Abstract

Objectives:
To systematically synthesise available evidence on the safety of advanced combination therapy (ACT) in adults with inflammatory bowel disease (IBD), with secondary exploratory evaluation of efficacy outcomes.

Design:
Systematic review and meta-analysis.

Data sources:
MEDLINE, Embase and PubMed were searched from 1-JAN-2015 to 31-MAR-2026. Additional studies were identified through hand-searching and reference list screening.

Eligibility criteria:
We included randomised controlled trials, observational and descriptive studies. Conference abstracts, reviews, editorials, and commentaries were excluded.

Data extraction and synthesis:
Two reviewers independently screened studies, extracted data, and assessed risk of bias using Joanna Briggs Institute tools and Cochrane RoB-1. Pooled proportions of total adverse events (TAEs), serious adverse events (SAEs), and treatment discontinuations were calculated using random-effects meta-analysis. Subgroup analyses were conducted by drug class. Where meta-analysis was not appropriate, findings were narratively synthesised.

Results:
Fifty-two studies (n=2022 participants) were included. The most frequent combinations were anti-TNFa plus integrin inhibitors and IL-23 plus integrin inhibitors. Pooled analyses demonstrated low rates of SAEs (e.g. anti-TNFa plus integrin inhibitors: 2.7%, 95% CI 0.22% to 6.86%) and discontinuations (6.38%, 95% CI 2.36% to 11.58%), although heterogeneity was substantial and certainty of evidence was very low, with some analysis based on small sample sizes.

Conclusions:
ACT may be associated with low rates of SAEs in selected patients with refractory IBD; however, the evidence is limited by small sample sizes, heterogeneity, and predominantly observational designs. Robust conclusions regarding safety and efficacy cannot be made due to very low GRADE certainty.

Study registration:
PROSPERO CRD420251025883.