Combination therapy with biologics and/or small molecules in inflammatory bowel disease: a comprehensive review

Advanced combination treatment (ACT)-the combination of two advanced agents such as biologics or small molecules-has emerged as a promising strategy in the management of inflammatory bowel disease refractory to conventional treatment, with severe extraintestinal manifestations, or with coexisting immune-mediated inflammatory diseases. ACT including complementary mechanisms of action aims to overcome the therapeutic ceiling observed with monotherapy. Its rationale is supported by preclinical and mechanistic data demonstrating synergistic immunological effects when distinct inflammatory pathways are targeted simultaneously. Although observational studies report pooled clinical and endoscopic remission rates of approximately 60% and 30%, respectively, the quality of evidence remains very limited. Most studies are retrospective, heterogeneous in patient populations and treatment regimens, and often report outcomes in aggregate, precluding firm conclusions regarding the efficacy of specific drug combinations. The two and only randomized controlled trials available to date have shown acceptable safety profiles but limited or no clear superiority of ACT over monotherapy. Safety data are reassuring, with no significant increase in serious adverse events. The optimal duration of ACT remains uncertain; while de-escalation to monotherapy following deep remission is feasible in selected patients, relapse rates vary, emphasizing the need for individualized treatment decisions and long-term follow-up. High treatment costs also pose a barrier to widespread adoption of ACT, though biosimilars may help offset these concerns. In summary, ACT may represent a potentially valuable therapeutic option in selected high-risk or treatment-resistant patients with inflammatory bowel disease; however, its true clinical benefit remains uncertain and requires confirmation through robust, well-powered randomized controlled trials.