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Introduction Frontline management of acute severe ulcerative colitis (ASUC) has changed little over the past two decades and continues to represent a medical emergency. Nearly half of patients fail to respond adequately to intravenous corticosteroids, and approximately 15% ultimately require colectomy during the acute flare. The systemic immune landscape underlying ASUC, particularly in relation to steroid responsiveness, has not been comprehensively defined. We performed longitudinal, multi-omic profiling of peripheral blood from patients with ASUC to delineate immune signatures associated with corticosteroid response and treatment resistance.Methods Peripheral blood samples were collected from 24 patients meeting Truelove & Witts’ criteria for ASUC, along with active UC controls matched for endoscopic severity (n=4) and patients with infectious Campylobacter colitis (n=3). Multi-omic analyses included single-cell RNA-seq/CITE-seq, bulk RNA-seq, ALAMAR NULISA proteomics, and ex vivo functional assays. All ASUC patients were managed according to standard Oxford criteria. Samples were obtained prior to corticosteroid initiation (day 1) and early after treatment (day 3), enabling both cross-sectional and dynamic assessments. Changes in cell-type composition and pathway activation were analysed to identify inflammatory programs associated with ASUC and with steroid response.Results Principal component analysis revealed that myeloid cells accounted for the greatest transcriptional variability in ASUC, exhibiting substantial reprogramming both from baseline to post-steroid timepoints and compared with disease controls (adjusted p = 3.0 × 10 -7) (figure 1a-c). Among the pathways upregulated in ASUC, IL-6/JAK/STAT3 signalling was the most prominently enriched in myeloid populations relative to active UC controls (FDR q < 0.01), and—unlike other inflammatory pathways—remained enriched despite corticosteroid therapy (figure 1d). Ex vivo stimulation studies demonstrated that IL6–JAK1 signalling in primary monocytes was relatively insensitive to hydrocortisone but could be suppressed by JAK1 inhibition, while TNF-driven pathways showed greater steroid responsiveness. In the three patients who ultimately required colectomy due to medical treatment failure, this JAK1-responsive myeloid signature increased from day 1 to day 3, suggesting progressive, steroid-resistant activation.Conclusions Longitudinal multi-omic analysis uncovers a myeloid-driven inflammatory program in ASUC that is relatively refractory to corticosteroid therapy, but responsive to JAK1 blockade. These findings provide mechanistic support for early or combination use of upadacitinib alongside corticosteroids in ASUC and strengthen the rationale for JAK1-targeted therapy in this high-risk population.Abstract P222 Figure 1Systemic myeloid transcriptional reprogramming in ASUC and persistence of IL-6/JAK/STAT3 signalling after corticosteroid therapy