Skip to main content

Advertisement

SpringerLink
Log in

Sphingosine 1-phosphate (S1P) receptor modulators as an induction and maintenance therapy for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

  • 2 Altmetric

Abstract

Background and objective

One sphingosine-1-phosphate (S1P) receptor modulator is approved (ozanimod) and another (etrasimod) is under investigation for the induction and maintenance of remission of ulcerative colitis (UC). We aim to evaluate the efficacy and safety of S1P modulators in patients with active UC.

Methods

We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through May 13th, 2023. We used the fixed-effect model to pool dichotomous data using risk ratio (RR) with a 95% confidence interval (CI).

Results

Five RCTs with a total of 1990 patients were included. S1P receptor modulators were significantly associated with increased clinical response during both the induction (RR 1.71 with 95% CI [1.50, 1.94], P = 0.00001) and maintenance phases (RR 1.89 with 95% CI [1.33, 2.69], P = 0.0004); clinical remission rates during both induction (RR 2.76 with 95% CI [1.88, 4.05], P = 0.00001) and maintenance phases (RR 3.34 with 95% CI [1.41, 7.94], P = 0.006); endoscopic improvement during both induction (RR 2.15 with 95% CI [1.71, 2.70], P = 0.00001) and maintenance phases (RR 2.41 with 95% CI [1.15, 5.05], P = 0.02); and histologic remission during both induction (RR 2.60 with 95% CI [1.89, 3.57] [1.17, 2.10], P = 0.00001) and maintenance phases (RR 2.52 with 95% CI [1.89, 3.37], P = 0.00001). Finally, there was no difference regarding safety outcomes as compared to placebo in both the induction and maintenance phases.

Conclusion

S1P receptor modulators are effective in inducing and maintaining remission in patients with moderate to severe UC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data and materials

Not applicable.

References

  1. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American college of gastroenterology, practice parameters committee. Am J Gastroenterol. 2010;105:501–23.

    Article  PubMed  Google Scholar 

  2. Ungaro R, Mehandru S, Allen PB, et al. Ulcerative colitis. Lancet. 2017;389:1756–1770. https://pubmed.ncbi.nlm.nih.gov/27914657/.

  3. Olivera P, Danese S, Peyrin-Biroulet L. Next generation of small molecules in inflammatory bowel disease. Gut. 2017;66:199–209. https://pubmed.ncbi.nlm.nih.gov/27856614/.

  4. Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016;374:1754–62. https://doi.org/10.1056/NEJMoa1513248.

    Article  CAS  PubMed  Google Scholar 

  5. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401:1159–71. https://doi.org/10.1016/S0140-6736(23)00061-2.

    Article  PubMed  Google Scholar 

  6. Kihara Y, Maceyka M, Spiegel S, et al. Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br J Pharmacol. 2014;171:3575–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pérez-Jeldres T, Tyler CJ, Boyer JD, et al. Cell trafficking interference in inflammatory bowel disease: therapeutic interventions based on basic pathogenesis concepts. Inflamm Bowel Dis. 2019;25:270–82.

    Article  PubMed  Google Scholar 

  8. Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al. Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis. Gastroenterology. 2020;158:550–61.

    Article  CAS  PubMed  Google Scholar 

  9. Blaho VA, Hla T. Thematic review series: Lysophospholipids and their receptors: an update on the biology of sphingosine 1-phosphate receptors. J Lipid Res. 2014;55:1596–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Camm J, Hla T, Bakshi R, et al. Cardiac and vascular effects of fingolimod: Mechanistic basis and clinical implications. Am Heart J. 2014;168:632–44.

    Article  CAS  PubMed  Google Scholar 

  11. Marsolais D, Rosen H. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat. Rev. Drug Discov. 2009;8:297–307. https://pubmed.ncbi.nlm.nih.gov/19300460/.

  12. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science (-80). 2002;296:346–9.

    Article  CAS  Google Scholar 

  13. Gräler MH, Goetzl EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 2004;18:551–3.

    Article  PubMed  Google Scholar 

  14. Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9:883–97.

    Article  CAS  PubMed  Google Scholar 

  15. Garris CS, Blaho VA, Hla T, et al. Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology. 2014;142:347–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Arlt O, Schwiebs A, Japtok L, et al. Sphingosine-1-phosphate modulates dendritic cell function: Focus on non-migratory effects in vitro and in vivo. Cell Physiol Biochem. 2014;34:27–44.

