Rescue Therapy in Steroid-Refractory Acute Severe Ulcerative Colitis: An Umbrella Review

Purpose Acute severe ulcerative colitis (ASUC) is a medical emergency defined by severe inflammation of the colon and systemic toxicity. Although intravenous corticosteroids are the initial standard therapy, the incidence of steroid resistance remains high, ranging from 30% to 40%. The current treatment paradigm for steroid-refractory ASUC (SR-ASUC) has undergone significant changes, transitioning from the initial use of cyclosporine and infliximab to the more recent addition of Janus kinase inhibitors and biologic dose escalation. This is the first umbrella review to systematically synthesize evidence from available meta-analyses and network meta-analyses evaluating pharmacologic rescue strategies in SR-ASUC. Methods We conducted a search of PubMed, EMBASE, and Cochrane Library databases from inception through December 2025. We included systematic reviews with meta-analyses, or network meta-analyses, of pharmacological therapies (infliximab, cyclosporine, tacrolimus, tofacitinib, and sequential therapy) for adults with SR-ASUC. We converted the reported summary results into equivalent odds ratios (eOR). Outcomes extracted were short-term (≤ 3 months) and long-term (≈ 12 months) colectomy-free survival (CFS) and/or colectomy outcomes, as reported. Methodological quality was assessed using AMSTAR-2, and certainty of evidence was evaluated using GRADE. Results Eleven reviews (2 network meta-analyses, 8 pairwise meta-analyses, and 1 systematic review) met eligibility criteria. In NMAs, tofacitinib was associated with a lower short-term colectomy risk versus placebo (eOR 0.09, 95% CI 0.02–0.52; moderate certainty). Randomized trials showed comparable 3-month colectomy outcomes with infliximab versus cyclosporine (eOR 1, 95% CI 0.64–1.59), whereas observational data favored infliximab in reducing long-term colectomy rates. Multiple-dose infliximab induction (≥ 3 doses of 5 mg/kg) was associated with higher 3-month colectomy-free survival compared to single-dose strategies (eOR 4.24, 95% CI 2.44–7.36), while empiric intensified or accelerated induction did not demonstrate consistent benefit. Sequential rescue therapy after initial failure achieved pooled response rates around 60% with 12-month CFS but was accompanied by serious infection rates of up to 2–13%. Conclusion Infliximab and cyclosporine remain comparable first-line options in randomized data, with multi-dose infliximab induction preferred over single-dose. Tofacitinib shows promise in network meta-analyses but requires confirmation. Routine accelerated/intensified induction and sequential rescue carry risks without consistent benefit. A phenotype-driven treatment algorithm is proposed to guide management. Registration: Registered on PROSPERO (ID: CRD420261293506) on February 10, 2026.