Anti-TNF antibody therapy for RA increases cancer and infection risk

[unseennude]

The use of the infliximab or adalimubab for 3 to 12 months to treat rheumatoid arthritis (RA) is associated with an increased risk of malignancies and serious infections, results of a meta-analysis suggest.

The monoclonal antibodies to tumor necrosis factor (anti-TNF) have "redefined therapy for RA," because of their efficacy when other conventional agents have failed, Dr. Tim Bongartz and his associates report in the Journal of the American Medical Association for May 17.

However, TNF is important in maintaining host defense against infection and controlling tumor growth. Randomized trials to date have been too small or too brief to accurately delineate the risk of rare events associated with these agents.

Dr. Bongartz, from Mayo Clinic in Rochester, Minnesota, and associates therefore conducted a meta-analysis based on a systematic literature search for randomized, controlled trials of infliximab and adalimubab, the only anti-TNF antibodies currently licensed for use in RA.

They identified nine trials that included subjects treated for 3 to 12 months, with 3493 patients assigned to anti-TNF antibody treatment and 1512 assigned to placebo.

Pooled data revealed 29 malignancies in the active treatment groups and 3 in the placebo groups (odds ratio 3.3). In a subanalysis, high-dose versus low-dose anti-TNF antibody treatment carried significantly different risks of malignancies (OR 44.3). The results were unchanged by omitting malignancies diagnosed with the first 6 weeks of treatment and omitting all nonmelanoma skin cancers.

Serious infections, defined as those that required antimicrobial therapy or hospitalization, were reported in 126 patients treated with anti-TNF antibodies and 26 among those in the control group (odds ratio 2.0). Comparison of high-dose versus low-dose active treatment yielded an OR of 1.4, which was not statistically significant.

The increased risks for both outcomes remained statistically significant after applying several statistical analyses (Mantel-Haenszel methods without a continuity correction, Bayesian fixed-effect model, and Bayesian random-effects analysis, that either included or excluded trials with zero events in both arms).

Dr. Bongartz's team estimates that the number needed to harm was 154 for one additional malignancy within a treatment period of 6 to 12 months. The corresponding number for serious infections during treatment of 3 to 12 months was 59.

"The reduction of joint destruction, gain in mobility, and increase in quality of life, even in patients with RA who responded poorly to treatment prior to the introduction of anti-TNF therapy, must be taken into account when considering the therapeutic risks and benefits in individual patients," the research team advises.

Dr. Bongartz and his colleagues suggest strategies to increase the safety of these treatments, which might include thorough screening for subclinical malignancies before starting and during treatment with anti-TNF antibodies, the use of lower doses, or use only as induction therapy.