    Article  CAS  PubMed  Google Scholar 

  17. Walzer T, Chiossone L, Chaix J, et al. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol. 2007;8:1337–44.

    Article  CAS  PubMed  Google Scholar 

  18. Xiong Y, Hla T. S1P control of endothelial integrity. Curr. Top. Microbiol. Immunol. 2014;378:85–105. https://pubmed.ncbi.nlm.nih.gov/24728594/.

  19. Brinkmann V, Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol. 2006;6:244–50.

    Article  CAS  PubMed  Google Scholar 

  20. Jain N, Bhatti MT. Fingolimod-associated macular edema: Incidence, detection, and management. Neurology. 2012;78:672–680. https://pubmed.ncbi.nlm.nih.gov/22371414/.

  21. Anon. Gilenya [package insert], E.H., NJ: Novartis; Pharmaceuticals Corp. 2016.

  22. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.

    Article  CAS  PubMed  Google Scholar 

  23. Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–56.

    Article  CAS  PubMed  Google Scholar 

  24. Peyrin-Biroulet L, Christopher R, Behan D, et al. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev. 2017;16:495–503.

    Article  CAS  PubMed  Google Scholar 

  25. Al-Shamma H, Lehmann-Bruinsma K, Carroll C, et al. The selective sphingosine 1-phosphate receptor modulator etrasimod regulates lymphocyte trafficking and alleviates experimental colitis. J Pharmacol Exp Ther. 2019;369:311–7.

    Article  CAS  PubMed  Google Scholar 

  26. Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15:373–81.

    Article  CAS  PubMed  Google Scholar 

  27. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173:1778–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sandborn WJ, Feagan BG, D’Haens G, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385:1280–91.

    Article  CAS  PubMed  Google Scholar 

  29. Anon. Highlights of prescribing information. Zeposia (ozanimod) capsules. 2020. Jan 9, 2023]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209899s000lbl.pdf.

  30. Buzard DJ, Kim SH, Lopez L, et al. Discovery of APD334: design of a clinical stage functional antagonist of the sphingosine-1-phosphate-1 receptor. ACS Med Chem Lett. 2014;5:1313–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee C, Taylor C, Tang Y, et al. P207 Effects of fluconazole, gemfibrozil, and rifampin on the pharmacokinetics, safety, and tolerability of etrasimod. In: 2022:A142.1-A142

  32. Vermeire S, Chiorean M, Panés J, et al. Long-term safety and efficacy of etrasimod for ulcerative colitis: results from the open-label extension of the OASIS study. J Crohn’s Colitis. 2021;15:950–9.

    Article  Google Scholar 

  33. Higgins JPT, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions. Cochrane Handb Syst Rev Interv. 2019. https://doi.org/10.1002/9781119536604.

    Article  Google Scholar 

  34. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med. 2021;18:e1003583. https://doi.org/10.1371/journal.pmed.1003583.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366. https://www.bmj.com/content/366/bmj.l4898 [Accessed July 16, 2022].

  36. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Guyatt GH, Oxman AD, Kunz R, et al. GRADE: what is “quality of evidence” and why is it important to clinicians? Chinese J. Evidence-Based Med. 2009;9:133–137. https://www.bmj.com/content/336/7651/995.

  38. Anon. Review Manager (RevMan). Version 5.4, The Cochrane Collaboration. 2020.

  39. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.

    Article  CAS  PubMed  Google Scholar 

  40. Sandborn WJ, Van AG, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:253–7.

    Article  Google Scholar 

  41. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699–710.

    Article  CAS  PubMed  Google Scholar 

  42. Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381:1201–14.

    Article  CAS  PubMed  Google Scholar 

  43. Feagan BG, Danese S, Loftus EV, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021;397:2372–84. https://doi.org/10.1016/S0140-6736(21)00666-8.

    Article  CAS  PubMed  Google Scholar 

  44. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399:2113–28.

    Article  CAS  PubMed  Google Scholar 

  45. Juif PE, Kraehenbuehl S, Dingemanse J. Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators. Expert Opin Drug Metab Toxicol. 2016;12:879–95.

    Article  CAS  PubMed  Google Scholar 

  46. Kiyomi K, Caroline L, Lisette A, et al. P045 effect of etrasimod on circulating lymphocyte subsets: data from a randomized phase 1 study in healthy japanese and caucasian men. Am J Gastroenterol. 2020;115:S12.

