Abstract Background Advanced combination therapy (ACT), using biologic–biologic or biologic–small molecule combinations, has progressed as a relevant treatment strategy for inflammatory bowel disease refractory to conventional therapy or when associated with severe extraintestinal manifestations/coexisting immune-mediated diseases. However, most published data are retrospective, heterogeneous and frequently combine Crohn’s disease and Ulcerative colitis (UC), limiting the ability to draw UC-specific conclusions. Previous pooled analyses did not stratify outcomes by disease subtype and included outdated combinations. The effectiveness of ACT in UC therefore remains unclear. We performed an updated systematic review and meta-analysis focused exclusively on UC. Methods We systematically searched PubMed, MEDLINE, Embase, and major gastroenterology conference abstracts (ECCO, DDW, UEGW) for studies published from January 2020 to August 2025. Eligible studies included observational cohorts, case series and clinical trials reporting ≥10 adult UC patients treated with ACT. ACT was defined as dual biologic therapy or a biologic combined with a JAK inhibitor. Mixed IBD studies were included only when UC-specific data was available. Clinical and endoscopic outcomes were pooled as reported using random-effects models (R-Studio, meta package). Results Five studies (4 observational, 1 RCT) met full inclusion criteria. These included biologic–biologic combinations (92 patients) and biologic–JAK inhibitor combinations (99), totalling 191 patients with extractable clinical and endoscopic outcomes within a median follow-up time of 25 (IQR 18-35) weeks. The pooled clinical response rate was 70% (95% CI 0.62–0.77) with no significant heterogeneity (I² = 0%; p=0,68), (Figure 1). The pooled endoscopic response rate, available from three studies (n = 116), was 46% (95% CI 0.09–0.87) reporting a significant heterogeneity (I² = 78%, p=0,0105), (Figure 2). Clinical and endoscopic remission were insufficiently reported for quantitative synthesis, and pooled serious adverse events (combined UC/CD data) was 3% (95% CI 0,01-0,07). Conclusion Among difficult to treat UC patients, ACT demonstrated high clinical response rates and moderate endoscopic response, representing the first UC-specific pooled analysis of advanced combination therapy. Although results are encouraging, evidence quality remains limited by small cohorts, heterogeneous regimens and inconsistent UC-specific reporting. This supports the ongoing randomized trials with standardized UC endpoints to define optimal ACT combinations, duration and de-escalation strategies. References: 1-Gisbert JP, Chaparro M. Combination therapy with biologics and/or small molecules in inflammatory bowel disease: a comprehensive review. J Crohns Colitis. 2025;19(9):jjaf161. doi:10.1093/ecco-jcc/jjaf161 2-Ahmed W, Galati J, Kumar A, et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022;20(3):e361-e379. doi:10.1016/j.cgh.2021.03.034 3-De Bernardi A, Bezzio C, Puricelli M, Gilardi D, Saibeni S. Combining Advanced Targeted Therapy in Inflammatory Bowel Disease: Current Practice and Future Directions. J Clin Med. 2025;14(2):590. Published 2025 Jan 17. doi:10.3390/jcm14020590 4-Altieri G, Zilli A, Parigi TL, et al. Dual Therapy in Inflammatory Bowel Disease. Biomolecules. 2025;15(2):222. Published 2025 Feb 3. doi:10.3390/biom15020222 Conflict of interest: Mr. Tomás, David: No conflict of interest Bastos, António: NONE Teixeira, Madalena: No conflict of interest Lopes, Sara: No conflict of interest Pereira, Marco: No conflict of interest Teixeira, Cristina: No conflict of interest Cardoso, Cláudia: No conflict of interest Freire, Ricardo: No conflict of interest
Tomás et al. (Thu,) studied this question.