S1P receptor modulators for moderate-to-severe ulcerative colitis: a systematic review, meta-analysis, and trial sequential analysis.

Outpatient positioning is unchanged from the ACG 2025 UC guideline and the AGA living guideline for moderate-to-severe UC. Confirm UC with endoscopy showing continuous colonic inflammation from the rectum plus histology, after excluding infection with two-step C. difficile testing. Treat mild-moderate disease with 5-ASA chosen by route and extent: suppository for proctitis, enema for left-sided disease, oral plus rectal for extensive disease. If 5-ASA fails, treat as moderate-to-severe rather than stepping up gradually. Position advanced therapy by efficacy tier, not by an anti-TNF-first rule. Advanced-therapy-naive, higher efficacy: infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, guselkumab. Intermediate: golimumab, ustekinumab, tofacitinib, filgotinib, mirikizumab. Lower: adalimumab. Previously TNF-exposed, higher efficacy: tofacitinib, upadacitinib, ustekinumab. Lower: adalimumab, vedolizumab, ozanimod, etrasimod. After anti-TNF primary non-response, switch mechanism rather than cycling within the class. Treat to target (STRIDE-II): endoscopic improvement, Mayo endoscopic subscore 0-1. Begin CRC surveillance 8-10 years after diagnosis for extensive or left-sided disease; isolated proctitis follows average-risk screening. Inpatient care now follows the 2026 AGA Clinical Practice Update (13 best-practice statements). Admit for severe symptoms refractory to outpatient therapy, suspected complications (obstruction, abscess, toxic megacolon) or significant malnutrition, and identify acute severe UC by Truelove-Witts. Give every patient admitted with diarrhea two-step C. difficile testing. Test for CMV, with early endoscopy, if symptoms worsen, the patient is systemically toxic or disease is steroid-refractory. Give routine VTE prophylaxis with LMWH or fondaparinux unless contraindicated, and individualize post-discharge extension. Give IV methylprednisolone 60 mg/day or equivalent; the AGA living guideline says 40-60 mg/day, and higher doses add no benefit. Do not give adjunctive antibiotics without infection. Involve surgery early. Assess response by day 3 (72 h) using stool frequency and CRP (Oxford criteria); do not continue IV steroids beyond about 7 days without response. Rescue steroid non-responders with infliximab (accelerated or intensified dosing in selected patients with high inflammatory burden or protein-losing colopathy), cyclosporine, or a JAK inhibitor at standard or intensified dosing, or with colectomy. Before discharge, the response should be stable and a transition plan should be in place.