Risk for Nonmelanoma Skin Cancer Appears Higher in Tumor Necrosis Factor Antagonist Recipients

Tumor necrosis factor (TNF)-α antagonists are approved for various chronic inflammatory conditions affecting the skin, joints, and gastrointestinal tract. Concerns about risks for infection and malignancy are noted in the package inserts for all approved anti–TNF-α agents. Study results though have been mixed, with more forceful results from new studies in the rheumatology literature.

Previous studies and meta-analyses produced varying findings on the increased risk for nonmelanoma skin cancers (NMSCs) with TNF antagonists. Chakravarty and colleagues1 examined the risk for NMSC in 15,784 patients with rheumatoid arthritis and found a nonsignificant trend toward greater risk with use of TNF inhibitors alone, but a significantly increased risk when these drugs were combined with methotrexate. Wolfe and Michaud,2 using an extension of the same database, observed a statistically significant increase in risk for NMSC (relative risk, 1.5; P<0.001) associated with the use of TNF antagonists. Lebwohl and colleagues3 used data from clinical trials and postmarketing studies of etanercept use in rheumatoid arthritis patients. Determination of squamous cell carcinoma (SCC) was confirmed histologically in the trial participants but was not definitively confirmed in the postmarketing study patients. When the researchers compared their findings with population-based rates in Minnesota and Arizona, they found no increase in SCC risk in etanercept recipients.

Two newer studies have now examined risk for NMSC in patients receiving TNF antagonists for rheumatologic inflammatory disease. Mariette and colleagues4 performed a meta-analysis of studies reported in the literature or presented at rheumatology meetings. After applying inclusion and exclusion criteria to 2039 full-text papers and 1979 conference abstracts, the researchers included 21 papers and 8 abstracts for analysis. Although neither all-site cancers nor hematologic cancers (including lymphoma) were increased in TNF-inhibitor recipients, the researchers did find a statistically significant 45% increase in NMSC (odds ratio, 1.45), and the findings suggested that melanoma risk was also increased. These authors noted that most cutaneous cancers were found in the first year of therapy and that the risk did not increase over time.

Amari and colleagues5 performed a retrospective cohort study of 20,648 rheumatoid arthritis patients seen and treated within the Veterans Affairs hospital system and included in the national VA database. The risk for NMSC was roughly 1.5 times greater in TNF-α antagonist recipients compared with recipients of other disease-modifying agents (DMARDs). In addition, patients treated with nonbiologic DMARDs had significantly longer NMSC-free survival than patients receiving TNF-α antagonists. However, the researchers also found no association between the duration of TNF-α antagonist exposure and increased NMSC risk. Lastly, they compared the rates of NMSC associated with use of anti-TNF therapy and methotrexate and observed a significant association between TNF therapy and higher NMSC rates. In a comparison among the three most commonly used TNF agents (etanercept, adalimumab and infliximab), NMSC rates were significantly higher with adalimumab than with etanercept.