Abstract Background Acute severe ulcerative colitis (ASUC) remains a medical emergency with limited therapeutic progress over the past two decades. Up to half of patients fail to respond to intravenous corticosteroids, and about 15% require colectomy during the acute episode. The systemic immune response in ASUC has not previously been characterised in detail. We performed longitudinal, multi-omic profiling of peripheral blood in ASUC to define immune signatures associated with steroid responsiveness and therapeutic resistance. Methods Peripheral blood from 24 patients with ASUC defined by Truelove 0.01), and persisted after corticosteroid therapy, whereas other inflammatory pathways were suppressed (Fig 2d). Ex vivo stimulation of primary monocytes confirmed that IL6-JAK1 signalling was relatively resistant to hydrocortisone but suppressed by JAK1 inhibition, whereas TNF inhibition remained steroid-sensitive. In 3 patients who required colectomy within 3 months due to treatment non-response, this myeloid JAK-1 responsive signature increased between day 1 and day 3, suggesting progressive steroid-resistant activation. Conclusion Longitudinal multi-omic profiling identifies a myeloid-driven inflammatory program in ASUC that is incompletely suppressed by corticosteroids, but responsive to JAK1 inhibition. These findings support early or adjunctive use of upadacitinib alongside corticosteroids in ASUC and provide a mechanistic rationale for JAK-1 targeted therapy in ASUC. References: 1.Adams A, Gupta V, Mohsen W, et al. Early management of acute severe ulcerative colitis in the biologics era: development and international validation of a prognostic clinical index to predict steroid response. Gut. 2023;72(3):433-442. Conflict of interest: Pakpoor, Julia: No conflicts of interest Dooley, Kyla: No conflicts Agarwal, Devika: No conflict of interest Pledger, Sam: No conflict of interest Fergusson, Joannah: None Cripps, Sarah: Consultancy fees: Abbvie, Advanz, Dr Falk, Galapagos, Pfizer, Lilly, SALTs healthcare, Sandoz, Takeda Sponsorship: Abbvie, BMS, Celltrion, Gilead, Lilly, Tillots Coles, Mark: Co-founder and shareholder in Mestag Therapeutics Satsangi, Jack: Grants to University of Oxford from Helmsley Trust and personal travel support from Janssen and Takeda Klenerman, Paul: No conflict of interest Powrie, Fiona: Receives consultancy fees or research support from Johnson and Johnson, AstraZeneca, and Genentech. Uhlig, Holm: Research support or consultancy fees from J&J, Eli Lilly, Bristol Myers Squibb BMS. No stocks or share options. Walsh, Alissa: Grant: Alfasigma, Helmsley Trust, Johnson & Johnson, Pfizer, Takeda Personal Fees: AbbVie, Alfasigma, Bristol Meyers Squibb, Dr Falk, Ferring, Johnson & Johnson, Lilly, Pfizer, Takeda, Tillotts Brain, Oliver: Speaker and Advisory Board Fees from AbbVie, Janssen-Cilag, Galapagos, BMS, Takeda, Pfizer Friedrich, Matthias: Received speaker and/or consultancy fees from EliLilly, Quell Therapeutics, Ono Pharma, Foghorn and received research funding from EliLilly. Dendrou, Calliope: No conflicts of interest Travis, Simon: Research Support: AbbVie, Celgene, Celsius, ECCO, Galapagos, GSK, Helmsley Trust, IOIBD, Janssen, Lilly, Pfizer, Takeda, UKIERI, 35Bio, Vifor, and Norman Collisson Foundation Consulting Fees: Alimentiv Apexian Apollo Arcturis AstraZeneca BMS Clario Cosmo Dova Health Endpoint Health EQrX Equillium Ferring Galapagos Genentech/Roche Gilead GSK Janssen Iterative Health Lilly Mestag Microbiotica ONO Pfizer Phesi Protagonist Sanofi Satisfai Sensyne Health Spyre Takeda Teva Theravance Tr1X Bio Speaker fees: BMS, Ferring, GSK, Janssen, Lilly, Pfizer, Sun Pharma, Takeda. Share options: Dova Health Inc Buckley, Christopher: Consultancy (Paid): GSK, AbbVie, Takeda, CICOR Roche, Janssen Innovative Medicines. Quell Therapeutics Investigator Initiated Grants (funds to University of Oxford) GSK, Janssen Innovative medicines Scientific Advisory Boards (pro bono): DRFZ Berlin, VIB Center for Inflammation Research Chair of Projects committee (pro bono) British Heart Foundation Co Editor in chief (paid) Arthritis Research and Therapy Founding shares: Mestag Therapeutics
Pakpoor et al. (Thu,) studied this question.