Tumor necrosis factor-alpha inhibitors and mycobacterial infections
- Kevin L Winthrop, MD, MPH
Kevin L Winthrop, MD, MPH
- Professor, School of Public Health
- Associate Professor, Department of Medicine
- Divisions of Infectious Disease and Ophthalmology,
- Oregon Health and Sciences University
- Section Editors
- C Fordham von Reyn, MD
C Fordham von Reyn, MD
- Section Editor — Tuberculosis; Nontuberculous Mycobacterial Infections
- Professor of Medicine
- Geisel School of Medicine at Dartmouth
- Kieren A Marr, MD
Kieren A Marr, MD
- Section Editor — Compromised Host Infections; Fungal Infections
- Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
Inhibitors of tumor necrosis factor (TNF)-alpha represent important treatment advances in a number of inflammatory conditions, including rheumatoid arthritis, the seronegative spondyloarthropathies, psoriasis, and inflammatory bowel disease. TNF-alpha inhibitors offer a targeted strategy that contrasts with the nonspecific immunosuppressive agents traditionally used to treat most inflammatory diseases.
However, multiple potential complications and adverse effects of targeted TNF-alpha inhibition have been identified. These include:
●Mycobacterial infections including those due to Mycobacterium tuberculosis (tuberculosis [TB]) and nontuberculous mycobacteria (NTM)
●Other infections (bacterial, viral, and fungal)
●Injection site reactionsTo continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Algood HM, Lin PL, Flynn JL. Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis 2005; 41 Suppl 3:S189.
- Kindler V, Sappino AP, Grau GE, et al. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 1989; 56:731.
- Flynn JL, Goldstein MM, Chan J, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2:561.
- Benini J, Ehlers EM, Ehlers S. Different types of pulmonary granuloma necrosis in immunocompetent vs. TNFRp55-gene-deficient mice aerogenically infected with highly virulent Mycobacterium avium. J Pathol 1999; 189:127.
- Bopst M, Garcia I, Guler R, et al. Differential effects of TNF and LTalpha in the host defense against M. bovis BCG. Eur J Immunol 2001; 31:1935.
- Randhawa PS. Lymphocyte subsets in granulomas of human tuberculosis: an in situ immunofluorescence study using monoclonal antibodies. Pathology 1990; 22:153.
- Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003; 3:148.
- Lin PL, Myers A, Smith L, et al. Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model. Arthritis Rheum 2010; 62:340.
- Bekker LG, Freeman S, Murray PJ, et al. TNF-alpha controls intracellular mycobacterial growth by both inducible nitric oxide synthase-dependent and inducible nitric oxide synthase-independent pathways. J Immunol 2001; 166:6728.
- Clay H, Volkman HE, Ramakrishnan L. Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. Immunity 2008; 29:283.
- Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098.
- Gómez-Reino JJ, Carmona L, Valverde VR, et al. 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.
- Fonseca JE, Canhão H, Silva C, et al. [Tuberculosis in rheumatic patients treated with tumour necrosis factor alpha antagonists: the Portuguese experience]. Acta Reumatol Port 2006; 31:247.
- Brassard P, Kezouh A, Suissa S. Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis 2006; 43:717.
- Wallis RS, Broder MS, Wong JY, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis 2004; 38:1261.
- Wallis RS, Broder M, Wong J, Beenhouwer D. Granulomatous infections due to tumor necrosis factor blockade: correction. Clin Infect Dis 2004; 39:1254.
- Askling J, Fored CM, Brandt 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.
- Dixon WG, Watson K, Lunt M, et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2006; 54:2368.
- Tubach F, Salmon D, Ravaud P, et al. 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.
- Winthrop KL, Baxter R, Liu L, et al. Mycobacterial diseases and antitumour necrosis factor therapy in USA. Ann Rheum Dis 2013; 72:37.
- Dixon WG, Hyrich KL, Watson KD, 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; 69:522.
- Hsia EC, Schluger N, Cush JJ, et al. Interferon-γ release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Arthritis Rheum 2012; 64:2068.
- Bykerk VP, Cush J, Winthrop K, et al. Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials. Ann Rheum Dis 2015; 74:96.
- Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis 2015; 74:2107.
- Carmona L, Hernández-García C, Vadillo C, et al. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 2003; 30:1436.
- Arkema EV, Jonsson J, Baecklund E, et al. Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments? Ann Rheum Dis 2015; 74:1212.
- Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004; 50:372.
- Bruns H, Meinken C, Schauenberg P, et al. Anti-TNF immunotherapy reduces CD8+ T cell-mediated antimicrobial activity against Mycobacterium tuberculosis in humans. J Clin Invest 2009; 119:1167.
- Saliu OY, Sofer C, Stein DS, et al. Tumor-necrosis-factor blockers: differential effects on mycobacterial immunity. J Infect Dis 2006; 194:486.
- Plessner HL, Lin PL, Kohno T, et al. Neutralization of tumor necrosis factor (TNF) by antibody but not TNF receptor fusion molecule exacerbates chronic murine tuberculosis. J Infect Dis 2007; 195:1643.
- Mohan AK, Coté TR, Block JA, et al. Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis 2004; 39:295.
