Etrasimod reduces circulating and mucosal inflammatory lymphocyte populations and alters innate immune and non-immune cell signatures in intestinal mucosa: ELEVATE UC phase 3 clinical data

Background and Aims: Innate and adaptive immune cell dysregulation contributes to ulcerative colitis pathogenesis. The sphingosine 1-phosphate receptor modulator etrasimod showed efficacy in ulcerative colitis treatment in Phase 3 ELEVATE UC studies. Changes in circulating immune cells and mucosal cell types were characterized in etrasimod-treated patients with ulcerative colitis. Methods: Blood (etrasimod n = 525, placebo n = 257 patients) and mucosal biopsies (etrasimod n = 411, placebo n = 200 patients) from patients in the ELEVATE UC trials were used to assess cellular and molecular changes for etrasimod versus placebo in clinical remitters and non-remitters using immunophenotyping, transcriptomic and proteomic techniques. Results: Selective and partial reduction in circulating T- and B-cell subsets was observed for etrasimod versus placebo (Week 12), with greater effects on CD4+ T cells, including Treg and Th17 cells, than CD8+ T cells, and on naive T cells and T central memory cells than T effector memory cells, without difference between remitters and non-remitters. No significant effects on monocytes nor NK cell numbers were observed. Mucosal biopsies showed corresponding reductions in T- and B-cell subsets, myeloid cells and neutrophils accompanied by downregulation of interleukin-17 and interleukin-8 signaling in both tissue and blood, most prominently in remitters, where non-immune cell changes were consistent with tissue repair. Conclusions: Etrasimod treatment of patients with ulcerative colitis drives T- and B-lymphocyte subset reductions in blood and intestinal mucosa, neutrophil reductions in tissue and mucosal downregulation of inflammatory pathways associated with ulcerative colitis pathogenesis. Clinical trials registration number: ClinicalTrials.gov (NCT03945188; NCT03996369). © The Author(s) 2026. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.