Advanced Combination Therapy in IBD

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, immune-mediated condition 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 separate advanced targeted agents, either two biologics or a biologic and a small molecule, 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 narrative review, based on a PubMed literature search, summarizes the biological rationale, current clinical evidence, safety considerations, and practical applications of ACT in IBD. Available evidence, largely derived from heterogeneous observational studies and phase 2 randomized trials, suggests potential improvements in clinical and endoscopic outcomes in selected patients. However, the incremental benefit over individual targeted therapies has not been consistently demonstrated. Although available studies have not identified a clear increase in short-term serious adverse events, the evidence remains insufficient to establish long-term safety. Important uncertainties persist regarding optimal patient selection, treatment sequencing, duration, de-escalation strategies, and cost-effectiveness. While ACT represents a potentially valuable therapeutic option for selected patients with IBD, its use for active IBD remains largely off-label, and current evidence does not support routine implementation. Larger randomized trials and long-term studies are needed to better define its efficacy, safety, and clinical positioning.