Increased Risk of Second Nonmelanoma Skin Cancer Among Patients Receiving Immunosuppressive Therapy

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Patients with rheumatoid arthritis treated with methotrexate had an increased risk of a second nonmelanoma skin cancer, and adding anti–tumor necrosis factor (TNF) may increase that risk, according to results of a retrospective cohort study reported in JAMA Dermatology. A similar association was seen for anti-TNFs among patients with inflammatory bowel disease, the investigators noted, although this finding was not statistically significant.

Immunosuppressive therapy is the standard of care for rheumatoid arthritis and inflammatory bowel disease, the authors noted, and “both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance in this population.” Drug-induced immunosuppression is also risk factor for nonmelanoma skin cancer, particularly squamous cell tumors.

‘Exposures of Interest’

Along with methotrexate and anti-TNFs, other medications considered “exposures of interest” included abatacept (Orencia), rituximab (Rituxan), and thiopurines.

The study looked at 9,460 individuals, 6,672 with rheumatoid arthritis only, 2,619 with inflammatory bowel disease only, and 169 with both rheumatoid arthritis and inflammatory bowel disease. All had an incident nonmelanoma skin cancer diagnosis after enrollment in Medicare from January 1, 2006, through December 31, 2012.

“This cohort has been used previously to evaluate the comparative effectiveness and safety of medications used to treat inflammatory bowel disease and rheumatoid arthritis,” the authors explained. Exclusion criteria included any other malignancy before the first diagnosis of nonmelanoma skin cancer, organ transplant, and human immunodeficiency virus, as well as “use of medications thought to affect the risk of nonmelanoma skin cancer before the first nonmelanoma skin cancer diagnosis, such as tacrolimus, cyclosporine, imiquimod, or fluorouracil,” the investigators noted.

“A total of 1,291 individuals developed a second [nonmelanoma skin cancer] (910 with [rheumatoid arthritis] only, 359 with [inflammatory bowel disease] only, and 22 with both [rheumatoid arthritis and inflammatory bowel disease]),” the researchers reported.

The incidence rate per 1,000 person-years of a second nonmelanoma skin cancer was 58.2 among patients with rheumatoid arthritis (95% confidence interval [CI] = 54.5–62.1) and 58.9 among patients with inflammatory bowel disease (95% CI = 53.2–65.2). In both groups of patients, men were more likely than women to have a second nonmelanoma skin cancer, and those with a second nonmelanoma skin cancer were more likely to have a history of actinic keratosis.

Other Immunosuppressants

“Among patients with [rheumatoid arthritis], methotrexate used in conjunction with other medications was associated with an increased risk of a second [nonmelanoma skin cancer] (hazard ratio [HR] = 1.60; 95% CI = 1.08–2.37). Adjusted for other medications, the risk of  [nonmelanoma skin cancer] increased with 1 year or more of methotrexate use (HR = 1.24; 95% CI = 1.04–1.48),” the researchers reported.

“Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of [nonmelanoma skin cancer] (HR = 1.49; 95% CI = 1.03–2.16). Abatacept and rituximab were not associated with increased [nonmelanoma skin cancer] risk. The nonsignificant [hazard ratios] for 1 year or more of thiopurine and anti-TNF use for [inflammatory bowel disease] were 1.49 (95% CI = 0.98–2.27) and 1.36 (95% CI = 0.76–2.44), respectively,” the investigators found.

“This is the largest study to date, to our knowledge, to examine the effect of commonly used therapies in [inflammatory bowel disease] and [rheumatoid arthritis] on the risk of cancer recurrence,” the authors stated. They cautioned that although the study “found an increased risk of a second [nonmelanoma skin cancer] with methotrexate and possibly anti-TNF drugs, we cannot conclude that the other immunosuppressive therapies represent safer alternatives. Further research examining these agents is required.” ■

Scott FI, et al: JAMA Dermatol. October 28, 2015 (early release online).