    Article  PubMed  Google Scholar 

  47. Siegmund B, Melmed GY, Irving PM, et al. P402 Incidence and outcomes of herpes zoster in the ozanimod phase, 3 ulcerative colitis and relapsing multiple sclerosis clinical program. J Crohn’s Colitis. 2022;16:i395–6.

    Article  Google Scholar 

  48. Singh S, Allegretti JR, Siddique SM, et al. AGA technical review on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158:1465-1496.e17.

    Article  CAS  PubMed  Google Scholar 

  49. Agrawal M, Kim ES, Colombel JF. Jak inhibitors safety in ulcerative colitis: Practical implications. J Crohn’s Colitis. 2020;14:S755–60.

    Article  Google Scholar 

  50. Kappos L, Radue E-W, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.

    Article  CAS  PubMed  Google Scholar 

  51. Tran JQ, Hartung JP, Peach RJ, et al. Results from the first-in-human study with ozanimod, a novel, selective sphingosine-1-phosphate receptor modulator. J Clin Pharmacol. 2017;57:988–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vaclavkova A, Chimenti S, Arenberger P, et al. Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2014;384:2036–45.

    Article  CAS  PubMed  Google Scholar 

  53. Cannavo A, Liccardo D, Komici K, et al. Sphingosine kinases and sphingosine 1-phosphate receptors: Signaling and actions in the cardiovascular system. Front Pharmacol. 2017. https://doi.org/10.3389/fphar.2017.00556.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Gergely P, Nuesslein-Hildesheim B, Guerini D, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012;167:1035–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

We received no funding for this study.

Author information

Author notes

  1. Husam Abu Suilik and Fouad Jaber have equal contributions and are co-first authors.

Authors and Affiliations

  1. Faculty of Medicine, Hashemite University, Zarqa, Jordan

    Husam Abu Suilik

  2. Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO, USA

    Fouad Jaber

  3. Faculty of Medicine, Tanta University, Tanta, Egypt

    Mohamed Abuelazm & Mohamed A. Elzeftawy

  4. Faculty of Medicine, South Valley University, Qena, Egypt

    Alaa Ramadan

  5. Faculty of Medicine, Cairo University, Cairo, Egypt

    Amr Elrosasy

  6. Faculty of Medicine, Alexandria University, Alexandria, Egypt

    Rana Ahmed Youssef

  7. West Virginia University, Morgantown, WV, USA

    Basel Abdelazeem

  8. Michigan State University, East Lansing, MI, USA

    Basel Abdelazeem

  9. Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA

    Jana G. Hashash & Francis A. Farraye

  10. Division of Gastroenterology and Hepatology, University of Missouri-Kansas City, Kansas City, MO, USA

    Hassan Ghoz

Authors
  1. Husam Abu Suilik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fouad Jaber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed Abuelazm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alaa Ramadan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohamed A. Elzeftawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amr Elrosasy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rana Ahmed Youssef
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Basel Abdelazeem
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jana G. Hashash
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Francis A. Farraye
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hassan Ghoz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MA conceived the idea. HAS and MA designed the research workflow. BA, HAS and MA searched the databases. AE, MAE, and RAY screened the retrieved records, extracted relevant data, assessed the quality of evidence, and HAS resolved the conflicts. AR performed the analysis. HAS, MA, and FJ wrote the final manuscript. BA, JGH, FAF and HG supervised the project. All authors have read and agreed to the final version of the manuscript.

Corresponding author

Correspondence to Fouad Jaber.

Ethics declarations

Conflict of interest

Francis A. Farraye declares the following: Consulting Fee: AbbVie, Avalo Therapeutics, BMS, Braintree Labs, Fresenius Kabi, GI Reviewers, GSK, IBD Educational Group, Iterative Health, Janssen, Pharmacosmos, Pfizer, Sandoz Immunology, Sebela, Viatris.

DSMB: Lilly, Optimize Study. The other authors declare no conflict of interest.

Ethics approval and consent to participate:

Not applicable.

Consent for publication:

Not applicable.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 331 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suilik, H.A., Jaber, F., Abuelazm, M. et al. Sphingosine 1-phosphate (S1P) receptor modulators as an induction and maintenance therapy for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials. Inflamm. Res. 73, 183–198 (2024). https://doi.org/10.1007/s00011-023-01829-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-023-01829-6

Keywords

Search

Navigation