Systematic Review With Meta-Analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Diseases

Background The systematic review and meta-analysis (SRMA) evaluates the safety and effectiveness of combining biologics and/or small molecules in treating refractory inflammatory bowel diseases (IBD). Methods Our 2022 SRMA identified 13 studies published until November 3, 2020. An updated systematic search was completed from May 2020 through January 31, 2024. Random-effects inverse variance model was used to calculate pooled estimates for adverse events (AEs) and clinical and endoscopic-radiologic response/remission rates in IBD patients. Results Twenty-seven eligible studies had 619 patients and 631 therapeutic trials (TTs). Upadacitinib (UPA) + vedolizumab (VDZ) and tofacitinib (Tofa) + anti-TNF (aTNF) had the lowest AEs rate (0%, 2 TTs) and (9.2%, 33 TTs), respectively. Higher AE rates were seen in natalizumab (NAT) + aTNF (92.3%, 52 TTs) and aTNF + guselkumab (63.4%, 71 TTs). No serious AEs (SAEs) were observed in NAT + aTNF (52 TTs), Tofa + ustekinumab (UST) (23 TTs), and UPA + VDZ (2 TTs). The highest rate of SAEs was observed in UPA + UST (23%, 17 TTs). UPA + UST and UPA + VDZ had 100% clinical response rates and the highest clinical remission rates (83.3%, 12 TTs) and (100%, 2 TTs), respectively. High clinical response rates were also seen in Tofa + aTNF (82.7%, 34 TTs), UST + aTNF (82.1%, 63 TTs), and VDZ + UST (82.0%, 71 TTs). Conclusions Combining biologics and/or small molecules may be effective for IBD patients who fail to achieve remission with monotherapy; however, safety profiles need to be carefully considered prior to implementing these strategies in clinical practice.