Advanced Combination Therapy Appears Safe for Refractory IBD, but Evidence Remains Limited
A systematic review and meta-analysis published in BMJ Open Gastroenterology suggests that advanced combination therapy (ACT)—the use of two advanced therapies targeting different inflammatory pathways—may be associated with low rates of serious adverse events (SAEs) in adults with refractory inflammatory bowel disease (IBD).
However, investigators caution that the evidence is based largely on small observational studies with substantial heterogeneity, limiting confidence in both safety and efficacy estimates.
Study Findings
The review included 52 studies involving 2022 adults with Crohn's disease or ulcerative colitis published between 2015 and March 2026. Investigators searched Embase, MEDLINE, and PubMed and included randomized controlled trials, observational studies, and descriptive studies while excluding conference abstracts, reviews, and editorials.
The most frequently studied ACT regimens paired anti–tumor necrosis factor-alpha (anti-TNFα) agents with integrin inhibitors or interleukin (IL)-23 inhibitors with integrin inhibitors, reflecting growing interest in targeting complementary inflammatory pathways in patients with treatment-refractory disease.
Across pooled analyses, ACT demonstrated relatively low rates of serious adverse events. For anti-TNFα plus integrin inhibitor combinations, the pooled SAE rate was 2.7% (95% CI, 0.22%-6.86%), while treatment discontinuation due to adverse events occurred in 6.38% of patients (95% CI, 2.36%-11.58%). Despite these encouraging findings, heterogeneity between studies was substantial, and many analyses were based on small patient cohorts, resulting in very low-certainty evidence according to GRADE criteria.
The review also explored efficacy as a secondary outcome. Although formal meta-analysis was not possible because studies used different outcome definitions and assessment tools, several reports described encouraging rates of clinical remission, endoscopic remission, clinical response, and endoscopic response, particularly among patients receiving IL-23 inhibitor plus integrin inhibitor combinations. However, the authors emphasized that the predominance of uncontrolled observational data and lack of standardized efficacy measures precluded definitive conclusions.
Clinical Implications
Advanced combination therapy is increasingly being considered for patients with refractory IBD who have failed multiple biologics or require treatment for concurrent immune-mediated diseases or extraintestinal manifestations. By combining agents with complementary mechanisms—such as systemic cytokine blockade with gut-selective leukocyte trafficking inhibition—clinicians hope to overcome the therapeutic ceiling observed with single-agent biologic therapy.
The current review provides reassurance that ACT has not demonstrated a major safety signal in carefully selected patients. However, clinicians should interpret these findings cautiously because most available evidence comes from observational studies with short follow-up, heterogeneous patient populations, and variable treatment regimens. Likewise, while early efficacy data for IL-23 plus integrin inhibitor combinations appear promising, the evidence remains insufficient to determine whether these regimens consistently improve remission or response compared with standard therapy.
Reference:
Radford S, Albuquerque DAN, Najeeb Z, et al. Safety and efficacy of advanced combination therapies for treating inflammatory bowel disease in adults: a systematic review and meta-analysis. BMJ Open Gastroenterology. 2026;13(1):e002307. https://doi.org/10.1136/bmjgast-2026-002307
