Abstract Background Ulcerative colitis (UC) is a chronic relapsing inflammatory disorder affecting the colon. A hallmark of UC is increased immune cell activity and dysregulated extracellular matrix (ECM) remodelling, particularly of the mucosal collagens type III and IV, leading to mucosal damage. Anti-TNF agents have significantly improved the management of UC–still, up to 40% of patients experience treatment failure, with the anti-α4β7 integrin agent vedolizumab (VDZ) being frequently initiated following anti-TNF failure. As the probability of sucecess declines with each line of treatment, there is an unmet need for biomarkers enabling early assessment of treatment success. We investigated whether biomarkers of neutrophil activity, type III, and IV collagen remodelling could serve as early indicators of VDZ failure in anti-TNF experienced patients with UC. Methods The cohort included 71 anti-TNF-experienced patients with UC switching to VDZ as second mode of pharmacological action. Serum was drawn at baseline, weeks 2, 6, 10, 14, and 52–or until VDZ discontinuation. Biomarkers of cross-linked type III collagen release (CTX-III), collagen type III and IV degradation (C3M, C4M), inflammatory associated fibroblast (IAF)-mediated degradation of type III collagen (C3F), and neutrophil activity (CPa9-HNE) were measured in serum for all timepoints. VDZ failure 1 year (due to non-response, loss of response, adverse events, or absence of clinical remission at 1 year) was the study outcome. Mann-Whitney tests and receiver operating characteristic (ROC) statistics with area under the curve (AUC) were applied. Results CTX-III was significantly elevated at weeks 2 and 6 in patients who did not fail VDZ (fig. 1A), with superior discriminative ability at week 2 (AUC 95%: 0.84 0.68–0.94). At weeks 6, 10, and 52, C3F was significantly higher in patients who failed VDZ than those without treatment failure (fig. 1B) with superior discriminative ability at week 10 (AUC 95%: 0.82 0.65–0.93). C3M and C4M were significantly elevated in patients who failed VDZ at week 52 (fig. 1C&D) (AUC 95%: 0.70 0.58 to 0.81 & 0.72 0.60 to 0.82). CPa9-HNE was significantly elevated at week 52 among patients failing VDZ (fig. 1E). Conclusion Early increase in CTX-III, reflecting resolution of fibrosis, was associated with the absence of VDZ failure. Conversely, increased neutrophil activity (CPa9-HNE), IAF-mediated collagen type III degradation (C3F) and mucosal damage (C3M, C4M) associated with the failure of VZD. Our findings support biomarkers reflecting neutrophil activity and inflammatory events in the mucosa as promising tools for early and dynamic assessment of later VDZ treatment outcomes in anti-TNF experienced patients with UC. Conflict of interest: Dr. Sorokina Alexdóttir, Marta: Employee at Nordic Bioscience Frimor, Camilla: Tsapanou Katranara, Thomai: Industrial PhD at Nordic Bioscience Satriano, Letizia: Employee of Nordic Bioscience Ainsworth, Mark Andrew: No conflict of interest Steenholdt, Casper: Lectures for Takeda, MSD and Janssen-Cilag research grant from Takeda. Mortensen, Joachim: Fulltime employee and shareholder at Nordic Bioscience
Alexdóttir et al. (Thu,) studied this question.