PPD value.

Statistical analysis was performed with the unpaired t-test and Fisher's two-tailed test. Results were considered statistically significant if p < 0.05.

The study was approved by the Research Ethics Committee (Comitê de Ética em Pesquisa - CEP) of the University Hospital of the Medical School of Ribeirão Preto (Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - HCFMRP) under process HCRP number 7694/2009. All patients signed the informed consent form to participate in the present study.

Results

A total of 1256 patients were evaluated in a total of 1552 treatments, including 415 in the Control group, 942 in the Anti-TNF group and 195 in the Other biologics group. The drug exposure times were 981 patient-years for the Control group, 1744 patient-years for the Anti-TNF group and 336 patient-years for the Other biologics group. Among the Anti-TNF group, the highest number of treatments (366, 39%) and the longest drug exposure time (676 patient-years) occurred with ADA, followed by IFX (293, 31%; 547 patient-years) and ETN (n = 283, 30%; 521 patient-years). No significant difference occurred between the three groups regarding sex, age and disease time (p = 0.6).

One case of TB occurred in the Control group and five cases in the Anti-TNF group, with 1.01/1000 patient-years and 2.86/1000 patient-years incidence rates, respectively. ADA had 4.43 cases/1000 patient-years incidence, followed by ETN (1.92 cases/1000 patient-years) and IFX (1.82 cases/1000 patient-years). No cases of TB were detected in the Other biologics group. Regarding the control group, the relative risk (RR) of developing tuberculosis associated with the use of anti-TNF was 2.83, which was highest among individuals treated with ADA (RR = 4.43). Table 1 outlines these data and the disease screening and chemoprophylaxis data, showing that PPD positivity and the presence of chest radiographic changes show no significant differences between study groups, similar to the ratio of individuals who received chemoprophylaxis (p = 0.7).

Table 1
Distribution of participants by study group, according to demographic data, related to tuberculosis screening and occurrence.

The case of TB in the Control group occurred after 18 months of exposure to treatment with DMARDs. In this case, no screening or chemoprophylaxis had been performed. The anti-TNF group showed 27.2 ± 11.0 months of drug exposure time until the occurrence of TB, with 22.7 ± 10.4 for ADA and 31 and 40 months for ETN and IFX, respectively. The standard deviations of ETN and IFX were not calculated because only one case of TB occurred for each drug. All patients had been subjected to standard screening with negative results. Individual data from patients who developed TB are outlined in Table 2.

Table 2
Clinical and laboratory data from the six patients who developed tuberculosis during treatment with anti-TNF.

Discussion

This study is the first conducted in Brazil evaluating patients using biologics in daily clinical practice and the occurrence of TB. Furthermore, although screening for LTBI was performed in most patients, the incidence of TB among RA patients using anti-TNF was higher than among patients who used synthetic DMARDs alone or in combination with other non-anti-TNF biologics. Since the first reports of a higher incidence of TB among anti-TNF users, the mean time to diagnosis of infection is shorter than one year.55 Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55. It should be noted that the occurrence of TB was late in this study, indicating that most patients acquired the infection during use and not due to the presence of latent TB undetected by screening.

Brazil is a developing country, with many problems related to quality of life and public health, consequences of high social inequality and, therefore, high levels of poverty. These facts contribute to an increase in the prevalence of opportunistic infections, such as TB. The prevalence and incidence of the disease in the country are very high when compared with the developed countries.2020 World Health Organization Global tuberculosis report 2016.Geneva: World Health Organization; 2016. p. 1–201. Available at: http://www.who.int/tb/publications/global report/en/.
http://www.who.int/tb/publications/globa...
Social problems may be implicated in the large differences in TB rates between developed and undeveloped countries because M. tuberculosis is universal. In 2012, 69,000 new cases of TB were reported in Brazil, with an incidence rate of 35.2/100,000 individuals. The highest absolute number of cases occurs in the state of São Paulo, and the state of Rio de Janeiro has the highest incidence rate. Comparing the incidence between capitals, Porto Alegre has the highest incidence rate, followed by Recife, Belém, Rio de Janeiro and Manaus.1010 Ministério da Saúde - Programa Nacional de Controle da tuberculose. Available at: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/741-secretaria-svs/vigilancia-de-a-a-z/tuberculose/11485-situacao-epidemiologica-dados.
http://portalsaude.saude.gov.br/index.ph...

