• tumour necrosis factor α
• safety
• biological agents

• CHF, congestive heart failure
• FDA, Federal Drug Administration
• NDRD, National Databank for Rheumatic Disease
• RA, rheumatoid arthritis
• SEER, Surveillance, Epidemiology and End Results (database)
• SIR, standardised incidence rate
• TNF, tumour necrosis factor

Tumour necrosis factor (TNF) antagonists have set a new therapeutic standard for rheumatoid arthritis (RA). The agents including infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira) have been shown to substantially improve the signs and symptoms, disability, and quality of life while significantly inhibiting joint damage in early and longstanding RA. As with any agent, safety issues in concert with efficacy determine a risk/benefit ratio and hence a position in the therapeutic algorithm. With TNF antagonists key safety considerations include (a) infection, both common and opportunistic; (b) cytopenias; (c) demyelinating disease; (d) lupus-like syndromes; (e) congestive heart failure (CHF) and malignancies, particularly lymphomas. In March 2003 the United States Federal Drug Administration (FDA) convened a meeting to update safety issues related to TNF antagonists, specifically focusing on solid tumours and lymphomas. Safety data from controlled clinical trials were presented for the three TNF antagonists with post-marketing safety data for etanercept and infliximab. All the data are available on the FDA website. The current review will focus on infection, CHF, and malignancy. Much of the information in this review was obtained from the FDA, Arthritis Adviser Committee, the National Databank for Rheumatic Disease (NDRD) of Dr Fred Wolfe, from data on file with Abbott Pharmaceuticals, Amgen Incorporated, and Centocor Incorporated.

Safety data may be obtained from a variety of sources, including placebo controlled, randomised clinical trials, post-approval databases, particularly the USA FDA MedWatch spontaneous reporting programme, and long term registries such as the NDRD of Fred Wolfe as well as registries in Sweden and Germany and England.

A number of factors significantly influence the interpretation of adverse event data. Within clinical trials issues of ascertainment bias in enrolling patients into trials, population homogeneity, lower comorbidities, restricted concomitant drugs, short trial duration, and a relatively small sample size may have substantial influences on …