- Centers for Disease Control and Prevention (CDC). Tuberculosis associated with blocking agents against tumor necrosis factor-alpha--California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004; 53:683.
- Hill PC, Brookes RH, Fox A, et al. Large-scale evaluation of enzyme-linked immunospot assay and skin test for diagnosis of Mycobacterium tuberculosis infection against a gradient of exposure in The Gambia. Clin Infect Dis 2004; 38:966.
- Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep 2010; 59:1.
- Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012; 64:625.
- Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016; 68:1.
- Hamilton CD. Tuberculosis in the cytokine era: what rheumatologists need to know. Arthritis Rheum 2003; 48:2085.
- Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis 2017; 64:e1.
- Kleinert S, Tony HP, Krueger K, et al. Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions. Ann Rheum Dis 2012; 71:1791.
- Mariette X, Baron G, Tubach F, et al. Influence of replacing tuberculin skin test with ex vivo interferon γ release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy. Ann Rheum Dis 2012; 71:1783.
- Winthrop KL, Weinblatt ME, Daley CL. You can't always get what you want, but if you try sometimes (with two tests--TST and IGRA--for tuberculosis) you get what you need. Ann Rheum Dis 2012; 71:1757.
- Canadian Tuberculosis Committee. Recommendations on Interferon Gamma Release Assays for the Diagnosis of Latent Tuberculosis Infection - 2010 Update. Can Commun Dis Rep 2010; 36:1.
- Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005; 52:1766.
- Winthrop KL, Siegel JN, Jereb J, et al. Tuberculosis associated with therapy against tumor necrosis factor alpha. Arthritis Rheum 2005; 52:2968.
- Winthrop KL, Iseman M. Bedfellows: mycobacteria and rheumatoid arthritis in the era of biologic therapy. Nat Rev Rheumatol 2013; 9:524.
- Duncan KO, Winthrop KL. Reply to: "Comment on 'Time to update guidelines on screening for latent tuberculosis infection in dermatologic patients being treated with tumor necrosis factor-alfa inhibitors'". J Am Acad Dermatol 2015; 73:e125.
- Centers for Disease Control and Prevention, National Institutes of Health, and Infectious Diseases Society of America guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on November 23, 2016).
- Centers for Disease Control and Prevention (CDC). Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep 2011; 60:1650.
- Matsumoto T, Tanaka T, Kawase I. Infliximab for rheumatoid arthritis in a patient with tuberculosis. N Engl J Med 2006; 355:740.
- Wallis RS, Kyambadde P, Johnson JL, et al. A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis. AIDS 2004; 18:257.
- Arend SM, Leyten EM, Franken WP, et al. A patient with de novo tuberculosis during anti-tumor necrosis factor-alpha therapy illustrating diagnostic pitfalls and paradoxical response to treatment. Clin Infect Dis 2007; 45:1470.
- Garcia Vidal C, Rodríguez Fernández S, Martínez Lacasa J, et al. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin Infect Dis 2005; 40:756.
- Wallis RS, van Vuuren C, Potgieter S. Adalimumab treatment of life-threatening tuberculosis. Clin Infect Dis 2009; 48:1429.
- Rivoisy C, Nicolas N, Mariette X, et al. Clinical features and risk factors of paradoxical aggravation of tuberculosis after anti-TNF-alpha withdrawal. A case-control study. European Society of Clinical Microbiology and Infectious Diseases 2012. Oral presentation O227.
- Hsu DC, Faldetta KF, Pei L, et al. A Paradoxical Treatment for a Paradoxical Condition: Infliximab Use in Three Cases of Mycobacterial IRIS. Clin Infect Dis 2016; 62:258.
- Winthrop KL, Yamashita S, Beekmann SE, et al. Mycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: case finding through the Emerging Infections Network. Clin Infect Dis 2008; 46:1738.
- Winthrop KL, Chang E, Yamashita S, et al. Nontuberculous mycobacteria infections and anti-tumor necrosis factor-alpha therapy. Emerg Infect Dis 2009; 15:1556.
- 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:e110922.
- van Ingen J, Boeree M, Janssen M, et al. Pulmonary Mycobacterium szulgai infection and treatment in a patient receiving anti-tumor necrosis factor therapy. Nat Clin Pract Rheumatol 2007; 3:414.
- Winthrop KL. Serious infections with antirheumatic therapy: are biologicals worse? Ann Rheum Dis 2006; 65 Suppl 3:iii54.
- Mori S, Tokuda H, Sakai F, et al. Radiological features and therapeutic responses of pulmonary nontuberculous mycobacterial disease in rheumatoid arthritis patients receiving biological agents: a retrospective multicenter study in Japan. Mod Rheumatol 2012; 22:727.
- TNF-ALPHA INHIBITORS
- TNF-ALPHA AND HOST DEFENSES
- Risk of TB
- - Influence of underlying RA
- - Biological basis of differential risks
- Time to onset
- Clinical features of TB in the anti-TNF setting
- Screening and prevention
- - Rescreening
- - Latent TB infection
- Indications for treatment
- - Active TB
- Disease worsening during TB treatment
- NONTUBERCULOUS MYCOBACTERIAL DISEASE
- Screening and diagnosis
- SUMMARY AND RECOMMENDATIONS