β Scribed by Carol Dukes Hamilton
No coin nor oath required. For personal study only.
Anticytokine agents and other biologic response modifiers represent an important advance in the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. While these agents are specific in their targets, they are not precise enough in their actions to avoid the negative consequences of perturbing the immune system. In this issue of Arthritis & Rheumatism, Go Β΄mez-Reino and colleagues report findings from a clinical database initiated in February 2000 to assess the safety of tumor necrosis factor (TNF) inhibitors used to treat patients with rheumatic diseases (1). The investigators compared infection rates in two cohorts of RA patients: those who had and those who had not received either etanercept or infliximab, the two TNF blockers in use during the time period studied. They found 17 culture-confirmed cases of tuberculosis (TB) among their cohort of 1,540 patients receiving TNF blockers. The authors calculated extraordinary incidences associated with the use of infliximab: 1,893 TB cases per 100,000 patients in the year 2000 and 1,113 TB cases per 100,000 patients in the year 2001. In contrast, the incidence of TB was 21 cases per 100,000 inhabitants in Spain in the year 2000, and there were 5.8 TB cases per 100,000 inhabitants in the US in the same year (2).
Go Β΄mez-Reino et al used data from an active surveillance project specifically designed for long-term followup to assess the safety of biologic response modifiers in patients with rheumatic disease in Spain. The Spanish registry is a significant step ahead of passive postmarketing surveillance programs and is surely welcome in the field of pharmacoepidemiology. However, the authors do not report on the "capture rate" or completeness of the database. In other words, what proportion of patients receiving the agents was actually registered in the database? Without this information, we are uncertain as to the completeness of the denominator, and therefore, the extremely high calculated TB case rates must be viewed with some uncertainty.
The report, which characterizes the 17 patients with TB, demonstrates the severity of TB associated with the use of TNF inhibitors. In this study, 6 of 17 patients (35%) developed disseminated or hepatosplenic disease, and 5 patients (29%) were reported to have disease affecting the nervous system. Sixty-five percent of patients had extrapulmonary TB, compared with the usual distribution of 70-80% with pulmonary disease and 15-25% with extrapulmonary disease in community populations in Europe and the US (2). Only patients with advanced acquired immunodeficiency syndrome (AIDS) are reported to have similarly high rates of extrapulmonary disease. In addition, 2 of 17 infliximabtreated patients (12%) died, compared with a TB mortality rate of 4.6% in the US in the year 2000.
The experience in Spain thus illustrates the association of infliximab treatment with the development of active TB in persons with latent TB. Animal models have suggested this possibility, since TNF plays a key role in granuloma formation, an essential element for host control of mycobacterial infections (3,4). In humans, a role for TNF has not been as easy to delineate, whereas inherited interferon-β₯ (5) and interleukin-12 (IL-12) receptor abnormalities (6) have been associated with
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