[Advanced Combination Therapy in Inflammatory Bowel Disease]

Despite the advances in biological and small-molecule therapies, a substantial proportion of patients with inflammatory bowel disease (IBD) experience multiple treatment failures, constituting difficult-to-treat IBD with remission rates plateauing at 30-50%. Advanced combination therapy (ACT), defined as the concomitant use of two advanced therapies with distinct mechanisms of action, has become a strategy to overcome this therapeutic ceiling. This review aims to synthesize the rationale, clinical evidence, safety profile, and practical implementation strategies of ACT in IBD. A narrative review of randomized controlled trials (RCTs), meta-analyses, and real-world observational studies evaluating ACT in IBD was performed, focusing on the mechanistic rationale, efficacy outcomes, safety data, and clinical application strategies. ACT is supported by pharmacokinetic synergy (reduced immunogenicity and improved drug exposure) and pharmacodynamic complementarity (simultaneous blockade of multiple inflammatory pathways). Proof-of-concept RCTs, including VEGA and EXPLORER, along with meta-analyses, revealed higher clinical and endoscopic remission rates with ACT than with monotherapy in refractory populations. The safety profiles are generally comparable to monotherapy, but regimen-specific heterogeneity exists. Although vedolizumab- or ustekinumab-based combinations show favorable long-term safety, regimens including natalizumab or JAK inhibitors warrant caution and close monitoring. Detailed clinical strategies include induction-bridge approaches with JAK inhibitors, safety-anchor strategies with gut-selective agents, mechanistic complementarity strategies for treatment failures, and double-indication strategies for extraintestinal manifestations. ACT is a promising rescue strategy for D2T IBD with encouraging efficacy and acceptable safety. Future research should focus on large-scale RCTs and biomarker-driven strategies to optimize patient selection and treatment protocols for ACT.