Background: Tumor necrosis factor (TNF)-α inhibitors are known to increase the risk of tuberculosis (TB). Objectives: To examine the factors associated with an increased risk of TB in patients receiving anti-TNF-α treatment (aTNF-α-T). Method: Of 3,094 patients who received aTNF-α-T between 2003 and 2013, a total of 1,964 subjects with a follow-up time longer than 6 months were identified and included in this retrospective analysis. Potential risk factors for the development of TB in patients receiving aTNF-α-T were evaluated. Results: Of the 1,964 patients, 1,009 (51%) were male and 955 (49%) were female, with a mean age of 39.7 ± 13.9 years. The primary conditions requiring aTNF-α-T included ankylosing spondylitis (n = 875), rheumatoid arthritis (n = 711), Behçet's disease (n = 83), and others (n = 295). Sixteen patients [8 (50%) males and 8 (50%) females; 5 (31.2%) with pulmonary TB and 11 (68.8%) with extrapulmonary TB] developed TB, with a corresponding TB incidence of 466/100,000. No significant associations were found between age, gender, smoking history, pack-years of smoking, isoniazid (INH) chemoprophylaxis, type of anti-TNF-α agent, use of other immunosuppressive drugs, and the risk of TB (p > 0.05). Multivariate logistic regression analysis showed a significantly higher risk of TB in patients diagnosed with Behçet's disease, and a significantly lower risk of TB in patients with a tuberculin skin test wheal ≥10 mm in diameter (p < 0.05). Conclusion: aTNF-α-T is associated with an increased risk of pulmonary or extrapulmonary TB, even when follow-up protocols and INH chemoprophylaxis are implemented, and TB often develops in the later stages of treatment. The risk of TB was higher in patients with Behçet's disease and lower in patients who had a strong tuberculin skin test reaction.

Keywords:
Tumor necrosis factor-α inhibitors, Tuberculosis, Risk factors
1.
World Health Organization: Global Tuberculosis Report 2013. http://www.who.int/tb/publications/global_report/en/ (accessed June 21, 2014).
2.
Schiff MH, Burmester GR, Kent JD, Pangan AL, Kupper H, Fitzpatrick SB, Donovan C: Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 2006;65:889-894.
3.
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;48:2122-2127.
4.
Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Cöster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, Romanus V, Klareskog L, Feltelius N: Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis Rheum 2005;52:1986-1992.
5.
Elbek O, Uyar M, Aydin N, Borekci S, Bayram N, Bayram H, Dikensoy O: Increased risk of tuberculosis in patients treated with antitumor necrosis factor alpha. Clin Rheumatol 2009;28:421-426.
6.
Mutlu GM, Mutlu EA, Bellmeyer A, Rubinstein I: Pulmonary adverse events of anti-tumor necrosis factor-alpha antibody therapy. Am J Med 2006;119:639-646.
7.
Vordermeier HM: T-cell recognition of mycobacterial antigens. Eur Respir J Suppl 1995;20:657-667.
8.
Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, Schreiber R, Mak TW, Bloom BR: Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995;2:561-572.
9.
Stenger S: Immunological control of tuberculosis: role of tumour necrosis factor and more. Ann Rheum Dis 2005;64(suppl 4):24-28.
10.
Engele M, Stossel E, Castiglione K, Schwerdtner N, Wagner M, Bolcskei P, Rollinghoff M, Stenger S: Induction of TNF in human alveolar macrophages as a potential evasion mechanism of virulent Mycobacterium tuberculosis. J Immunol 2002;168:1328-1337.
11.
American Thoracic Society: Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;61:221-247.
12.
British Thoracic Society Standards of Care Committee: BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-α treatment. Thorax 2005;60:800-805.
13.
Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lortholary O, Mariette X; 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: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009;60:1884-1894.
14.
Brassard P, Kezouh A, Suissa S: Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis 2006;43:717-722.
15.
Wallis RS: Tumour necrosis factor antagonists: structure, function, and tuberculosis risks. Lancet Infect Dis 2008;8:601-611.
16.
Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO: Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004;38:1261-1265.
17.
Kıter G, Uçan ES: Prevention of tuberculosis. Toraks 2001;2:85-90.
18.
World Health Organization: Turkey - tuberculosis profile. 2011. https://extranet.who.int/sree/Reports?op=Replet&name=/WHO_HQ_Reports/G2/PROD/EXT/TBCountryProfile&ISO2=TR&outtype=html (accessed June 21, 2014).
19.
