Abstract
Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated disorders characterized by considerable clinical and biological heterogeneity. Despite major advances in biologic therapies and small molecules, a considerable proportion of patients fail to achieve sustained clinical and endoscopic remission, highlighting the therapeutic ceiling of current treatment strategies. Increasing evidence suggests that treatment failure may result from the activation of multiple, partially overlapping inflammatory pathways that are not adequately controlled by single-agent therapy. Advanced combination therapy (ACT), defined as the concomitant use of two targeted therapies with complementary mechanisms of action, has emerged as a potential strategy to overcome these limitations, particularly in patients with refractory disease, extraintestinal manifestations, or concomitant immune-mediated inflammatory diseases. This review summarizes the biological rationale, current clinical evidence, safety considerations, and practical applications of ACT in IBD. Available observational studies and emerging prospective data suggest that ACT may improve clinical and endoscopic outcomes in selected patients without a clear short-term increase in serious adverse events. However, important uncertainties remain regarding optimal patient selection, treatment sequencing, duration of therapy, de-escalation strategies, long-term safety, and cost-effectiveness.As the therapeutic landscape continues to evolve, ACT represents a promising step toward a more personalized and mechanism-based approach to IBD management. Ongoing clinical studies and the development of novel multi-target therapeutic strategies will be critical to define its future role in clinical practice.