Abstract Background There is a significant clinical need for tools to guide therapeutic sequencing in patients with Crohn’s disease (CD). This study aimed to address this gap by evaluating whether specific biomarkers reflecting extracellular matrix (ECM) remodelling, neutrophil activity and macrophage activity can accurately predict short- and long-term treatment responses to vedolizumab (VDZ) following anti-TNF treatment failure. Methods Serum samples were obtained from a single-centre cohort of CD patients treated sequentially with anti-TNF and VDZ. Serum was collected at anti-TNF failure (n = 29) and at VDZ initiation (n = 30), within 30 days before treatment start. VDZ treatment outcomes were assessed at 3 and 12 months based on clinical remission (CR) (HBI 5), clinical response (reduction in HBI ³2) and objective remission (OR) (SES-CD ≤2 (n = 15), faecal calprotectin 200mg/g (n = 8), or absence of inflammatory activity on imaging(n = 3)). All samples were analysed for ECM biomarkers, including degradation markers (C3M, C4M, C3F, CPa9-HNE, CTX-III, and C4G) and formation markers (PRO-C3, PRO-C6, and PRO-C22). These biomarkers collectively reflect turnover of collagen types III, IV, VI, and XXII, as well as neutrophil and inflammatory fibroblast activity. Data were analysed using non-parametric statistics. Results At VDZ baseline, several biomarker profiles predicted treatment outcomes. 12-month CR was associated with low C3F (AUCROC 0.78 0.60-0.95, p = 0.01) (fig.1) and with a composite profile of high CTX-III and PRO-C3 combined with low C3M and C3F (AUCROC=0.89 0.75-1.00 p = 0.002) (fig.2). The 3-month response was associated with high CPa9-HNE (AUCROC=0.74 0.56-0.92 p = 0.018), and CPa9-HNE combined with high PRO-C3 (AUCROC =0.76 0.58-0.94 p = 0.019). Finally, 3-month remission was associated with low PRO-C6 (AUCROC =0.75 0.47-1.00 p = 0.047) and high C3M (AUCROC=0.79 0.58-1.00 p = 0.017), with discriminative ability further improved combining both with high CPa9-HNE (AUCROC=0.85 0.62-1.00 p = 0.02). OR was not associated with biomarker levels, either at baseline or at anti-TNF failure. Biomarker levels at the time of anti-TNF failure were not associated with outcomes after 3-months. However, 12-month CR was associated with low CPa9-HNE (AUCROC=0.82 0.65-0.98 p = 0.003), with discriminative power improved by adding low C3F (AUCROC=0.87 0.70-1.00, p = 0.003). Conclusion Remission after 12 months of VDZ treatment is associated with increased resolution of fibrosis and reduced neutrophil activity, inflammatory fibroblast-mediated collagen degradation, fibroblast activation, and mucosal damage. This calls for confirmatory studies on the clinical utility of ECM biomarkers in the choice of treatment sequencing to VDZ. Conflict of interest: Mrs. Frimor, Camilla: No conflict of interest Sorokina Alexdóttir, Marta: Full-time employee at Nordic Bioscience. Tsapanou Katranara, Thomai: Full-time employee at Nordic Bioscience. Satriano, Letizia: lesa@nordicbio.com Ainsworth, Mark Andrew: Other: None Mortensen, Joachim: Full time employee and shareholder at Nordic Bioscience. Steenholdt, Casper: No conflict of interest
Frimor et al. (Thu,) studied this question.