Doğan C, Kıral N, Cömert SS, Fidan A, Çağlayan B, Salepçi B: Tuberculosis frequency in patients taking TNF-alpha blockers. Turks Toraks Derg 2012;13:93-98.
20.
Hanta I, Ozbek S, Kuleci S, Kocabas A: The evaluation of latent tuberculosis in rheumatologic diseases for anti-TNF therapy: experience with 192 patients. Clin Rheumatol 2008;27:1083-1086.
21.
Cagatay T, Aydin M, Sunmez S, et al: Follow-up results of 702 patients receiving tumor necrosis factor-alpha antagonists and evaluation of risk of tuberculosis. Rheumatol Int 2010;30:1459-1463.
22.
Cagatay T, Bingol Z, Yegin Z, Okumus G, Kiyan E, Arseven O, Erkan F, Gulbaran Z, Erelel M, Ece T, Kilicaslan Z: Clinical characteristics of tuberculosis patients who were on therapy of tumor necrosing factor alpha antagonists. Chest 2014;145:137A.
23.
Keser G, Direskeneli H, Akkoç N, et al: Rheumatology Research and Education Foundation's Consensus Report on using TNF-α inhibitors. 2005. http://www.romatoloji.org/Romatizma.asp?RAED=RaporveKilavuzlar&SubShf=IIRAEDUzlasi (accessed April 14, 2013).
24.
Lasco TM, Cassone L, Kamohara H, Yoshimurac T, McMurraya DN: Evaluating the role of tumor necrosis factor-alpha in experimental pulmonary tuberculosis in the guinea pig. Tuberculosis 2005;85:245-258.
25.
Philips JA, Ernst JD: Tuberculosis pathogenesis and immunity. Annu Rev Pathol Mech Dis 2012;7:353-384.
26.
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM: Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-1104.
27.
Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC: Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003;3:148-155.
28.
Toussirot E, Wendling D: The use of TNF-alpha blocking agents in rheumatoid arthritis: an overview. Expert Opin Pharmacother 2004;5:581-594.
29.
Roberts L, McColl GJ: Tumour necrosis factor inhibitors: risks and benefits in patients with rheumatoid arthritis. Intern Med J 2004;34:687-693.
30.
Imaizumi K, Sugishita M, Usui M, Kawabe T, Hashimoto N, Hasegawa Y: Pulmonary infectious complications associated with anti-TNF alpha therapy (infliximab) for rheumatoid arthritis. Intern Med 2006;45:685-688.
31.
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;10:1127-1132.
32.
Manadan AM, Joyce K, Sequeira W, Block JA: Etanercept therapy in patients with a positive tuberculin skin test. Clin Exp Rheumatol 2007;25:743-745.
33.
Churchyard GJ, Fielding KL, Lewis JJ, Coetzee L, Corbett EL, Godfrey-Faussett P, Hayes RJ, Chaisson RE, Grant AD; Thibela TB Study Team: A trial of mass isoniazid preventive therapy for tuberculosis control. N Engl J Med 2014;370:301-310.
34.
Carmona L, Hernández-García C, Vadillo C, Pato E, Balsa A, González-Alvaro I, Belmonte MA, Tena X, Sanmartí R; EMECAR Study Group: Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 2003;30:1436-1439.
35.
Yamada T, Nakajima A, Inoue E, Tanaka E, Hara M, Tomatsu T, Kamatani N, Yamanaka H: Increased risk of tuberculosis in patients with rheumatoid arthritis in Japan. Ann Rheum Dis 2006;65:1661-1663.
36.
Brassard P, Lowe AM, Bernatsky S, Kezouh A, Suissa S: Rheumatoid arthritis, its treatments, and the risk of tuberculosis in Quebec, Canada. Arthritis Rheum 2009;61:300-304.
37.
Kim HW, Park JK, Yang JA, Yoon YI, Lee EY, Song YW, Kim HR, Lee EB: Comparison of tuberculosis incidence in ankylosing spondylitis and rheumatoid arthritis during tumor necrosis factor inhibitor treatment in an intermediate burden area. Clin Rheumatol 2014;33:1307-1312.
38.
Efthimiou J, Hay PE, Spiro SG, Lane DJ: Pulmonary tuberculosis in Behçet's syndrome. Br J Dis Chest 1988;82:300-304.
39.
Coelho PC, da Silva JA, Romeu JC, da Costa JC, de Queiroz MV: Simultaneous appearance of Behçet's disease and pulmonary tuberculosis. Clin Exp Rheumatol 1994;12:692.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.