Abstract Background Filgotinib, a Janus Kinase (JAK)-1-preferential inhibitor, provides rapid symptom relief in ulcerative colitis (UC)1, but its effects on the inflammatory proteome are incompletely defined. We profiled proteomic trajectories in an observational cohort of 39 patients with moderate-to-severe UC initiating filgotinib. Methods We quantified serum cytokines and chemokines at baseline and follow-up with Multiplex Luminex, and assessed Mayo score, C-reactive protein (CRP), and fecal calprotectin. Healthy controls (HC) provided reference ranges. Corticosteroid-free response at week 24, defined by improvement in the clinical Mayo score relative to baseline, was evaluated. For responders, follow-up was at week 24, for non-responders, therapy failure determined the follow-up timing. Analyses assessed within-patient change and concordance between clinical, biochemical and proteomic relative to HC. Results Responders (n = 23) showed improvement in the total Mayo score, CRP and calprotectin. Several inflammatory mediators demonstrated longitudinal changes that correlated with clinical and biochemical improvement, indicating partial concordance between proteomic and clinical trajectories. However, several inflammatory mediators, including soluble receptors (TNFR1/2), chemokines (MCP1 (exemplified in figure), CCL18), cytokines (IL-18), and lectins (Galectin-1, Galectin-3), remained elevated despite clinical improvement. Non-responders (n = 16) exhibited similar analyte profile trajectories, despite absent clinical benefit. Persistently elevated mediators spanned multiple molecular classes, suggesting a broader residual inflammatory program rather than isolated pathway escape. This clinical–proteomic discordance implies that JAK1 inhibition may uncouple symptom and acute-phase readouts from persistent immune activation, potentially reflecting pathway redundancy, incomplete upstream driver coverage, or tissue-compartmentalized inflammation not captured by standard biomarkers. Conclusion Our findings indicate that while filgotinib improves clinical and biochemical endpoints, elements of the inflammatory proteome remain sustained relative to HC and appear only partially aligned with clinical, endoscopic and traditional biochemical responder status. These data should be corroborated using tissue-resolved endpoints in the inflamed mucosa, alongside peripheral immunophenotyping to map compartment-specific effects. If validated, proteomic readouts could refine treat-to-target strategies beyond CRP and fecal calprotectin, and clarify whether JAK1 inhibition primarily suppresses symptom-generating downstream signalling or achieves deeper resolution of mucosal immune activity. Reference: 1. 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. The Lancet. 2021;397(10292):2372-2384. doi:10.1016/S0140-6736(21)00666-8 Conflict of interest: Mr. Louwers, Jonas: This research was supported by an unrestricted grant from Galapagos and Alfasigma S.p.A. Veltkamp, Suzanne H C: No conflict of interest Voorneveld, Philip: No conflict of interest Duijvestein, Marjolijn: Grant: Speaking fees from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, Dr. Falk, Advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda Grant/Research support: Pfizer, Bristol Meyers Squibb, Galapagos, Alfasigma, Janssen, Lilly Van der Meulen - de Jong, Andrea Elisabeth: Andrea van der Meulen has received independent research funding from Nestle, Norgine, Cablon, Galapagos and has served on advisory boards for Tramedico, Janssen, Takeda, Galapagos, Vedanta, Ferring, Abbvie and Dear Health. Nanne de Boer has served as a speaker for AbbVie and MSD and has served as a consultant and principal investigator for TEVA Pharma BV and Takeda. He has received a research grant (unrestricted) from Dr. Falk, EVA Pharma BV, Dutch Digestive Foundation (MLDS) and Takeda. van Wijk, Femke: Femke van Wijk is a speaker and/or consultant for Janssen, Johnson & Johnson and Takeda. She has received research funding from LEO Pharma, Takeda, Galapagos/Alfasigma S.p.A, Sanofi and Bristol-Myers Squibb, all unrelated to this research. Oldenburg, Bas: Unrestricted grants: Abbvie, Takeda, Pfizer, Galapagos, AlphaSigma. Advisory boards: Abbvie, Takeda, Pfizer, Lilly, Galapagos, Janssen
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