Extracellular matrix remodeling proteins as biomarkers for clinical assessment and treatment outcomes in eosinophilic esophagitis

Abstract

Background: Eosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted. Aims: To investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients. Methods: Protein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention. Results: Patients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p < 0.01), whereas low CTX-III levels were observed in patients achieving histological remission (< 15 eos/hpf) (vs. no histological remission (p < 0.05). Progression of endoscopic fibrosis after intervention was associated with increased levels of type-III (PRO-C3) and -VI collagen (PRO-C6) formation (all; p < 0.05). A baseline EREFS inflammatory subscore ≥ 2 correlated with higher neutrophilic activity (Cpa9-HNE) at week 6 (p < 0.05). Moreover, increased degradation of type-III (C3M) and -IV (C4M/PRO-C4) collagens were associated with remission of food impaction after intervention (all; p < 0.05). Conclusion: Serum extracellular matrix remodeling proteins demonstrated potential as surrogate biomarkers for assessing histological disease remission, endoscopic fibrosis, and remission of symptoms of food impaction after diet intervention in adult EoE patients.