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Background and aims <p>S1P receptor modulators are emerging oral therapies for moderate-to-severe ulcerative colitis (UC); however, a comprehensive synthesis incorporating the largest number of RCTs to date, alongside Trial Sequential Analysis (TSA) and GRADE-based certainty assessment, remains lacking. We aim to evaluate the efficacy and safety of S1P receptor modulators in moderate-to-severe UC and assess the conclusiveness and certainty of the evidence.</p> Methods <p>PubMed, Cochrane Library, Europe PMC, and Google Scholar were searched from inception through February 28, 2026. Eligible studies were RCTs comparing any S1P receptor modulator with placebo in adults (≥ 18&#xa0;years) with UC. Pooled risk ratios (RRs) with 95% CIs were estimated using a random-effects model.</p> Results <p>A total of ten RCTs were included. During induction, S1P receptor modulators were superior to placebo for clinical remission (RR 2.77; 95% CI, 2.17–3.55; <i>I</i><sup>2</sup> = 0%), clinical response (RR 1.69, 95% CI 1.52–1.87; <i>I</i><sup><i>2</i></sup> = 0%), endoscopic improvement (RR, 2.29; 95% CI, 1.91–2.75; <i>I</i><sup><i>2</i></sup> = 0%), and histological remission (RR 2.77; 95% CI, 2.11–3.63; <i>I</i><sup><i>2</i></sup> = 0%). Maintenance outcomes were similarly significant but heterogeneous (<i>I</i><sup><i>2</i></sup> = 48%–65%), fully resolved when restricted to treat-through designs. SAEs were not increased, while TEAEs were modestly higher overall during combined induction and maintenance periods, mainly with etrasimod. TSA provided supportive evidence of conclusive superiority for clinical response at both induction and maintenance, and for endoscopic improvement at induction; evidence for other outcomes remained inconclusive. GRADE certainty of evidence was moderate to high across all efficacy outcomes.</p> Conclusion <p>S1P receptor modulators demonstrated moderate-to-high certainty evidence of efficacy across all outcomes, without a significant increase in SAEs. These findings provide robust quantitative support for current guideline recommendations endorsing this oral drug class as an effective advanced therapy for moderate-to-severe UC.</p>

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

  • 期刊论文

  • 发表日期：

    2026年8月2日

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  • Abdulkareem Jomaa,
  • Rani Bshara,
  • Mohammed Alani,
  • Bilind Ismail,
  • Yousif Rajab,
  • Dani Hayder,
  • Halder J. Abozait,
  • Wasim Jomaa,
  • Weys Neda,
  • Mostafa Najim,
  • Hasan Al-Obaidi

摘要

Background and aims

S1P receptor modulators are emerging oral therapies for moderate-to-severe ulcerative colitis (UC); however, a comprehensive synthesis incorporating the largest number of RCTs to date, alongside Trial Sequential Analysis (TSA) and GRADE-based certainty assessment, remains lacking. We aim to evaluate the efficacy and safety of S1P receptor modulators in moderate-to-severe UC and assess the conclusiveness and certainty of the evidence.

Methods

PubMed, Cochrane Library, Europe PMC, and Google Scholar were searched from inception through February 28, 2026. Eligible studies were RCTs comparing any S1P receptor modulator with placebo in adults (≥ 18 years) with UC. Pooled risk ratios (RRs) with 95% CIs were estimated using a random-effects model.

Results

A total of ten RCTs were included. During induction, S1P receptor modulators were superior to placebo for clinical remission (RR 2.77; 95% CI, 2.17–3.55; I2 = 0%), clinical response (RR 1.69, 95% CI 1.52–1.87; I2 = 0%), endoscopic improvement (RR, 2.29; 95% CI, 1.91–2.75; I2 = 0%), and histological remission (RR 2.77; 95% CI, 2.11–3.63; I2 = 0%). Maintenance outcomes were similarly significant but heterogeneous (I2 = 48%–65%), fully resolved when restricted to treat-through designs. SAEs were not increased, while TEAEs were modestly higher overall during combined induction and maintenance periods, mainly with etrasimod. TSA provided supportive evidence of conclusive superiority for clinical response at both induction and maintenance, and for endoscopic improvement at induction; evidence for other outcomes remained inconclusive. GRADE certainty of evidence was moderate to high across all efficacy outcomes.

Conclusion

S1P receptor modulators demonstrated moderate-to-high certainty evidence of efficacy across all outcomes, without a significant increase in SAEs. These findings provide robust quantitative support for current guideline recommendations endorsing this oral drug class as an effective advanced therapy for moderate-to-severe UC.