TNF Inhibitor Use, Follicular Lymphoma Risk Linked Among Patients With RA


Patients with rheumatoid arthritis (RA) who used tumor necrosis factor (TNF) inhibitors had significantly higher rates of nonmelanoma skin cancer and non-Hodgkin lymphoma.

A new report based on thousands of Medicare claims suggests exposure to tumor necrosis factor (TNF) inhibitors among older patients with rheumatoid arthritis (RA) confers a higher risk of nonmelanoma skin cancers and non-Hodgkin lymphoma.

No association was found between TNF inhibitors and other cancer sites. The study was published in Cancer Epidemiology, Biomarkers & Prevention.

The authors explained that TNF is highly expressed in the joint tissue of patients with RA, making it an attractive target for drug developers. TNF inhibitors have been shown effective at controlling RA and preventing progressive joint damage, but they also appear to have immunosuppressive effects that some fear might lead to a higher risk of certain cancers, particularly those with infectious or immune-related etiologies, they said.

“This issue is especially pertinent for lymphomas and lung cancer, because RA patients already have an increased risk of these cancers compared to the general population, likely related to RA disease activity and chronic immune stimulation,” the authors wrote.

In hopes of better understanding and quantifying the potential for excess cancer risk among patients with RA who take TNF inhibitors, the authors consulted the Surveillance, Epidemiology, and End Results Medicare database, which links data from 18 central cancer registries to data from Medicare. They sought to identify patients with a first cancer diagnosis between the ages of 66 and 99 during 2007 to 2015. A control group was created by a random sample of 5% of cancer-free Medicare beneficiaries from matching years. Patients with RA were identified from within those groups.

A total of 10,263 patients with a first cancer diagnosis were identified and compared with 30,475 cancer-free controls.

An analysis of Medicare Part B and Part D claims showed that 16.2% of controls overall were exposed to TNF inhibitors. Among patients with cancer, the percentage exposed to TNF inhibitors ranged from 12.8% to 33.7%, depending on the cancer site.

Logistic regression showed TNF inhibitor use was associated with an increased risk of nonmelanoma skin cancer (adjusted odds ratio [aOR], 1.32; 95% CI, 1.06-1.63) and non-Hodgkin lymphoma (aOR, 1.28; 95% CI, 1.06-1.56). More specifically, the data suggested follicular lymphoma risk was much higher among patients with a history of TNF inhibitor exposure (aOR, 2.63; 95% CI, 1.63-4.24).

No heightened risk was found for basal cell carcinoma, squamous cell carcinoma, or other non-Hodgkin lymphoma subtypes, the investigators said.

They noted that the relationship between TNF inhibitors and cancer is complex and that the existing literature is mixed, adding they believe this is the first sizable study to find a greater risk of follicular lymphoma among patients who had taken TNF inhibitors.

The authors said their study had positive findings in showing there does not appear to be a heightened risk of cancers linked with immunosuppression, such as diffuse large B-cell lymphomas and human papillomavirus–associated cancers. Although the risk of nonmelanoma skin cancer was relatively small, the authors said patients on TNF inhibitors should receive regular skin cancer screenings and counseling on how to protect themselves from excess sun exposure.

Their conclusion bears out that their findings about follicular lymphoma may help explain the association between lymphoma and TNF inhibitors reported in this and other studies.

“Although these findings may have an immune explanation, the lack of strong immunosuppression in RA patients treated with TNF [inhibitors] and the pattern of association with cancer suggests that other mechanisms could underlie this increased risk,” they said.


D’Arcy ME, Beachler DC, Pfeiffer RM, et al. Tumor necrosis factor inhibitors and the risk of cancer among older Americans with rheumatoid arthritis. Cancer Epidemiol Biomarkers Prev. Published online August 23, 2021. doi:10.1158/1055-9965.EPI-21-0125

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