Combination Biologic and Small-Molecule Therapy Shows Promise in Refractory IBD, Meta-Analysis Finds
An updated systematic review and meta-analysis suggests that combining biologics and/or small molecules may offer clinical benefit for patients with refractory inflammatory bowel disease (IBD), though safety profiles vary widely by regimen.
The analysis expanded on a prior 2022 review and incorporated studies published through January 31, 2024. In total, 27 studies were included, encompassing 619 patients and 631 therapeutic trials. Using a random-effects model, investigators evaluated pooled rates of adverse events (AEs), serious adverse events (SAEs), and clinical and endoscopic-radiologic outcomes across various combination regimens.
Safety outcomes differed substantially between combinations. Upadacitinib plus vedolizumab and tofacitinib plus anti–tumor necrosis factor (anti-TNF) therapy were associated with the lowest overall AE rates, at 0% and 9.2%, respectively. By contrast, natalizumab plus anti-TNF therapy and anti-TNF plus guselkumab were linked to markedly higher AE rates, reaching 92.3% and 63.4%. Notably, no SAEs were reported with natalizumab plus anti-TNF, tofacitinib plus ustekinumab, or upadacitinib plus vedolizumab, while the highest SAE rate occurred with upadacitinib plus ustekinumab.
Efficacy signals were strongest for regimens incorporating Janus kinase inhibition. Upadacitinib combined with ustekinumab or vedolizumab achieved 100% clinical response rates, with clinical remission rates of 83.3% and 100%, respectively. High response rates were also observed with tofacitinib plus anti-TNF therapy, ustekinumab plus anti-TNF therapy, and vedolizumab plus ustekinumab, all exceeding 80%.
The authors concluded that “combining biologics and/or small molecules may be effective for IBD patients who fail to achieve remission with monotherapy,” but emphasized that “safety profiles need to be carefully considered prior to implementing these strategies in clinical practice.”
For gastroenterologists, the key takeaway is that dual-targeted therapy may represent a viable option for highly refractory IBD, particularly when conventional approaches have failed. However, careful selection of drug combinations and close monitoring for adverse events remain essential, underscoring the need for individualized risk–benefit assessment and further prospective study.
Reference
Anderson SR, Osman A, Zamani M, et al. Systematic review with meta-analysis: safety and effectiveness of combining biologics and small molecules in inflammatory bowel diseases. Inflamm Bowel Dis. 2026;32(1):39-52. doi:10.1093/ibd/izaf188
