A population-based study of tuberculosis incidence among rheumatic disease patients under anti-TNF treatment

Autoři: Natália Sarzi Sartori aff001;  Paulo Picon aff002;  Afonso Papke aff001;  Jeruza Lavanholi Neyeloff aff003;  Rafael Mendonça da Silva Chakr aff001
Působiště autorů: Department of Rheumatology, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil aff001;  Department of Internal Medicine, UFRGS, Porto Alegre, Brazil aff002;  Planning and Evaluation Advisory Office, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224963



Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. The advent of immunobiologic therapy with TNF inhibitors agents, has been associated with a significant increase in incident cases of tuberculosis in this population.


To estimate the incidence of tuberculosis in patients receiving TNF inhibitors therapy for rheumatic diseases. As secondary objectives, we sought to evaluate mortality and the clinical impact of screening for latent tuberculosis infection.


This retrospective study included patients with rheumatic diseases of Public Health System from the Brazilian state, a high TB incidence area, who received prescriptions of TNF inhibitors agents between 2006 and 2016.


A total of 5853 rheumatic disease patients were included. Patients were predominantly women (68.7%) aged 49.5 (± 14.7) years old. Forty-three cases of TB were found (2.86 cases per 1000 person-years; 18 times higher than in the general population). Adalimumab and certolizumab users presented a higher risk for TB development compared to etanercept users (RR: 3.11, 95%CI 1.16–8.35; 7.47, 95%CI 1.39–40.0, respectively). In a subgroup of patients, screening for latent tuberculosis infection was performed in 86% of patients, and 30.2% had a positive tuberculin skin test. Despite latent TB treatment, TB was diagnosed in 2 out of 74 (2.7%) patients. Overall, TB diagnosis did not increase mortality.


In this population-based study of rheumatic disease patients from a high incident area, TNF inhibitor exposure was associated with an 18-time increased TB incidence. Adalimumab and certolizumab were associated with greater and earlier TB diagnosis compared to etanercept.

Klíčová slova:

Ankylosing spondylitis – Brazil – Cytokines – Rheumatoid arthritis – Rheumatology – Tuberculosis – Psoriatic arthritis


1. Lee SK, Kim SY, Kim EY, Jung JY, Park MS, Kim YS, et al. Mycobacterial infections in patients treated with tumor necrosis factor antagonists in South Korea. Lung. 2013;191(5):565–71. doi: 10.1007/s00408-013-9481-5 23728990

2. Garcia-Vidal C, Rodríguez-Fernández S, Teijón S, Esteve M, Rodríguez-Carballeira M, Lacasa JM, et al. Risk factors for opportunistic infections in infliximab-treated patients: The importance of screening in prevention. Eur J Clin Microbiol Infect Dis. 2009;28(4):331–7. doi: 10.1007/s10096-008-0628-x 18797940

3. Gómez-Reino JJ, Carmona L, Rodríguez Valverde V, Mola EM, Montero MD. 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(8):2122–7. doi: 10.1002/art.11137 12905464

4. Koike T, Harigai M, Ishiguro N, Inokuma S, Takei S, Takeuchi T, et al. Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: Postmarketing surveillance report of the first 3,000 patients. Mod Rheumatol. 2012;22(4):498–508. doi: 10.1007/s10165-011-0541-5 21993918

5. Mariette X, Gottenberg JE, Ravaud P, Combe B. Registries in rheumatoid arthritis and autoimmune diseases: Data from the French registries. Rheumatology. 2011;50(1):222–9. doi: 10.1093/rheumatology/keq368 21148156

6. Burmester GR, Landewé R, Genovese MC, Friedman AW, Pfeifer ND, Varothai NA, et al. Adalimumab long-term safety: Infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76(2):414–7. doi: 10.1136/annrheumdis-2016-209322 27338778

7. Chiu Y. M., Tang C. H., Hung S. T., Yang Y. W., Fang C. H., and Lin H. Y., “A real-world risk analysis of biological treatment (adalimumab and etanercept) in a country with a high prevalence of tuberculosis and chronic liver disease: a nationwide population-based study,” Scand. J. Rheumatol., vol. 46, no. 3, pp. 236–240, 2017.

