Abstract Background Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract, characterized by excessive extracellular matrix (ECM) remodeling that leads to fibrosis and stricture formation. Strictures are primarily detected using imaging techniques, such as computed tomography and magnetic resonance imaging. However, no validated biomarkers are currently available to assess the presence of strictures. The discovery of such biomarkers would improve early diagnosis and facilitate more effective patient management using anti-fibrotic and anti-inflammatory treatments. In the current study, we aimed to investigate the association of biomarkers reflecting ECM remodeling, fibroblast activity, and neutrophil activity with CD phenotypes. Methods The cohort included 41 controls (CTR) without a family history of CD or resections, and 129 CD patients divided into four phenotypes: stricture (S) (n = 41), inflammation no stricture (I) (n = 32), no active inflammation no stricture (NI) (n = 46), and stricture with penetrating disease (S/IP) (n = 10). Serum markers of collagen type VI formation (PRO-C6), type III and type VII degradation (C3M, C7M), and a human neutrophil elastase-derived fragment of calprotectin (CPa9-HNE) were measured using ELISA. Patients were grouped based on phenotypes, and biomarkers were evaluated by one-way ANOVA, correcting for multiple comparisons using Dunn’s test. For two-group comparisons, Mann-Whitney test was applied. Correlations were assessed with the Spearman method. The global stricture score includes both inflammatory and non-inflammatory components. Results C3M, CPa9-HNE, and PRO-C6 showed moderate to significant elevation in CD compared to CTR (C3M: p=0.01; CPa9-HNE: p=0.05; PRO-C6: p=0.07). In patients with CD, PRO-C6 was higher in stricturing than in non-inflamed CD (p=0.04), and CPa9-HNE, C7M, and C3M/PRO-C3 were higher in stricture with penetrating CD than in non-inflamed CD (CPa9-HNE: p =0.02, C7M: p =0.02, C3M/PRO-C3: p =0.009) (Fig. 1A). Levels of CPa9-HNE, C3M, and C7M positively correlated with global stricture severity score, and along with PRO-C6, differed moderately to significantly between the upper and lower quartiles of this score (CPa9-HNE: p=0.03, C3M: p=0.03, C7M: p=0.001, PRO-C6: p =0.06) (Fig. 1B). Conclusion The fibrosis marker (PRO-C6) was associated with stenosis and was elevated in CD patients with high levels of global stricture scores. Markers of mucosal damage (C7M, C3M/PROC3) and inflammation (CPa9-HNE) were associated with patients with stenosis and penetrating disease and showed a positive association with the global stricture score. These data suggest that markers of ECM remodeling could be valuable tools for assessing fibrostenosis in patients with CD. Conflict of interest: Dr. Satriano, Letizia: Full time employee at Nordic Bioscience Auffret, Lucie: Internal CCF grant (Digestive Disease Institute Chief Innovation Award) Sorokina Alexdóttir, Marta: Full time employee at Nordic Bioscience Tsapanou Katranara, Thomai: Industrial PhD at Nordic Bioscience Larsen, Catherine: No conflict of interest Razmjouei, Soha: No conflict of interest Gauriloff, Samantha: No conflict of interest Bay-Jensen, Anne-Christine: Full time employee and stakeholder at Nordic Bioscience A. Karsdal, Morten: Full time employee and stakeholder at Nordic Bioscience Mortensen, Joachim: Full time employee and shareholder at Nordic Bioscience Rieder, Florian: Personal Fees: Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, 89Bio
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