COMPARATIVE RISK OF LYMPHOMA IN INFLAMMATORY BOWEL DISEASE PATIENTS TREATED WITH THIOPURINES AND/OR ANTI-TNF AGENTS: AN UMBRELLA REVIEW OF META-ANALYSES

Abstract INTRODUCTION Inflammatory bowel disease (IBD) is commonly treated with thiopurines and anti-tumor necrosis factor (anti-TNF) agents, either as monotherapy or in combination. Although these therapies are highly effective for induction and maintenance of remission, they have been associated with an increased risk of malignancies, particularly lymphoma. Several meta-analyses have evaluated this association, but no single review has synthesized the evidence across all drug exposures. This umbrella review aimed to summarize and compare pooled risk estimates of lymphoma in IBD patients receiving thiopurines, anti-TNF agents, or combination therapy. METHODS A comprehensive search of PubMed, EMBASE, and Cochrane Library was conducted from database inception through the most recent update to identify meta-analyses evaluating lymphoma risk with thiopurines and/or anti-TNF agents in IBD. Only meta-analyses reporting standardized incidence ratios (SIR) or incidence rate ratios (IRR) with 95% confidence intervals were included. Data extraction focused on exposure categories (monotherapy or combination), effect sizes, subgroup analyses, and study quality. Overlap between primary studies was assessed using corrected covered area (CCA) to account for redundancy across meta-analyses, and findings were synthesized qualitatively. RESULTS Kandiel et al., 2005 reported a fourfold increased lymphoma risk with thiopurines (SIR 4.18; 95% CI, 2.07–7.51) and a relative risk of 2.92 (95% CI, 1.05–8.13) compared with unexposed IBD patients. Kotlyar et al., 2015 found an overall SIR of 4.92 (95% CI, 3.10–7.78), with risk significantly higher in referral center studies (SIR 9.24) versus population-based cohorts (SIR 2.80). Risk was greatest among current users (SIR 5.71) and patients younger than 30 years. Chupin et al., 2020 demonstrated elevated lymphoma risk with anti-TNF monotherapy (IRR 1.52), thiopurine monotherapy (IRR 2.23), and combination therapy (IRR 3.71), with combination therapy conferring the highest risk CONCLUSION Current evidence consistently shows increased lymphoma risk with thiopurines, anti-TNF agents, and especially combination therapy. Although the absolute risk is low, it is most pronounced among young males and during active thiopurine exposure. These findings underscore the importance of individualized risk-benefit discussions and support minimizing combination therapy duration when possible.