8. Tarkiainen M, Tynjälä P, Vähäsalo P, Lahdenne P. Occurrence of adverse events in patients with JIA receiving biologic agents: Long-term follow-up in a real-life setting. Rheumatol (United Kingdom). 2015;54(7):1170–6.

9. Liao H, Zhong Z, Liu Z, Zou X. Comparison of the risk of infections in different anti-TNF agents: a meta-analysis. Int J Rheum Dis. 2017;20(2):161–8. doi: 10.1111/1756-185X.12970 28160418

10. Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka Y, Yamanaka H, et al. Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis. Ann Rheum Dis. 2008;67(2):189–94. doi: 10.1136/ard.2007.072967 17644554

11. Kaufmann SH. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol. 2001;1(1):20–30. doi: 10.1038/35095558 11905811

12. Russell DG. Who puts the tubercle in tuberculosis? Nat Rev Microbiol [Internet]. 2007;5(1):39–47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17160001 17160001

13. Wallis RS. Tumour necrosis factor antagonists: structure, function, and tuberculosis risks. Lancet Infect Dis. 2008;8(10):601–11. doi: 10.1016/S1473-3099(08)70227-5 18922482

14. Favalli EG, Desiati F, Atzeni F, Sarzi-Puttini P, Caporali R, Pallavicini FB, et al. Serious infections during anti-TNF?? treatment in rheumatoid arthritis patients. Autoimmun Rev [Internet]. 2009;8(3):266–73. Available from: http://dx.doi.org/10.1016/j.autrev.2008.11.002 19022409

15. Ai JW, Zhang S, Ruan QL, Yu YQ, Zhang BY, Liu QH, et al. The Risk of Tuberculosis in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor-alpha Antagonist: A Metaanalysis of Both Randomized Controlled Trials and Registry/Cohort Studies. J Rheumatol. 2015;42(12):2229–37. doi: 10.3899/jrheum.150057 26472414

16. WHO. Global Tuberculosis Report 2017. World Health Organization. 2017. 1–262 p.

17. Ministério da Saúde. Secretaria de Vigilancia em Saúde. Departamento de Vigilancia Epidemiologica. Manual de Recomendações para o Controle da Tuberculose no Brasil. 2011;(61).

18. BRASIL M da SS de V em S. Implantação do Plano Nacional pelo Fim da Tuberculose como Problema de Saúde Pública no Brasil: primeiros passos rumo ao alcance das metas. Bol Epidemiológico 11 [Internet]. 2018;49(11):18. Available from: http://portalarquivos2.saude.gov.br/images/pdf/2018/marco/26/2018-009.pdf

19. Yeh JJ, Wang YC, Sung FC, Kao CH. Rheumatoid arthritis increases the risk of nontuberculosis mycobacterial disease and active pulmonary tuberculosis. PLoS One. 2014;9(10)

20. 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(7):1986–92. doi: 10.1002/art.21137 15986370

21. Ke W-M, Chen L-S, Parng I-M, Chen W-W, On AWF. Risk of tuberculosis in rheumatoid arthritis patients on tumour necrosis factor-alpha inhibitor treatment in Taiwan. Int J Tuberc Lung Dis [Internet]. 2013;17(12):1590–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24200274 24200274

22. Arkema EV, Jonsson J, Baecklund E, Bruchfeld J, Feltelius N, Askling J. Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments? Ann Rheum Dis [Internet]. 2014;1–6. http://www.ncbi.nlm.nih.gov/pubmed/24608401

23. Wang X, Wong SH, Wang X-S, Tang W, Liu C-Q, Niamul G, et al. Risk of tuberculosis in patients with immune-mediated diseases on biological therapies: a population-based study in a tuberculosis endemic region. Rheumatology. 2019;58(5):803–10. doi: 10.1093/rheumatology/key364 30561745

