Acute severe ulcerative colitis is a potentially life-threatening emergency marked by frequent bloody stools, systemic toxicity, and the need for urgent hospitalization. It develops in up to one-quarter of ulcerative colitis patients during their disease course. Intravenous corticosteroids remain the recommended first line of attack, yet roughly 30 to 40 percent of patients fail to respond adequately after three to five days. At that point, clinicians must choose quickly between medical rescue therapy and colectomy, because delayed surgery or ineffective drug treatment can compound the danger.

For decades, the two established rescue options have been infliximab, a monoclonal antibody that neutralizes tumor necrosis factor, and calcineurin inhibitors such as ciclosporin. Landmark randomized trials, including the CySIF trial and the pragmatic CONSTRUCT study, found no meaningful difference between the two drugs in treatment failure, colectomy, or serious adverse events. But the therapeutic landscape has grown more complicated. Accelerated and high-dose infliximab regimens have been proposed to counteract the rapid drug clearance seen in severely inflamed patients, while oral Janus kinase inhibitors such as tofacitinib and upadacitinib have emerged as candidates, particularly for patients already exposed to biologic therapy.

To untangle this crowded field, an international team of researchers led by investigators at Brookdale University Hospital and Medical Center in New York, with collaborators spanning institutions in the United States, Egypt, and beyond, searched five major electronic databases from inception through June 30, 2026. They screened 5,498 records and ultimately included 18 studies: three randomized controlled trials and 15 comparative observational studies. The team conducted separate frequentist random-effects network meta-analyses for four outcomes: colectomy at approximately 12 to 14 weeks, colectomy during hospitalization or within 30 days, colectomy at approximately 12 months, and serious adverse events. The review was registered with PROSPERO under identifier CRD420261412884.

The headline result concerned the classic head-to-head comparison. At the short-term follow-up window of roughly 12 to 14 weeks, ciclosporin was associated with significantly higher odds of colectomy than standard-dose infliximab, with an odds ratio of 2.19 and a 95 percent confidence interval of 1.17 to 4.12. The pattern held at earlier and later time points: ciclosporin showed roughly three-fold higher odds of early colectomy, defined as surgery during the index hospitalization or within 30 days, and more than three-fold higher odds of colectomy at 12 months. Notably, serious adverse events were statistically indistinguishable between the two drugs, with an odds ratio of 0.94.

By contrast, neither accelerated infliximab induction, in which the second and third infusions are given earlier than the conventional week-2 and week-6 schedule, nor high-dose infliximab at 10 milligrams per kilogram showed a significant advantage over the standard 5-milligram-per-kilogram regimen. The confidence intervals for these intensified strategies were strikingly wide, reflecting small treatment groups and sparse event counts. Tacrolimus, another calcineurin inhibitor, also did not differ significantly from standard-dose infliximab at either early or 12-month follow-up, though its network estimate rested on a single retrospective study of just 61 patients.

The Janus kinase inhibitor evidence told an intriguing but incomplete story. In a retrospective matched case-control study, tofacitinib was associated with a lower adjusted 90-day colectomy risk than matched standard-care controls among biologic-experienced hospitalized patients, with an adjusted hazard ratio of 0.28. A separate international comparison of tofacitinib and upadacitinib found nearly identical colectomy-free survival, 79 percent versus 80 percent at day 98, with no difference between the survival curves. However, these studies could not be validly connected to the main infliximab-ciclosporin network because they lacked a common comparator, so no global ranking across drug classes was possible.

Beneath the surface of the pooled estimates lies a critical tension. The apparent efficacy advantage of infliximab over ciclosporin was driven predominantly by observational studies, which pooled to an odds ratio of 2.88 favoring infliximab, whereas the direct randomized comparison in the Laharie trial was essentially neutral, with an odds ratio of 0.78. The authors identify several plausible explanations for this divergence. Many observational cohorts compared patients treated in nonoverlapping calendar periods, meaning ciclosporin cohorts often predated infliximab cohorts and may have benefited less from improvements in supportive care, infection screening, thromboprophylaxis, and surgical decision-making. Moreover, ciclosporin was frequently used as a temporary bridge to thiopurines, while infliximab could be continued as long-term maintenance therapy, potentially skewing 12-month colectomy rates in favor of the latter strategy.

Risk of bias assessments reinforced the need for caution. All three randomized trials were judged to have some concerns, largely because open-label designs could have influenced decisions about additional rescue treatment or the timing of surgery. Among the 15 observational studies, 14 were rated as having serious risk of bias, primarily due to confounding by indication: patients with more severe inflammation, lower albumin, or prior biologic failure were more likely to receive intensified infliximab, tacrolimus, or JAK inhibitors. Using the GRADE framework, the certainty of evidence ranged from low to very low, and no comparison achieved moderate or high certainty.

The practical message for clinicians is nuanced rather than revolutionary. Standard-dose infliximab emerges as an effective and practical default rescue strategy, with the added advantage that it can be continued for maintenance after successful induction. Yet ciclosporin should not be dismissed as obsolete; randomized trials continue to support it as a legitimate option, particularly in thiopurine-naïve patients, those with contraindications to anti-TNF therapy, or centers experienced in therapeutic drug monitoring. The PREDICT-UC randomized trial, which found no benefit of an initial 10-milligram-per-kilogram dose or accelerated induction over standard dosing, argues against routine intensification for all patients, though individualized escalation may still help those with profound hypoalbuminemia or suspected rapid drug clearance.

The authors conclude that adequately powered randomized comparisons are urgently needed, incorporating contemporary biologic-exposed populations and newer small-molecule therapies, with standardized definitions of steroid failure and consistent reporting of colectomy across time points. Until such trials arrive, treatment selection should remain individualized, weighing previous therapy, disease severity, serum albumin, comorbidities, and institutional expertise. And one principle remains nonnegotiable: early surgical consultation should run in parallel with medical rescue planning, because no drug ranking, however sophisticated the statistics, should justify delaying colectomy in a deteriorating patient.

Subject of Research: Comparative efficacy and safety of medical rescue therapies for steroid-refractory acute severe ulcerative colitis

Article Title: Comparative outcomes of advanced medical rescue therapies in steroid-refractory acute severe ulcerative colitis: a systematic review and network meta-analysis

Article References: Alabdallat, M. Y., Al Ta’ani, O., Bakain, T., Al-Dwairy, A., Ghannam, M., Atasi, A., Mashal, F., Moghib, K., Bakheet, N., Jagroo, J. G., Hehr, R., Salem, A., & Cheung, D. (2026). Comparative outcomes of advanced medical rescue therapies in steroid-refractory acute severe ulcerative colitis: a systematic review and network meta-analysis. Frontiers in Gastroenterology, 5, Article 1937925. https://doi.org/10.3389/fgstr.2026.1937925

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1937925

Keywords: ulcerative colitis, infliximab, ciclosporin, colectomy, network meta-analysis, rescue therapy, tacrolimus, JAK inhibitors, steroid refractory, acute severe ulcerative colitis, gastroenterology, systematic review