DOP065Circulating inflammatory proteins as prognostic biomarkers for disease progression in Inflammatory Bowel Disease

Abstract Background Biological mechanisms driving disease progression in patients with inflammatory bowel disease (IBD) are incompletely understood. While proteomic studies in IBD have largely focused on disease determinants and changes at pre- and post-diagnostic stages, identification of biomarkers for disease progression is lagging behind. Here, we aimed to investigate relationships between circulating plasma proteins and disease progression risk in patients with IBD. Methods Eighty-three inflammation-related plasma proteins were measured in a large established IBD cohort consisting of 996 patients using proximity extension assay technology (Olink Inflammation panel). Disease progression was defined as the requirement for IBD-related surgical intervention, or, in patients with Crohn’s disease (CD), new or progressive stenosis. Cox proportional hazards regression, with multiple testing correction using the Benjamini-Hochberg method, was used to investigate associations between plasma proteins and risk of disease progression. Analyses were repeated across different subgroups based on disease activity and disease location. In patients with CD, analyses were also performed separately for development of intestinal stenosis and CD-related surgery. Differences in disease progression-free survival were evaluated using Kaplan-Meier estimates and log-rank tests. Results In total, 558 patients with CD and 438 with ulcerative colitis (UC) were included. During a median follow-up of 9.5 years (IQR: 7–12.3), 188 patients with CD (33.7%) and 47 patients with UC (10.7%) experienced disease progression. On multivariable analysis, 21 proteins were significantly associated with disease progression in CD (FDR0.1), and 10 proteins in UC. The four proteins most strongly associated with disease progression in CD were Delta and Notch-like epidermal growth factor-related receptor (HR per doubling 0.38, 95%CI 0.25–0.57, FDR 0.05), interferon gamma (HR1.23, 95%CI 1.07–1.41, FDR0.05), interleukin-17 A (HR1.45, 95%CI 1.21–1.73, FDR0.05) and macrophage colony stimulating factor 1 (HR3.01, 95%CI 1.75–5.15, FDR0.05) (Fig. 1). In UC, these were C-X-C motif chemokine ligand 9 (HR1.52, 95%CI 1.21–1.91, FDR 0.05), C-X-C motif chemokine ligand 11 (HR1.47, 95%CI 1.19–1.82, FDR0.05), interleukin-8 (HR1.32, 95%CI 1.12–1.56, FDR 0.05) and interleukin-10 (HR1.26, 95%CI 1.09–1.46, FDR0.05) (Fig. 1). These signals were consistently observed across different subgroups (Fig. 2). Conclusion This study demonstrates distinct shifts in circulating proteins in patients who later experience disease progression in both CD and UC. This study highlights the potential of inflammatory proteins as prognostic biomarkers for future disease progression risk in IBD. Conflict of interest: Veenstra, Fokkelien: No conflict of interest Al Radi, Zainab M.: No conflict of interest Geertsema, Sem: No conflict of interest Hu, Shixian: No conflict of interest Visschedijk, Marijn: No conflict of interest Faber, Klaas-Nico: No conflict of interest Dijkstra, Gerard: Grant: Royal DSM Personal Fees: Consultancy fee from Astra-Zeneca and Speakers fee from Abbvie Festen, Eleonora: No conflict of interest Weersma, Rinse K: R.K.W. acted as consultant for Takeda Pharmaceuticals received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring and received speaker’s fees from MSD, Abbvie and Janssen Pharmaceuticals. Spekhorst, Lieke: No conflict of interest Bourgonje, Arno R.: A.R.B. received speaker’s fees from AbbVie and Ferring, outside the submitted work.