Similar to other case series, we found that the subgroup given treatment with a monoclonal antibody against TNF had the highest incidence of TB (ADA).2121 Cantini F, Niccoli L, Goletti D. Adalimumab, etanercept, infliximab, and the risk of tuberculosis: data from clinical trials, national registries, and postmarketing surveillance. J Rheumatol Suppl. 2014;91:47-55. The patients treated with IFX had the lowest incidence in the group, and ETN had an intermediate value, in contrast to the findings of other case series.2222 Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Cöster L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005;52:1986-92.,2323 Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, et al. Research Axed on Tolerance of Biotherapies Group Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy. Arthritis Rheum. 2009;60:1884-94. None of these patients had received previous anti-TNF treatment. The Other biologics group showed no cases of TB, a result also in agreement with most of the available data thus far, which show the relative safety of those drugs regarding the occurrence of TB.2424 Cantini F, Niccoli L, Goletti D. Tuberculosis risk in patients treated with non-anti-tumor necrosis factor-α (TNF-α) targeted biologics and recently licensed TNF-α inhibitors: data from clinical trials and national registries. J Rheumatol Suppl. 2014;91:56-64.,2525 Souto A, Maneiro JR, Salgado E, Carmona L, Gomez-Reino JJ. Risk of tuberculosis in patients with chronic immune-mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis of randomized controlled trials and long-term extension studies. Rheumatology (Oxford). 2014;53:1872-85.

The relative risk for tuberculosis development is increased among RA patients using anti-TNF, reaching a magnitude of 2-4 times higher than that of patients using synthetic DMARDs alone. Furthermore, treatment with anti-TNF is apparently a key risk factor for the extrapulmonary and disseminated forms of TB, as observed in three patients - two with the ganglionar form and one with the disseminated form. The occurrence of extrapulmonary TB is higher among anti-TNF users and, in a country such as Brazil, where the incidence of TB is high among the general population, this group should also be considered a priority in the context of public health surveillance policies for monitoring the occurrence of the disease, especially extrapulmonary forms. Our study showed an incidence of TB very similar to that of other studies conducted in European countries, the USA and Japan.2626 Goh L, Jewell T, Laversuch C, Samanta A. A systematic review of the influence of anti-TNF on infection rates in patients with rheumatoid arthritis. Rev Bras Reumatol. 2013;53:501-15.

27 Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69:522-8.
-2828 Gómez-Reino JJ, Carmona L, Angel Descalzo M. Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. Arthritis Rheum. 2007;57:756-61. Therefore, anti-TNF therapy apparently removes the effect of improved life conditions in protecting against the occurrence of TB, showing that the granuloma destabilization is the crucial step to the high risk of disease development among these individuals.

The incidence of TB among the group of patients using synthetic DMARDs was also higher than among the general Brazilian population (101 vs. 37.2 cases/100,000 individual-years). Although the event occurred in only one individual, this datum is in agreement with findings from several countries, showing that the incidence of TB is higher among RA patients, regardless of the use of biologics, most likely partly because of the disease itself and partly because of the treatment with synthetic DMARDs.

Screening for LTBI is essential but has failed to identify patients at high risk of developing the disease.1818 Titton D, Louzada-Junior P, Guimaraes I, Hayata AL, Carvalho HM, Ranza R, et al. Brazilian biologic registry: BiobadaBrasil implementation process and preliminary results. Rev Bras Reumatol. 2011;51:152-60.,2121 Cantini F, Niccoli L, Goletti D. Adalimumab, etanercept, infliximab, and the risk of tuberculosis: data from clinical trials, national registries, and postmarketing surveillance. J Rheumatol Suppl. 2014;91:47-55.,2929 Keystone EC, Papp KA, Wobeser W. Challenges in diagnosing latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. J Rheumatol. 2011;38:1234-43. PPD positivity in the general Brazilian population ranges from 25 to 35%,1010 Ministério da Saúde - Programa Nacional de Controle da tuberculose. Available at: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/741-secretaria-svs/vigilancia-de-a-a-z/tuberculose/11485-situacao-epidemiologica-dados.
http://portalsaude.saude.gov.br/index.ph...
although, as expected, PPD positivity was lower in our study, ranging from 10.1% to 16.7%, because the patients used immunosuppressants. Regional studies assessing PPD positivity among patients with RA before starting biologics showed similar results to those of our registry, including 14% in Pernambuco,3030 Marques CM, Duarte ÂLBP, Lorena VMB, Souza JR, Souza W, Gomes YM, et al. Attenuated response to PPD in the diagnosis of latent tuberculosis infection in patients with rheumatoid arthritis. Rev Bras Reumatol. 2009;49:121-5. 15% in Ceará3131 Callado MRM, Lima JR, Nobre CA, Vieira WP. Low prevalence of reactive PPD prior to infliximab use: comparative study on a population sample of Hospital Geral de Fortaleza. Rev Bras Reumatol. 2011;51:40-52. and 21% in São Paulo.3232 Bonfiglioli KR, Ribeiro ACM, Moraes JCB, Saad CG, Souza FH, Calich AL, et al. LTBI screening in rheumatoid arthritis patients prior to anti-TNF treatment in an endemic area. Int J Tuberc Lung Dis. 2014;18:905-11.

