Relapse Rates and Predictors Following Azathioprine Withdrawal in Inflammatory Bowel Disease: A Systematic Review, Meta-Analysis, and Meta-Regression

Background/Objectives: Azathioprine (AZA) is widely used for maintaining remission in inflammatory bowel disease (IBD), but the implications of its withdrawal remain unclear. This study evaluates relapse rates after AZA discontinuation in adult IBD patients in remission and identifies predictors of relapse. Methods: A systematic review and meta-analysis were conducted according to PRISMA 2020 guidelines and registered in PROSPERO (CRD420251016594). Databases were searched from inception to 4 January 2025, including RCTs and cohort studies involving adult IBD patients who discontinued AZA in clinical remission. The main outcome assessed was relapse incidence, with additional outcomes covering time until relapse, predictors of relapse, and management following relapse. Random-effects meta-analysis, subgroup analyses, and meta-regression were performed. Results: Twenty-two studies comprising 3057 patients were included. The pooled relapse rate after AZA withdrawal was 32.5% (95% CI: 28.2–37.2%; I² = 94.2%). UC patients exhibited higher relapse rates (41.3%) than CD patients (24.7%, p = 0.003). Shorter AZA duration, elevated CRP, and absence of mucosal healing were associated with increased relapse risk. Meta-regression identified AZA duration as a significant predictor (β = −0.18, p = 0.009). Post-relapse management often involved AZA reintroduction or escalation to biologics, with low surgery rates. The GRADE assessment revealed that the certainty of evidence for the majority of primary outcomes was classified as low to very low. Conclusions: While this meta-analysis suggests that relapse after AZA withdrawal occurs frequently in IBD patients, the low to very low certainty of evidence limits definitive recommendations. The significant heterogeneity indicates that relapse risk varies across different patient populations and different settings.