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Objective Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P1 receptor expression on cardiac cells is involved in cardiac conduction. We report cardiovascular treatment-emergent adverse events (TEAEs) associated with S1P receptor modulators and other cardiovascular events in the etrasimod UC clinical programme.Methods Patients were analysed in the Placebo-controlled UC cohort and All UC cohort. Incidence rates (IRs, per 100 patient-years) of cardiovascular-related TEAEs associated with S1P receptor modulators, including bradycardia/atrioventricular (AV) block and hypertension, and other cardiovascular events, including coronary artery disease (CAD) and cerebrovascular disease (CVD), were analysed.Results In patients receiving etrasimod, cardiovascular-related TEAEs were infrequent (≤2.6% per AE). In the Placebo-controlled UC cohort, IRs (95% CIs) for cardiovascular-related TEAEs were higher for patients receiving etrasimod (n=577) vs placebo (n=314), respectively, for bradycardia/sinus bradycardia, 3.85 (1.58 to 6.13) vs 0 and AV block, 1.40 (0.03 to 2.76) vs 0; and numerically higher for hypertension, 5.31 (2.62 to 7.99) vs 3.40 (0.07 to 6.72). Most bradycardia/AV block events were reported on day 1. All bradycardia and hypertension TEAEs were non-serious. One serious second-degree AV block type 1 TEAE occurred in the etrasimod group; no events of second-degree AV block type 2 or higher were reported. One event each of CAD and CVD occurred in two patients receiving etrasimod.Conclusions In the etrasimod UC clinical programme, IRs of cardiovascular-related TEAEs and other cardiovascular events were low. Most cardiovascular-related TEAEs were non-serious.Trial registration numbers NCT02447302; NCT03945188; NCT03996369; NCT02536404; NCT03950232; NCT04176588.

Introduction Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC.Methods and analysis In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score

Objective To infer potential mechanisms driving disease subtypes among patients with inflammatory bowel disease (IBD), we profiled the transcriptome of purified circulating monocytes and CD4 T-cells.Design RNA extracted from purified monocytes and CD4 T-cells derived from the peripheral blood of 125 endoscopically active patients with IBD was sequenced using Illumina HiSeq 4000NGS. We used complementary supervised and unsupervised analytical methods to infer gene expression signatures associated with demographic/clinical features. Expression differences and specificity were validated by comparison with publicly available single cell datasets, tissue-specific expression and meta-analyses. Drug target information, druggability and adverse reaction records were used to prioritise disease subtype-specific therapeutic targets.Results Unsupervised/supervised methods identified significant differences in the expression profiles of CD4 T-cells between patients with ileal Crohn’s disease (CD) and ulcerative colitis (UC). Following a pathway-based classification (Area Under Receiver Operating Characteristic - AUROC=86%) between ileal-CD and UC patients, we identified MAPK and FOXO pathways to be downregulated in UC. Coexpression module/regulatory network analysis using systems-biology approaches revealed mediatory core transcription factors. We independently confirmed that a subset of the disease location-associated signature is characterised by T-cell-specific and location-specific expression. Integration of drug-target information resulted in the discovery of several new (BCL6, GPR183, TNFAIP3) and repurposable drug targets (TUBB2A, PRKCQ) for ileal CD as well as novel targets (NAPEPLD, SLC35A1) for UC.Conclusions Transcriptomic profiling of circulating CD4 T-cells in patients with IBD demonstrated marked molecular differences between the IBD-spectrum extremities (UC and predominantly ileal CD, sandwiching colonic CD), which could help in prioritising particular drug targets for IBD subtypes.