The high efficacy of isoniazid treatment in LTBI cases is well known3333 Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst Rev. 2000;2:CD001363.; thus, defining who will receive the drug remains a key discussion point. Treatment for LTBI could have been presumably protective in various patients who did not receive it and were subsequently diagnosed with TB because no patient treated with the drug developed the disease. Screening methods must be improved, especially for non-reactors to PPD. It must be questioned herein whether it would be pertinent to perform tests for a PPD booster effect3434 Salles CG, Ruffino-Netto A, Lapa-e-Silva JR, Kritski AL, Cailleaux-Cesar M, Queiroz-Mello FC, et al. The presence of a booster phenomenon among contacts of active pulmonary tuberculosis cases: a retrospective cohort. BMC Public Health. 2007;7:38. or even to use an interferon-gamma release assay (IGRA) for improving the tests for latent TB.2929 Keystone EC, Papp KA, Wobeser W. Challenges in diagnosing latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. J Rheumatol. 2011;38:1234-43. In our survey, these methods were not mentioned. Some hospital departments in Brazil may perform such tests, but they are not used on a daily basis due to technical difficulties and cost.

Among our patients, all cases of TB occurred after negative initial screening, and TB occurred in one patient within 12 months of treatment, raising the possibility of screening failure. However, in the other four groups of patients with RA, TB occurred after at least 24 months, suggesting contact with the mycobacterium during treatment.

In conclusion, this study is the first conducted in Brazil assessing the occurrence of TB in patients using biologics in daily clinical practice, based on the Brazilian Registry of Biological Therapies in Rheumatic Diseases (Registro Brasileiro de Monitoração de Terapias Biológicas - BiobadaBrasil). The incidence of TB among patients with RA using anti-TNF and the late disease onset should be noted, indicating that most patients acquired the infection during use and not due to the presence of LTBI undetected by screening.

