Among patients with rheumatoid arthritis (RA), the use of anti-tumor necrosis factor (anti-TNF) agents may lead to an increased risk for nonmelanoma skin cancer, particularly squamous cell skin cancer, according to research results published in Clinical Rheumatology.

Researchers conducted a systematic review and meta-analysis of current research to determine the relationship between anti-TNF therapy and the risk for nonmelanoma skin cancer in patients with RA. Researchers searched Cochrane Library, EMBASE, and PubMed from database inception to April 2019.

In total, 5149 articles were screened and 6 were ultimately included in the review. These studies included the data of 123,031 patients with an RA diagnosis, a majority of whom were women. Of these patients, 5090 (4.1%) developed nonmelanoma skin cancer, including 1941 who received anti-TNF agents and 3149 who did not.

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In 5 of 6 studies, researchers compared the risk for nonmelanoma skin cancer among patients with RA who received anti-TNF agents and those who were biologic-naive; researchers of 1 study compared the nonmelanoma skin cancer risk among patients with RA who received anti-TNF agents and those who never received anti-TNF agents. The researchers reported hazard ratio outcomes in 5 studies that ranged from 0.40 to 1.42; only 1 study presented odds ratio outcomes that ranged from 0.90 to 1.70.

Results of the fixed-effects model using meta-analysis data demonstrated that the use of anti-TNF agents vs no anti-TNF agents was associated with a higher risk for nonmelanoma skin cancer (relative risk [RR], 1.28; 95% CI, 1.19-1.38; =45.6%).

Subgroup analyses, stratified by type of nonmelanoma skin cancer, study quality, geographic area, and adjustment for smoking, were conducted to assess the consistency of the results. Investigators found that use of an anti-TNF agent also led to an increased risk for squamous cell skin cancer, but not basal cell skin cancer (RR, 1.30 and 1.13; 95% CI, 1.09-1.54 and 0.97-1.31, respectively; =0%). Patients with RA who received anti-TNF agents also had a higher nonmelanoma skin cancer risk regardless of study quality and source of patients with RA. No statistical significance was noted for adjustment based on smoking status.

The researchers also conducted a sensitivity analysis by sequentially omitting each study and observing whether there was a substantial change in results. Results of this analysis demonstrated that no exclusion changed the magnitude or direction of the effect of the correlation between anti-TNF therapy and nonmelanoma skin cancer risk in this patient population.

Study limitations included an elevated risk for indelible bias, primarily confounding, in the cohort studies, possible bias from unmeasured confounders, and possible publication bias. In addition, the 6 included studies were published in English and included patients from Europe and America, thus limiting generalizability.

According to the researchers, anti-TNF therapies should be avoided in patients with RA who have an elevated risk for nonmelanoma skin cancer. “Moreover,” they concluded, “this detrimental effect of anti-TNF is more obvious in [squamous cell skin cancer], but not [basal cell carcinoma].”

Further clinical and basic research studies are needed to further validate these results.


Wang J-L, Yin W-J, Zhou L-Y, et al. Risk of non-melanoma skin cancer for rheumatoid arthritis patients receiving TNF antagonist: A systematic review and meta-analysis [published online December 10, 2019]. Clin Rheumatol. doi:10.1007/s10067-019-04865-y