Review
Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management

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Summary

Cases of active tuberculosis have been reported worldwide with the use of therapeutic agents that inhibit tumour necrosis factor (TNF) α. TNFα has a central role in mycobacterial infection and disease. Accordingly, progression of recently acquired tuberculosis infection or reactivation of remotely acquired infection should be expected with the use of anti-TNF agents. The available in-vitro and epidemiological evidence for the two currently approved agents, infliximab and etanercept, shows that the risk of development of active tuberculosis is greater with infliximab. Tuberculin skin testing (TST) should be undertaken before any significant immunosuppressive therapy including these agents, though the possibility of false-negative reactions in immuno- compromised populations must be borne in mind. A positive TST should be followed by medical assessment and chest radiography, as well as by other tests judged appropriate by the physician to identify active disease. Active tuberculosis must be treated appropriately before initiation of treatment with an anti-TNF agent. Treatment of latent tuberculosis can be considered on an individual basis for TST-negative patients receiving anti-TNF agents when significant risk factors for infection are present.

Section snippets

Role of TNF in M tuberculosis infection and disease

TNFα has a central role both in the host immune response to M tuberculosis infection and in the immunopathology of tuberculosis (figure 1). TNFα is a proinflammatory cytokine produced primarily by activated monocytes/macrophages in response to various stimuli, including lipopolysaccharide, viral infection, and Gram-negative and Gram-positive pathogens.7, 8 TNFα can also be expressed by activated T cells, B lymphocytes, natural killer cells, and some tumour cells.7 TNFα exists in soluble and

Anti-TNF therapies

Several therapeutic agents that neutralise TNFα have been developed; of these, infliximab and etanercept have been studied most extensively (figure 2). Infliximab is a human-murine (25% murine) chimeric monoclonal antibody with high binding affinity31 and specificity for TNFα .34 It forms stable complexes with the monomeric and trimeric forms of soluble TNFα and with the transmembrane forms of TNFα.35 As an antibody, infliximab also has the ability to cross-link TNFα molecules. Binding to

Tuberculosis risk with anti-TNF agents

Clinical use of anti-TNFα agents has been implicated in the reactivation of recent or remotely acquired tuberculosis infection, although the relative proportions of disease due to recent infection and to reactivation of latent infection are not known. In a study by Keane and colleagues, 70 cases of tuberculosis were identified among about 147 000 patients worldwide who had received treatment with infliximab for rheumatoid arthritis, Crohn's disease, and other illnesses.5 40 patients had

Risk factors for tuberculosis infection and progression to active disease

The risk of reactivation from anti-TNF therapy depends on two variables: the immunomodulating effect of the therapy and the underlying rate of latent tuberculosis infection or risk of previous infection in the population. The rate of latent tuberculosis infection in turn depends on many variables, including the person's age, country of origin, socioeconomic status, ethnic origin, travel history to high-prevalence countries, and occupation (eg, work in a healthcare facility or shelter for

Tuberculin testing

Tuberculin skin testing (TST) is the standard screening test for latent tuberculosis infection in high-risk populations. The test dose is bioequivalent to 5 tuberculin units of standard purified protein derivative injected intradermally (not subcutaneously) into the volar surface of the forearm.2, 73 In patients previously exposed to tuberculosis, sensitised T cells are recruited to the site of injection and release cytokines, which induce a local induration.73 If given correctly, the injection

Conclusions

Anti-TNF agents are an important addition to treatments for rheumatoid arthritis and other autoimmune disorders. That these agents have been suggested to increase the risk of active tuberculosis is not surprising given the central role of TNFα in the host defence against tuberculosis—killing of M tuberculosis by macrophages, granuloma formation, apoptosis, and prevention of dissemination of infection to other sites. Differences in potency and route of administration as well as differences in

Search strategy and selection criteria

Data for this review were identified by searches of papers published in English on Medline with the key words: “infliximab”, “etanercept”, “tumour necrosis factor alpha inhibitors”, “TNF”, “anti-TNF”, “adalimumab”, “D2E7”, “CDP870”, “PEGylated TNF”, and “PEGylated TNFR1” in association with “tuberculosis”, “Crohn's disease”, “psoriasis”, and “ankylosing spondylitis”. Relevant references were also obtained from articles acquired through the search strategy. Clinical practice guidelines from

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