References

  • 1
    Chen YF, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess. 2006;10:iii-iv.
  • 2
    Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443-50.
  • 3
    Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26-37.
  • 4
    Hyrich KL, Watson KD, Silman AJ, Symmons DP. Predictors of response to anti-TNF-a therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology. 2006;45:1558-65.
  • 5
    Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-55.
  • 6
    Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med. 2001;345:1098-104.
  • 7
    Mohan AK, Cote TR, Block JA, Manadan AM, Siegel JN, Braun MM. Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis. 2004;39:295-9.
  • 8
    Gómez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Biobadaser Group Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum. 2003;48:2122-7.
  • 9
    Global tuberculosis control: WHO report 2010. Available at: http://whqlibdoc.who.int/publications/2010/9789241564069_eng.pdf
    » http://whqlibdoc.who.int/publications/2010/9789241564069_eng.pdf
  • 10
    Ministério da Saúde - Programa Nacional de Controle da tuberculose. Available at: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/741-secretaria-svs/vigilancia-de-a-a-z/tuberculose/11485-situacao-epidemiologica-dados
    » http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/741-secretaria-svs/vigilancia-de-a-a-z/tuberculose/11485-situacao-epidemiologica-dados
  • 11
    Baronnet L, Barnetche T, Kahn V, Lacoin C, Richez C, Schaeverbeke T. Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. Joint Bone Spine. 2011;78:279-84.
  • 12
    Campbell L, Chen C, Bhagat SS, Parker RA, Östör AJ. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology. 2011;50:552-62.
  • 13
    Weinblatt ME, Moreland LW, Westhovens R, Cohen RB, Kelly SM, Khan N, et al. Safety of abatacept administered intravenously in treatment of rheumatoid arthritis: integrated analyses of up to 8 years of treatment from the abatacept clinical trial program. J Rheumatol. 2013;40:787-97.
  • 14
    Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Dev Ther. 2013;8:87-100.
  • 15
    Sociedade Brasileira de Pneumologia e Tisiologia, Sociedade Brasileira de Infectologia e Sociedade Brasileira de Reumatologia. Projeto Diretrizes da Associação Médica Brasileira e Conselho Federal de Medicina. Tuberculose infecção latente: diagnóstico. Available at: http://www.projetodiretrizes.org.br/ans/diretrizes/77.pdf
    » http://www.projetodiretrizes.org.br/ans/diretrizes/77.pdf
  • 16
    Da Mota LM, Cruz BA, Brenol CV, Pereira IA, Rezende-Fronza LS, Bertolo MB, et al. 2012 Brazilian Society of Rheumatology Consensus for the treatment of rheumatoid arthritis. Rev Bras Reumatol. 2012;52:152-74.
  • 17
    Nobre CA, Callado MR, Lima JR, Gomes KW, Martiniano GV, Vieira WP. Tuberculosis infection in rheumatic patients with infliximab therapy: experience with 157 patients. Rheumatol Int. 2012;32:2769-75.
  • 18
    Titton D, Louzada-Junior P, Guimaraes I, Hayata AL, Carvalho HM, Ranza R, et al. Brazilian biologic registry: BiobadaBrasil implementation process and preliminary results. Rev Bras Reumatol. 2011;51:152-60.
  • 19
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315-24.
  • 20
    World Health Organization Global tuberculosis report 2016.Geneva: World Health Organization; 2016. p. 1–201. Available at: http://www.who.int/tb/publications/global report/en/
    » http://www.who.int/tb/publications/global report/en/
  • 21
    Cantini F, Niccoli L, Goletti D. Adalimumab, etanercept, infliximab, and the risk of tuberculosis: data from clinical trials, national registries, and postmarketing surveillance. J Rheumatol Suppl. 2014;91:47-55.
  • 22
    Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Cöster L, et al. Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum. 2005;52:1986-92.
  • 23
    Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, et al. Research Axed on Tolerance of Biotherapies Group Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy. Arthritis Rheum. 2009;60:1884-94.
  • 24
    Cantini F, Niccoli L, Goletti D. Tuberculosis risk in patients treated with non-anti-tumor necrosis factor-α (TNF-α) targeted biologics and recently licensed TNF-α inhibitors: data from clinical trials and national registries. J Rheumatol Suppl. 2014;91:56-64.
  • 25
    Souto A, Maneiro JR, Salgado E, Carmona L, Gomez-Reino JJ. Risk of tuberculosis in patients with chronic immune-mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis of randomized controlled trials and long-term extension studies. Rheumatology (Oxford). 2014;53:1872-85.
  • 26
    Goh L, Jewell T, Laversuch C, Samanta A. A systematic review of the influence of anti-TNF on infection rates in patients with rheumatoid arthritis. Rev Bras Reumatol. 2013;53:501-15.
  • 27
    Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis. 2010;69:522-8.
  • 28
    Gómez-Reino JJ, Carmona L, Angel Descalzo M. Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. Arthritis Rheum. 2007;57:756-61.
  • 29
    Keystone EC, Papp KA, Wobeser W. Challenges in diagnosing latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. J Rheumatol. 2011;38:1234-43.
  • 30
    Marques CM, Duarte ÂLBP, Lorena VMB, Souza JR, Souza W, Gomes YM, et al. Attenuated response to PPD in the diagnosis of latent tuberculosis infection in patients with rheumatoid arthritis. Rev Bras Reumatol. 2009;49:121-5.
  • 31
    Callado MRM, Lima JR, Nobre CA, Vieira WP. Low prevalence of reactive PPD prior to infliximab use: comparative study on a population sample of Hospital Geral de Fortaleza. Rev Bras Reumatol. 2011;51:40-52.
  • 32
    Bonfiglioli KR, Ribeiro ACM, Moraes JCB, Saad CG, Souza FH, Calich AL, et al. LTBI screening in rheumatoid arthritis patients prior to anti-TNF treatment in an endemic area. Int J Tuberc Lung Dis. 2014;18:905-11.
  • 33
    Smieja MJ, Marchetti CA, Cook DJ, Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst Rev. 2000;2:CD001363.
  • 34
    Salles CG, Ruffino-Netto A, Lapa-e-Silva JR, Kritski AL, Cailleaux-Cesar M, Queiroz-Mello FC, et al. The presence of a booster phenomenon among contacts of active pulmonary tuberculosis cases: a retrospective cohort. BMC Public Health. 2007;7:38.

Publication Dates

  • Publication in this collection
    2017

History

  • Received
    17 Aug 2015
  • Accepted
    24 May 2017
Sociedade Brasileira de Reumatologia Av Brigadeiro Luiz Antonio, 2466 - Cj 93., 01402-000 São Paulo - SP, Tel./Fax: 55 11 3289 7165 - São Paulo - SP - Brazil
E-mail: sbre@terra.com.br
Accessibility / Report Error