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Accompanying the tremendous excitement about the introduction of TNF inhibitors into the clinic has been caution about potential adverse events that may be associated with the use of these potent immunomodulators. Increased susceptibility to certain infections, particularly Mycobacterium tuberculosis (TB), has been a particular concern.1 Data from animal studies suggest that TNF has a central role in host defence against TB, in part related to effective granuloma formation.2 For infliximab, 277 cases of TB had been reported world wide through August 2002 among more than 365 000 patients treated. Interestingly, although about 75% of infliximab use has been in the United States, more than two thirds of the reported TB cases were from outside the USA, mainly from the European Union. Part of the reason for this discrepancy may relate to a higher incidence of latent TB infection in the EU. However, we suggest that cigarette smoking may also be a relevant factor. In 2000, just over 23% of adults in the USA were current cigarette smokers, compared with about 30% of European adults (http://www.cdc.gov/tobacco; http://www.cisid.who.dk/tobacco—accessed 29/8/03). It has recently been shown that acetylcholine can inhibit the release of macrophage TNFα and attenuate inflammatory responses.3 The inhibition is through a post-transcriptional mechanism that is dependent on the α7 subunit of the nicotinic acetylcholine receptor on human macrophages. Nicotine is a potent agonist of these α7 receptors, providing some explanation for the immunomodulatory effects of cigarette smoking in conditions such as ulcerative colitis.4 Interestingly, an association between tobacco smoking and TB has been noted in patients from southern India, with an odds ratio among smokers of 2.48 (95% confidence interval 1.42 to 4.37).5 Unfortunately, information on smoking histories among patients with RA and TB treated with TNF inhibitors is not readily available from pharmacovigilance data. Among the varied deleterious effects cigarette smoking has on pulmonary funtion, it can damage the respiratory mucosa, thereby impairing host resistance to infection. Interestingly, it has recently been noted in a trial of anakinra that patients with underlying pulmonary disease seemed to be at a particular risk for developing pneumonia.6 Therefore, rheumatologists ought to elicit a smoking history and advise stopping smoking among patients with RA, particularly those being considered for treatment with TNF inhibitors.
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