**5. Conclusion**

The TNF-α inhibitors, including the four currently available anti-TNF monoclonal antibodies and the soluble TNF receptor, have revolutionized the treatment of rheumatoid arthritis and other chronic inflammatory diseases since their introduction over a decade ago. However, their use is associated with an increased risk of granulomatous infections, including tuberculosis and NTM disease. The biological basis of this infection risk is the critical role played by TNF in the host response to mycobacterial infection, via its role in macrophage activation, cell recruitment, and granuloma formation and maintenance.

The magnitude of the risk of tuberculosis associated with TNF-antagonist therapy appears to be between 1.5 and 30 times above the risk associated with rheumatoid arthritis alone. The risk of tuberculosis differs amongst the various TNF-α inhibitors; the monoclonal antibodies portend more risk and are associated with a shorter tuberculosis onset time than the soluble TNF receptor. These differences may be related to different pharmacokinetic properties of the drugs, differential binding of soluble and transmembrance receptors, and differential effects on immune cell function and death.

All patients should be clinically evaluated for latent tuberculosis infection prior to the initiation of TNF-α inhibitor therapy. This evaluation should include a history, chest radiograph, and either a tuberculin skin test or an IGRA. IGRAs appear to be more specific for latent tuberculosis infection than tuberculin skin tests; they may also be more sensitive but this has not been definitively established. Most national guidelines recommend the tuberculin skin test as the diagnostic tool of choice for latent tuberculosis infection in this setting. The treatment of latent tuberculosis infection prior to the initiation of TNF-α inhibitors has proven benefit. Isoniazid therapy for a duration of 9 months is the most commonly recommended regimen, although some national guidelines recommend other regimens. The duration of therapy required before starting anti-TNF-α therapy is not well established.

The presentation of active tuberculosis in patients on TNF-α inhibitors is different from classically described tuberculosis; it is more likely to be extra-pulmonary and more likely to be disseminated at presentation. Discontinuation of anti-TNF-α therapy may be associated with a paradoxical worsening of tuberculosis disease, but discontinuation of therapy is still recommended in most guidelines.

NTM disease is an under recognized but important complication of TNF-antagonist therapy. Some research has suggested that NTM disease may be more common than tuberculosis in the setting of TNF-α inhibitor therapy, however the magnitude of the risk of NTM disease in this setting is unknown. NTM disease is associated with a high level of morbidity and mortality when it develops on TNF-α inhibitor therapy and may have atypical presentations. The best approach to screening and prevention of NTM disease prior to initiation of TNF-α inhibitor therapy is unknown.

Future research should include prospective studies establishing the magnitude of the risk of NTM disease with TNF-α inhibitor therapy; such studies may guide development of preventive strategies. Prospective studies estimating the positive predictive value of IGRA responses compared with tuberculin skin test responses for the developent of tuberculosis in patients treated with TNF-α inhibitors are also needed. Reports on treatment and outcomes of tuberculosis and NTM disease in the setting of TNF-α inhibitor therapy are also necessary.
