P301 Distinct plasma proteomic biomarkers associate with disease progression in patients with Inflammatory Bowel Diseases

Abstract

Abstract Background Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are characterized by complex pathophysiology, phenotypic heterogeneity and disease progression. Patients with IBD show distinct shifts in circulating inflammatory proteins, which may be suggestive of biological mechanisms behind clinical disease progression. Thus far, proteomics studies in IBD have primarily focused on changes in the plasma proteome at pre- and post-diagnostic stages, as well as its genetic and phenotypic determinants. However, studies focusing on proteomic biomarkers for predicting the risk of disease progression are lacking. Here we aimed to identify plasma proteomic biomarkers associated with disease progression in patients with IBD. Methods In this study, a total of 83 inflammation-related plasma proteins were quantified in a cohort of 452 patients with IBD (267 with CD, 185 with UC) who participated in the 1000IBD project and had available follow-up data. Proximity extension assay technology was leveraged to measure these proteins. Disease progression outcomes, including the development of intestinal stenosis, IBD-related surgical interventions, and extraintestinal manifestations (EIMs), were extracted from electronic health records. Logistic regression analyses and Cox proportional hazards regression models were used to investigate associations between plasma proteins and the risk of disease progression outcomes. Results During a median follow-up of 10.3 (interquartile range [IQR] 7.6-11.1) years, 63 (23.6%) patients with CD developed intestinal stenosis, 53 (19.9%) patients with CD and 14 (7.6%) patients with UC underwent IBD-related surgery, and 120 (44.9%) patients with CD and 45 (24.3%) patients with UC developed EIMs. On multivariable analysis, macrophage colony-stimulating factor-1 (CSF-1) was most strongly associated with the presence of stricturing disease (Montreal B2 phenotype) (odds ratio [OR] per doubling in protein level 4.5, 95%CI: 1.6-12.9, P=0.005) and with a shorter stenosis-free survival (hazard ratio [HR] per doubling 4.2, 95%CI: 1.5-11.6, P=0.006). Furthermore, interferon-gamma (IFN-γ) was most strongly associated with surgery in CD (OR per doubling 1.6, 95%CI: 1.2-2.2, P=0.003) and with shorter surgery-free survival in CD (HR per doubling 1.4, 95%CI: 1.2-1.7, P<0.001) in multivariable analysis. Conclusion This study highlights that disease progression in IBD is associated with elevated levels of specific inflammatory plasma proteins. Specifically, CSF-1 and IFN-γ show most promise as possible proteomic biomarkers for the future development of intestinal stenosis and the risk of surgical interventions in patients with CD, respectively.