24. Cagatay T, Bingol Z, Kıyan E, Yegin Z, Okumus G, Arseven O, et al. Follow-up of 1887 patients receiving tumor necrosis-alpha antagonists: Tuberculin skin test conversion and tuberculosis risk. Clin Respir J. 2018;12(4):1668–75. doi: 10.1111/crj.12726 29028148

25. Seong S-S, Choi C-B, Woo J-H, Kang WB, Joung C-L, Uhm W-S, et al. Incidence of tuberculosis in Korean patients with Rheumatoid Arthritis (RA): Effects of RA itself and of tumor necrosis factor blockers. J Rheumatol [Internet]. 2007;34(4):706–11. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-34247332718&partnerID=40&md5=37282bf3735840802a493e16fce30fa9 17309133

26. Conde MB, De Melo FAF, Marques AMC, Cardoso NC, Pinheiro VGF, Dalcin PDTR, et al. III Diretrizes para Tuberculose da Sociedade Brasileira de Pneumologia e Tisiologia. J Bras Pneumol. 2009;35(10):1018–48.

27. Maria L, Cruz BA, Brenol CV, Pereira IA, Rezende-fronza LS, Bertolo MB, et al. Reumatologia para o tratamento da artrite reumatoide. Rev Bras Reumatol [Internet]. 2012;52(2):152–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22460407

28. Cantini F, Nannini C, Niccoli L, Iannone F, Delogu G, Garlaschi G, et al. Guidance for the management of patients with latent tuberculosis infection requiring biologic therapy in rheumatology and dermatology clinical practice. Autoimmun Rev [Internet]. 2015;14(6):503–9. Available from: http://dx.doi.org/10.1016/j.autrev.2015.01.011 25617816

29. Gomez-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(5):756–61. doi: 10.1002/art.22768 17530674

30. Pérez-Sola MJ, Torre-Cisneros J, Pérez-Zafrilla B, Carmona L, Descalzo MA, Gómez-Reino JJ. Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry. Med Clin (Barc). 2011;137(12):533–40.

31. Yonekura CL, Oliveira RDR, Titton DC, Ranza R, Ranzolin A, Hayata AL, et al. Incidência de tuberculose em pacientes com artrite reumatoide em uso de bloqueadores do TNF no Brasil: dados do Registro Brasileiro de Monitoração de Terapias Biológicas BiobadaBrasil. Rev Bras Reumatol [Internet]. 2017;57(S 2):477–83. Available from: http://dx.doi.org/10.1016/j.rbr.2017.05.003

32. Dixon WG, Symmons DPM, Lunt M, Watson KD, Hyrich KL, Silman AJ. Serious infection following anti–tumor necrosis factor α therapy in patients with rheumatoid arthritis: Lessons from interpreting data from observational studies. Arthritis Rheum [Internet]. 2007;56(9):2896–904. Available from: http://doi.wiley.com/10.1002/art.22808 17763441

33. Furst DE, Wallis R, Broder M, Beenhouwer DO. Tumor Necrosis Factor Antagonists: Different Kinetics and/or Mechanisms of Action May Explain Differences in the Risk for Developing Granulomatous Infection. Semin Arthritis Rheum. 2006;36(3):159–67. doi: 10.1016/j.semarthrit.2006.02.001 16884970

34. Brassard P, Kezouh A, Suissa S. Antirheumatic Drugs and the Risk of Tuberculosis. Clin Infect Dis [Internet]. 2006;43(6):717–22. Available from: https://academic.oup.com/cid/article-lookup/doi/10.1086/506935 16912945

35. Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero D, Pascual-Gómez E, Mola EM, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum. 2005;52(6):1766–72. doi: 10.1002/art.21043 15934089

36. Baddley JW, Cantini F, Goletti D, Gómez-Reino JJ, Mylonakis E, San-Juan R, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents). Clin Microbiol Infect. 2018;24:S10–20. doi: 10.1016/j.cmi.2017.12.025 29459143

37. Siqueira RC. The potential of the IGRA (Interferon Gamma Release Assay) test for the diagnosis of ocular. 2019;78(3):202–9.

