P0422Type I and II interferon blood signatures correlate with ultrasound markers of intestinal fibrostenosis and predict surgical outcomes in Crohn’s disease

Abstract Background Intestinal fibrostenosis (B2 phenotype) is a frequent complication of Crohn’s disease (CD), often necessitating surgical intervention. Intestinal ultrasound (IUS) is an established, non-invasive tool to assess transmural inflammation and bowel wall thickening and in Germany frequently used to evaluate and monitor fibrostenotic disease. Over the past years, several validated IUS-based scores have been introduced to provide a more objective quantification of disease activity and severity, including the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) and the Simplified Ultrasound Score for Crohn’s Disease (SUS-CD). Despite these advances, no IUS- or blood-based molecular predictors for intestinal fibrostenosis or associated surgery have yet been established. Methods The study was conducted on a cross-sectional cohort of 179 patients with CD recruited between 2010 and 2017 at the University Hospital in Kiel. Detailed clinical phenotypes and five-year follow-up data, including surgical outcomes, were obtained from electronic medical records. In total, IUS data were available for 42 CD patients who will undergo fibrostenosis-related intestinal surgery within 5 years. These were matched for age, sex, and disease activity with IUS data from 42 CD patients without surgery within 5 years. Ultrasound-based scores (IBUS-SAS and SUS-CD) were calculated from collected IUS parameters, including bowel wall thickness (BWT), length of inflammation or stricture, and Doppler signal. Peripheral blood samples were obtained at baseline from all patients and subjected to RNA sequencing. Differential gene expression analysis was performed to identify molecular signatures associated with fibrostenosis or the necessity for stenosis-related surgery within 5 years. Results BWT (p = 0.0002), SUS-CD (p 0.0001), and IBUS-SAS score (p 0.0001) were significantly associated with fibrostenosis-related intestinal surgery within 5 years. Receiver operating characteristic (ROC) analyses demonstrated that the SUS-CD and IBUS-SAS scores showed similar discriminatory performance for surgical outcome (AUROC = 0.81 / 0.83) with an optimal cut-off value of 2.5 and 41.1, respectively. Baseline blood RNA-seq revealed type I and type II interferon signatures strongly correlating with BWT and IUS scores and distinguishing between patients who required stenosis-related surgery within 5 years. However, no clear molecular differences were observed between B1, B2, and B3 Montreal subgroups at baseline. Conclusion IUS-derived scores and BWT are strong predictors of fibrostenosis-related surgery in Crohn’s disease. Baseline transcript modules linked to interferon signalling may further refine risk stratification and warrant prospective validation. Reference: 1. Sævik F, Eriksen R, Eide GE, Gilja OH, Nylund K. Development and validation of a simple ultrasound activity score for Crohn’s disease. J Crohns Colitis. 2021;15(1):115-124. doi:10.1093/ecco-jcc/jjaa112. Conflict of interest: Nasehi, Fatemeh: No conflicts Blömer, Lisa: No conflict of interest Mishra, Neha: none Kimmig, Franziska: No conflicts P. Bernardes, Joana: I have no conflict of interest to declare Bourgery, Matthieu: No conflicts Wolff, Christopher Marco: No conflicts. Hinrichsen, Finn: Received travel support from Pfizer. Holds shares in 10x Genomics Received research material from CatalYm Guggeis, Martina: No conflicts. Nikolaus, Susanna: No conflict of interest Lieb, Wolfgang: No conflict of interest Franke, Andre: I have no conflicts of interest. Aden, Konrad: Personal Fees: Lecture fee: Takeda, Janssen, Lilly, Abbvie Consulting fee: Takeda, Jannsen, Lilly, Guidepoint Schreiber, Stefan Wolfgang: Personal Fees: AbbVie, Alfasigma, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Rosenstiel, Philip: stock ownership Gerion Prof. Dr. Tran, Florian: No conflict of interest