P509 Biomarkers of neutrophil activity and extracellular matrix turnover predict long-term response to vedolizumab in patients with Crohn’s disease

Abstract

Background Crohn‘s disease (CD) is a form of inflammatory bowel disease characterized by high infiltration of immune cells into the intestinal tissue, resulting in increased proteolytic mediated extracellular matrix (ECM) remodeling. Disease management has improved with the use of biologics such as vedolizumab (VEDO). However, considering the high rate of primary non-response to VEDO, there is an unmet need for predictive serum biomarkers capable of determining response to treatment prior to its initiation. This study investigated whether biomarkers of neutrophil activity, mucosal damage, and ECM remodeling could serve as non-invasive tools for predicting long-term response to VEDO in patients with CD. Methods Serum biomarkers of human neutrophil elastase (HNE)-derived fragment of calprotectin (CPa9-HNE [serum calprotectin]) and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n=32) before VEDO therapy initiation. The ratio C4M/C4G (myeloid/lymphoid mediated degradation) was computed. Long-term response was defined as the continuation of treatment beyond one year after the start of therapy. Baseline biomarker levels were compared between responders and non-responders using Mann-Whitney U-tests, and area under the curve (AUC) values were generated using receiver operating characteristics (ROC) statistics. Biomarker levels were divided into tertiles and chi-square tests were used to investigate the relationship between tertiles and response proportions. Results Biomarkers CPa9-HNE, C1M, C3M, C4M, PRO-C3, C3M/PRO-C3, and C4M/C4G were significantly increased at baseline in non-responders compared with responders (all P<0.05). All markers were able to predict response to VEDO at baseline (AUC [95% CI]: CPa9-HNE 0.81 [0.66–0.96]; C1M 0.85 [0.75–0.98]; C3M 0.79 [0.62–0.95]; C4M 0.77 [0.6–0.93]; C3M/PRO-C3 0.78 [0.6–0.95]; C4M/C4G 0.74 [0.56–0.92] all P<0.05). Proportions of long-term VEDO users were highest in the first tertiles for all the markers (73–91%) and decreased in a concentration-dependent manner across the second and third tertiles, indicating that patients with the lowest concentrations of these markers less frequently discontinued treatment at one year after initiation (Figure 1). Conclusion Baseline levels of serum biomarkers for neutrophil activity (CPa9-HNE [serum calprotectin]) and mucosal damage (C1M, C3M, C4M, C4G, PRO-C4, and PRO-C3) could predict long-term response to VEDO in patients with CD. Therefore, these biomarkers could aid in early decision making concerning treatment with vedolizumab in patients with CD.

Pursuing neutrophils: systematic scoping review on blood-based biomarkers as predictors of treatment outcomes in inflammatory bowel disease

“…The 34 selected records explored 17 different biomarkers (Figure 1), including 9 molecules from the granules 21–34 ; 2 found in the cytoplasm, 27,35–39 2 in the plasmatic membrane, 31,32,40–48 and 4 only formed in the plasma. 25,32,43,46,49–54 The most mentioned biomarker was nCD64 (index or ratio; 7 times), 31,40–45 followed by calprotectin (5 times) 27,35–38 and oncostatin M (OSM), 31–34 neutrophil elastase (HNE)-generated calprotectin (S100a9) fragment (CPa9-HNE), 49–52 and triggering receptor expressed on myeloid cells 1 (TREM1) 32,46…”

“…In all, 18 studies included only CD patients, 27,29–31,34,35,40,41,43–49,51–53 5 just UC patients, 21,24,25,36,54 and 11 covered both UC and CD. 22,23,26,28,32,33,37–39,42,50 In these, unless otherwise described, results were assumed to apply to both UC and CD.…”

“…Of the 34 selected studies, 19 had key endpoints based on disease activity, 21–23,26–29,31,35,38,39,41,43–45,48–50,52 8 on endoscopic response/mucosal healing, 25,32,34,38,46,50,53,54 8 on treatment-related endpoints, 29,33,37,40,42,43,45,51 7 on clinical manifestations and/or complications, 24,29,30,33,36,47,26 and 3 on biochemical response (all FC-based definitions). 31,41,42…”

“…In total, 19 studies focused exclusively on patients taking infliximab (IFX) and/or adalimumab (ADA), 22,23,25,27,30,31,34,35,39–41,43,45–47,49,52–54 and only five did not include anti-TNFα treatments. 21,37,42,50,51…”

“…49 In 32 CD patients on vedolizumab, higher baseline levels were observed in non-responders compared with responders ( p = 0.003); CPa9-HNE predicted response at baseline with an AUC (95% CI) of 0.81 (0.66–0.96). 51 Serum CPa9-HNE of 88 UC and 120 CD patients treated with eldelumab (anti-interferon-gamma-inducible protein-10 antibody) was analyzed in two double-blind, randomized, placebo-controlled trials. CD patients achieving endoscopic remission had lower baseline values, even though results did not translate to UC patients nor predicted clinical remission.…”