38. Bonfiglioli KR, Ribeiro ACM, Moraes JCB, Saad CGS, Souza FHC, 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(8):905–11. doi: 10.5588/ijtld.13.0755 25199003

39. Garziera G, Morsch ALB, Otesbelgue F, Staub FL, Palominos PE, Brenol CV, et al. Latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents. Clin Rheumatol. 2017;36(8):1891–6. doi: 10.1007/s10067-017-3714-6 28589321

40. Marques CDL, Duarte ÂLBP, de Lorena VMB, de Souza JR, Souza W, de M Gomes Y, et al. Resposta atenuada ao PPD no diagnóstico de infecção tuberculosa latente em pacientes com artrite reumatoide. Rev Bras Reumatol [Internet]. 2009;49(2). Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0482-50042009000200004&lng=pt&nrm=iso&tlng=pt

41. Ehlers S. Role of tumour necrosis factor (TNF) in host defence against tuberculosis: Implications for immunotherapies targeting TNF. Ann Rheum Dis. 2003;62(SUPPL. 2):37–42.

42. 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 [Internet]. 2003;3(3):148–55. Available from: http://linkinghub.elsevier.com/retrieve/pii/S1473309903005450 12614731

43. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous Infectious Diseases Associated with Tumor Necrosis Factor Antagonists. Clin Infect Dis [Internet]. 2004;38(9):1261–5. Available from: https://academic.oup.com/cid/article-lookup/doi/10.1086/383317 15127338

44. Lahiri M, Dixon WG. Risk of infection with biologic antirheumatic therapies in patients with rheumatoid arthritis. Best Pract Res Clin Rheumatol [Internet]. 2015;29(2):290–305. Available from: http://dx.doi.org/10.1016/j.berh.2015.05.009 26362745

45. Titton DC, Silveira IG, Louzada-junior P, Hayata AL, Carvalho HMS, Ranza R, et al. Registro Brasileiro de Biológicos : preliminares do BiobadaBrasil. Rev Bras Reum. 2011;51(2):145–60.

46. Kisacik B, Pamuk ON, Onat AM, Erer SB, Hatemi G, Ozguler Y, et al. Characteristics predicting tuberculosis risk under tumor necrosis factor-α inhibitors: Report from a large multicenter cohort with high background prevalence. J Rheumatol. 2016;43(3):524–9. doi: 10.3899/jrheum.150177 26773107

47. Nisar MK, Rafiq A, Östör AJK. Biologic therapy for inflammatory arthritis and latent tuberculosis: real world experience from a high prevalence area in the United Kingdom. Clin Rheumatol [Internet]. 2015;34(12):2141–5. Available from: http://link.springer.com/10.1007/s10067-015-3099-3 26497501

48. Keane J. TNF-blocking agents and tuberculosis: New drugs illuminate an old topic. Rheumatology. 2005;44(6):714–20. doi: 10.1093/rheumatology/keh567 15741198

49. Sichletidis L, Settas L, Spyratos D, Chloros D, Patakas D. Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis. Int J Tuberc Lung Dis. 2006;10(10):1127–32. 17044206

50. Nobre CA, Callado MRM, Lima JRC, Gomes KWP. Tuberculosis infection in rheumatic patients with infliximab therapy: Experience with 157 patients. Rheumatol Int. 2012;32(9):2769–75. doi: 10.1007/s00296-011-2017-5 21822912

51. Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, et al. 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(3):522–8. doi: 10.1136/ard.2009.118935 19854715

52. Denis B, Lefort A, Flipo RM, Tubach F, Lemann M, Ravaud P, et al. Long-term follow-up of patients with tuberculosis as a complication of tumour necrosis factor (TNF)-a antagonist therapy: safe re-initiation of TNF-a blockers after appropriate anti-tuberculous treatment. 2007;183–6.

53. Rossato D., Diego S., De Tarso P., and Dalcin R., “Factors Associated with Mortality in Hospitalized Patients with Newly Diagnosed Tuberculosis,” pp. 33–41, 2010. doi: 10.1007/s00408-009-9224-9 20131479

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