Risk of Nonmelanoma Skin Cancer Associated With the Use of Immunosuppressant and Biologic Agents in Patients With a History of Autoimmune Disease and Nonmelanoma Skin Cancer

IMPORTANCE: Immune dysfunction underlies the pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Immunosuppressive therapy is the standard of care for these diseases. Both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance in this population. Drug-induced immunosuppression is a risk factor for nonmelanoma skin cancer (NMSC), particularly squamous cell tumors. For patients with a history of NMSC, data are limited on the effect of these drugs on the risk of additional NMSCs. OBJECTIVE: To determine the relative hazard of a second NMSC in patients with RA or IBD who use methotrexate, anti–tumor necrosis factor (anti-TNF) therapy, or thiopurines after an initial NMSC. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, we studied 9460 individuals with RA or IBD enrolled in Medicare from January 1, 2006, through December 31, 2012. EXPOSURES: Exposure to methotrexate, thiopurines, anti-TNFs, sulfasalazine, hydroxychloroquine, abatacept, or rituximab after the incident NMSC surgery. MAIN OUTCOMES AND MEASURES: A second NMSC occurring 1 year or more after the incident NMSC using Cox proportional hazards regression models. RESULTS: Among 9460 individuals (6841 with RA and 2788 with IBD), the incidence rate of a second NMSC per 1000 person-years was 58.2 (95% CI, 54.5-62.1) and 58.9 (95% CI, 53.2-65.2) in patients with RA and IBD, respectively. Among patients with RA, methotrexate used in conjunction with other medications was associated with an increased risk of a second NMSC (hazard ratio [HR], 1.60; 95% CI, 1.08-2.37). Adjusted for other medications, the risk of NMSC increased with 1 year or more of methotrexate use (HR, 1.24; 95% CI, 1.04-1.48). Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of NMSC (HR, 1.49; 95% CI, 1.03-2.16). Abatacept and rituximab were not associated with increased NMSC risk. The nonsignificant HRs for 1 year or more of thiopurine and anti-TNF use for IBD were 1.49 (95% CI, 0.98-2.27) and 1.36 (95% CI, 0.76-2.44), respectively. CONCLUSIONS AND RELEVANCE: Methotrexate use is associated with an increased risk of a second NMSC. Anti-TNF use may increase the risk of a second NMSC when used with methotrexate for RA. Further long-term studies are required before one can conclude that thiopurine and/or anti-TNF do not increase the risk of a second NMSC in patients with IBD.