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Tuberculosis and other infections in the anti-tumour necrosis factor-alpha (anti-TNF-α) era

https://doi.org/10.1016/j.berh.2011.06.001Get rights and content

We review the global experience of infections in patients treated with tumour necrosis factor (TNF)-α inhibitors, which shows that the overall incidence of severe infections is at least doubled. In particular, this is true regarding tuberculosis. Screening and prophylactic measures have substantially reduced but not eliminated the risk. Recent improvements in immunologic testing for non-Bacillus Calmette–Guerin (BCG)-related antigens allow more sensitive identification of latent tuberculosis and wider use of such methods holds promise as pre-treatment screening instruments.

Section snippets

Most frequent infections in different therapies

A number of bacterial, viral and fungal infections occurred in patients with rheumatic diseases treated with anti-TNF-α [11], [12], [13]. the risk of infection is higher early after initiating treatment [14] and decreases with prolonged exposure to anti-TNF-α treatment [15].

Listing et al. [16] followed up for 3 years about 1000 RA patients and 601 control patients treated with TNF-α (512 patients receiving etanercept and 346 patients receiving infliximab) and anakinra (70 patients). The total

Data from registries

Clinical trials and post-marketing analysis are fundamental to monitor the safety profile of biologic therapies. Other good instruments are the national or local registries. The data are extrapolated from the real-world setting and are not biased on inclusion/exclusion criteria, mandatory for the clinical trials.

The ‘RA observation of Biologic Therapies’ (RABBIT) German registry evidenced a significant difference between patients treated with infliximab or etanercept and patients with only

TB

Even in the 21st century, TB kills more people than any other infective agent [48]. Mycobacterium tuberculosis can persist within the human host for years or even for life without causing disease, in a syndrome known as latent tuberculosis infection (LTBI) [49]. In 2008, World Health Organization (WHO) reported that about one-third of the world’s population is believed to harbour LTBI [50] and approximately 10% of immunocompetent persons with LTBI will develop active TB [50], eluding immune

Recommendations

Several recommendations for detecting LTBI have been proposed in different countries [64], [65].

In 2002, the RATIO study group established new recommendations in France [66], [67]. Patients were considered to have LTBI when chest X-rays showed present residual nodular lesions larger than 1 cm3 or old lesions, or when a skin reaction larger than 10 mm induration at tuberculin skin test (TST) is found. Treatment lasting at least 6 months, including at least 2 months with combination

Other opportunistic infections (OIs)

Many infectious adverse events have been reported and the most common pathogens were granulomatous infection [2], aspergillosis [1], Listeria monocitogenes [91] and Salmonella [2].

Other opportunistic infections (OIs), such as hystoplasmosis [92], coccidiomycosis [93] pneumocystosis and other fungal or viral infections have been described in patients on anti-TNF-α blockers.

Significant differences in the rate of serious bacterial infections (which required intravenous antibiotic therapy) were

Viral

Viral disease could be differentiated in three patterns of infectivity (Calabrese). The first one is typical of acute infections such as influenza, which is self-limited. Herpes simplex, Epstein–Barr virus (EBV) and varicella zoster are characterised by a period of acute primary infections, followed by a period of latency. After specific stimuli they may be reactivated, often with different clinical manifestations. Few viral pathogens have the capacity to cause a primary infection and then

Conclusions

Anti-TNF-α therapy has dramatically improved the management of many rheumatic diseases and conditions with altered immunoreactivity.

Conversely, an increased risk of TB and opportunistic infections is reported in clinical trials in post-marketing observations and in national and local registries.

Screening for LTBI and for hepatitis infection is mandatory to reduce the risk of reactivation.

Moreover, a close and careful safety monitoring during treatment is strongly recommended to exclude

References (119)

  • P. Andersen et al.

    Specific immune-based diagnosis of tuberculosis

    Lancet

    (2000 Sep 23)
  • V.V. Jain et al.

    Reactivation histoplasmosis after treatment with anti-tumor necrosis factor alpha in a patient from a nonendemic area

    Respiratory Medicine

    (2006 Jul)
  • E.G. Favalli et al.

    Marchesoni A.Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients

    Autoimmunity Reviews

    (2009 Jan)
  • A. Strangfeld et al.

    Infection and musculoskeletal conditions: bacterial and opportunistic infections during anti-TNF therapy

    Best Practice and Research Clinical Rheumatology

    (2006 Dec)
  • M.G. Netea et al.

    Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: association with decreased interferon-gamma production and Toll-like receptor 4 expression

    Arthritis and Rheumatism

    (2003 Jul)
  • R.S. Wallis et al.

    Granulomatous infectious diseases associated with tumor necrosis factor antagonists

    Clinical Infectious Diseases

    (2004 May 1)
  • C.D. Hamilton

    Infectious complications of treatment with biologic agents

    Current Opinion in Rheumatology

    (2004 Jul)
  • K.L. Hyrich et al.

    Anti-tumour necrosis factor alpha therapy in rheumatoid arthritis: an update on safety

    Annals of the Rheumatic Diseases

    (2004 Dec)
  • M.F. Doran et al.

    Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study

    Arthritis and Rheumatism

    (2002 Sep)
  • H.A. Capell

    Disease modifying antirheumatic drugs: longterm safety issues

    Journal of Rheumatology Supplement

    (2001)
  • O.Y. Saliu et al.

    Tumor-necrosis-factor blockers: differential effects on mycobacterial immunity

    Journal of Infectious Diseases

    (2006 Aug 15)
  • W. Kievit et al.

    A higher rate of serious infections in patients treated with TNF alpha blocking agents

    Arthritis and Rheumatism

    (2006)
  • Y. Komano et al.

    Analysis of severe adverse events in patients with rheumatoid arthritis under the treatment with biologics; report from the registry of Japanese rheumatoid arthritis patients for long-term safety

    Annals of the Rheumatic Diseases

    (2009)
  • M.J. Pérez-Sola et al.

    Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry

    Medicina Clinica (Barcelona)

    (2011 Apr 21)
  • J. Askling et al.

    Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden

    Arthritis and Rheumatism

    (2005 Jul)
  • J.P. Leombruno et al.

    The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events

    Annals of Rheumatic Diseases

    (2009 Jul)
  • J. Listing et al.

    Infections in patients with rheumatoid arthritis treated with biologic agents

    Arthritis and Rheumatism

    (2005 Nov)
  • A. Alonso-Ruiz et al.

    Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety

    BMC Musculoskeletal Disorders

    (2008 Apr 17)
  • G. Gartlehner et al.

    The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis

    Journal of Rheumatology

    (2006 Dec)
  • J. Keane et al.

    Tuberculosis associated with infliximab, a tumor necrosis factor a-neutralizing agent

    New England Journal of Medicine

    (2001)
  • F. Wolfe et al.

    Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy

    Arthritis and Rheumatism

    (2004)
  • N. Nakelchik et al.

    Reactivation of histoplasmosis after treatment with infliximab

    American Journal of Medicine

    (2002)
  • T. Ellerin et al.

    Infections and anti-tumor necrosis factor alpha therapy

    Arthritis and Rheumatism

    (2003)
  • P.E. Lipsky et al.

    Infliximab and methotrexate in the treatment of rhematoid arthritis. Anti tumor necrosis factor trials in rheumatoid arthritis with concomitant therapy study group

    New England Journal of Medicine

    (2000)
  • R.N. Maini et al.

    Sustained improvement over two years in physical function, structural damage, and sign and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate

    Arthritis and Rheumatism

    (2004)
  • E.W. St Claire et al.

    Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomization, controlled trial

    Arthritis and Rheumatism

    (2004)
  • A.K. Mohan et al.

    Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor

    Clinical Infectious Diseases

    (2004)
  • M.C. Genovese et al.

    Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes

    Arthritis and Rheumatism

    (2002)
  • P.L. van Riel et al.

    Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study

    Annals of Rheumatic Diseases

    (2006)
  • L. Klareskog et al.

    Etanercept Stusy 301 Investigators. Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in patients with rheumatoid arthritis

    Clinical and Experimental Rheumatology

    (2011 Mar–Apr)
  • D.E. Furst et al.

    Adalimumab, a fully anti tumor necrosis factor-a monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis)

    Journal of Rheumatology

    (2003)
  • L.B. van de Putte et al.

    Efficacy and safety of Adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying anti rheumatic drug treatment has failed

    Annals of Rheumatic Diseases

    (2004)
  • M.E. Weinblatt et al.

    Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

    Arthritis and Rheumatism

    (2003 Jan)
  • M.E. Weinblatt et al.

    Long-term efficacy and safety of Adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4-year extended study

    Annals of Rheumatic Diseases

    (2005)
  • E.C. Keystone et al.

    Radigraphic, clinical and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled 52-week trial

    Arthritis and Rheumatism

    (2004)
  • M.H. Schiff et al.

    Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis

    Annals of Rheumatic Diseases

    (2006)
  • V. Strand et al.

    Rapid and sustained improvements in health-related quality of life, fatigue, and other patient-reported outcomes in rheumatoid arthritis patients treated with certolizumab pegol plus methotrexate over 1 year: results from the RAPID 1 randomized controlled trial

    Arthritis Research and Therapy

    (2009)
  • V. Strand et al.

    Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial

    Annals of Rheumatic Diseases

    (2011 Jun)
  • J. Kay et al.

    Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study

    Arthritis and Rheumatism

    (2008)
  • P. Emery et al.

    Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis

    Arthritis and Rheumatism

    (2009 Aug)
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      Citation Excerpt :

      The increased clinical use of TNF-α antagonists dramatically improved the management of immunomediated diseases, but has led to a higher incidence of infections with intracellular agents.1–8 Keane et al. were the first to describe an increased incidence of tuberculosis (TB) in patients with rheumatoid arthritis (RA) treated with TNF-α blockers,9 and a relatively large proportion of extra-pulmonary and disseminated forms has been diagnosed, despite the previous latent TB screening and treatment.10,11 There is no gold standard method to define latent TB, and its treatment before anti-TNF-α drugs institution may not be sufficient to protect from the disease.

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