Infectious Complications

One of the most important and common safety concerns for the use of TNF inhibitors is the occurrence of infectious complications. In clinical trials, the rate of upper respiratory tract infections occurring in patients receiving TNF inhibitors, usually with concomitant methotrexate, is higher than that in patients receiving placebo injections or infusions together with metho-trexate. However, the rate of serious infections has been consistently comparable between the groups receiving placebo and TNF inhibitor. Nonetheless, one of the most frequently occurring serious infections in the early days of anti-TNF treatment was Mycobacterium tuberculosis, with extrapulmonary disease in about a third of cases. The incidence of complicating tuberculosis early in the history of infliximab therapy was approximately one in a thousand cases. However, the rate has substantially fallen since the introduction of screening programmes. Tuberculosis has been reported as a complication of all biologic anti-TNF agents but with a varying prevalence, depending on the country in which the drug was used. Occurrence of complicating tuberculosis is strongly influenced by age, low socio-economic status, and geography. The background rate in the population is important, as the majority of cases of tuberculosis occurring following exposure to anti-TNF agents are thought to represent reactivation of latent TB. This may be because TNF blockade is a particularly effective way of breaking down granuloma walls. Where tuberculosis has been reported, the median time of onset in patients receiving etanercept is approximately 11 months, whereas 97% of patients treated with infliximab and having TB reported developed the complication within 7 months (Keane et al. 2001). Screening for and treating latent tuberculosis infection will prevent reactivation in most patients. Latent tuberculous infectious screening should include a careful history including history of BCG vaccination, tuberculin skin test, and a chest radiograph. Skin testing is problematic, however, because of the occurrence of anergy in rheumatoid arthritis and high rate of false negative tuberculin skin tests as a consequence. Furthermore, for those inexperienced in skin testing, it is not uncommon to place injections or read the results inappropriately and therefore training is required. Because of the difficulties in interpreting tuberculin skin testing, there is now much interest in a newer generation of ELISPOT tests, more sensitive, more specific, and more convenient than tuberculin skin tests. This test requires a single blood sample for the detection of interferon -secreting T cells, with reactivity to peptides highly specific for latent Mycobacterium tuberculosis infection (Lalvani et al. 2001). However, the ELISPOT test is not yet widely available because it is costly and requires isolation of mononuclear cells, a procedure that is not performed in routine clinical laboratories.

Where latent tuberculosis is diagnosed or strongly suspected, prophylactic treatment should be offered in accordance with local guidelines and advice; for example, isoniazid for 9 months (Keane et al. 2005). Although screening has greatly reduced the occurrence of Mycobacterium tuberculosis with TNF antagonists, it has not completely eliminated it and there must always be a high degree of awareness for this and other granu-lomatous diseases.

A number of opportunistic infections have been reported with TNF inhibitors, both in the context of clinical trials and in adverse events reporting after drug approval. Although such infections are relatively rare, the most frequently occurring include histoplasmosis, Pneumocystis carinii, listeriosis and aspergillosis. The occurrence of these infections varies according to geographical location.

Because of the potential for infectious complications with TNF inhibitors, this class of drug is relatively contra-indicated in patients with chronic infectious states such as bronchiectasis or chronic sinusitis.

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