Rockville, MD - According to the Food and Drug Administration (FDA), the potential link between tumor-necrosis factor-a (TNF-a) inhibitors and increased lymphoma risk for people with rheumatoid arthritis (RA) was not strong enough to warrant additional warnings on the TNF-a package labeling. However, the FDA states that it will continue to monitor the safety profile of this new class of medications.

Earlier this month at the FDA Arthritis Advisory Committee meeting, Drs. Li Liang and Tim Cote (FDA Center for Drug Evaluation and Research, Rockville, MD) supplied data showing that lymphomas had been associated with all three of the approved TNF-a inhibitors (infliximab, etanercept, adalimumab). According to the report, this is a complicated issue because there is incomplete information in the case reports and potential multiple compounding factors, like exposure to other immunosuppressant medications (i.e. methotrexate).

As a result of those discussions, the FDA is now asking rheumatologists to report as much detailed information as possible about the histopathology (the scientific study of the nature of disease and its causes, processes, development, and consequences) of any cancers that occur in patients taking TNF-a inhibitors, as well as reporting information on prior or concurrent use of immunosuppressive drugs in such cases.

"There may be an increased risk of lymphoma when TNF-a inhibitors are used. This risk is unquantifiable at this time, given the small numbers of patients affected so far, the inherent risk of lymphoma associated with unrelenting RA without any therapy, and the risk of lymphoma associated with therapies that typical patients treated with TNF-a inhibitors have been exposed to, such as methotrexate. We would like to see further definition from a pathologic point of view of each tumor as it happens," said Dr. Lee Simon. He is the director of the FDA's Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products.

Adding to the already complex situation, there are differences in study design, patient populations have made it harder to compare lymphoma rates among the different clinical trials, and there is an increased risk of lymphoma in RA patients than in the general population - at least double the risk and perhaps 25-fold in patients with high inflammatory activity. Furthermore, some of the lymphomas associated with TNF-a inhibitors (like some of those associated with methotrexate) disappeared when treatment was discontinued, prompting rheumatologists to question whether they were "pseudolymphomas" (false or fake lymphomas).

Dr. Simon emphasized that what the FDA has detected to date is a "signal" or suggestion that there may be an association between TNF-a inhibitor treatment and the lymphomas reported in these patients, but there is not yet firm evidence of a cause-effect relationship.

Clinicians are urged to report all malignancies, especially lymphomas, occurring in patients who are being treated with TNF-a inhibitors to the FDA's MedWatch program at its website (www.fda.gov/medwatch/articles.htm) or by calling 1-800-332-1088. However, this is still a voluntary program.