Cancer risk with methotrexate-TNF antagonist combination therapy compared to TNF-antagonist monotherapy in IBD

Background and aims In patients with inflammatory bowel diseases (IBD), tumor necrosis factor antagonists (anti-TNFs) are frequently used alongside immunomodulators to improve treatment efficacy. While an increased risk of cancers with thiopurines is well established, there is sparse data on cancer risk with methotrexate. Methods We conducted a retrospective cohort study of patients with Crohn’s disease (CD) or ulcerative colitis (UC) at a large, integrated healthcare system. Eligible patients received either anti-TNF monotherapy or combination (anti-TNF + methotrexate) between 1999 and 2025. The primary outcome was incident cancer confirmed by chart review. Cox-proportional hazards models were used to identify the independent effect of combination therapy on cancer risk, adjusting for relevant covariates. Results Our study included 2332 patients with IBD (80.9%) on anti-TNF monotherapy and 549 (19.1%) on combination therapy. Mean age at inclusion was 35 years, and 75.8% had CD. Mean follow-up duration was 3.3 years. Over 1353 and 8031 person-years of follow-up, incidence rates of all cancers were 7.4 and 6.4 per 1000 person-years in the combination and monotherapy groups, respectively (P = .64). We observed no increased risk of cancer between groups for all cancers (adjusted HR 0.94, 95% CI, 0.47-1.89), skin cancer (adjusted HR 0.57, 95% CI, 0.07-4.51) or non-skin cancers (adjusted HR 1.00, 95% CI, 0.48-2.11). Age ≥ 60 years and prior thiopurine exposure were associated with an increased risk of cancer. Conclusions Combination anti-TNF and methotrexate therapy was not associated with an increased cancer risk compared to anti-TNF monotherapy in patients with IBD in our cohort.