Objective:

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.

Approach:

• Design: Systematic review and meta-analysis.
• Data Sources: Searches of Embase, MEDLINE, and PubMed; hand-searching and reference list screening.
• Eligibility Criteria: Included randomised controlled trials, observational and descriptive studies; excluded conference abstracts, reviews, editorials, and commentaries.
• Data Extraction and Synthesis: Two reviewers screened studies, extracted data, and assessed risk of bias; pooled proportions of total adverse events (TAEs), serious adverse events (SAEs), and treatment discontinuations calculated using random-effects meta-analysis.

Key Findings:

• Fifty-two studies (n=2022 participants) were included.
• Most frequent combinations were anti-TNFa plus integrin inhibitors and interleukin (IL) 23 plus integrin inhibitors.
• Pooled analyses showed low rates of SAEs (e.g., anti-TNFa plus integrin inhibitors: 2.7%, 95% CI 0.22% to 6.86%) and treatment discontinuations (6.38%, 95% CI 2.36% to 11.58%).
• Evidence quality was very low due to substantial heterogeneity and small sample sizes.

Interpretation:

The evidence is limited by small sample sizes, heterogeneity, and predominantly observational designs.

Limitations:

• Small sample sizes in many studies.
• Substantial heterogeneity in findings.
• Predominantly observational study designs.

Conclusion:

Robust conclusions regarding safety and efficacy cannot be made due to very low GRADE certainty.

Sources:

• PROSPERO registration