Abstract
BackgroundReliable identification and quantitation of intestinal fibrosis in the setting of co-existing inflammation due to Crohn’s disease (CD) is difficult. We aimed to identify serum biomarkers which distinguish inflammatory from fibrostenotic phenotypes of CD using serum glycoproteome profiles.MethodsSubjects with fibrostenotic and inflammation-predominant CD phenotypes (n = 20 per group) underwent comparison by quantitative serum glycoproteome profiles as part of a single tertiary care center cohort study. Following lectin elution, glycoproteins underwent liquid chromatography followed by tandem mass spectrometry. Identified candidate biomarkers of fibrosis were also measured by serum ELISA, a widely available technique.ResultsFive (5) glycoproteins demonstrated a ≥20% relative abundance change in ≥80% of subjects, including cartilage oligomeric matrix protein (COMP) and hepatocyte growth factor activator (HGFA). COMP (431.7±112.7 vs. 348.7±90.5 ng/mL, p = 0.012) and HGFA (152.7±66.5 vs. 107.1±38.7 ng/mL, p = 0.031) serum levels were elevated in the fibrostenotic vs. inflammatory CD groups using ELISA. Within the fibrostenotic group, intra-individual changes of candidate biomarkers revealed HGFA levels significantly declined following the resection of all diseased intestine (152.7±66.5 vs. 107.1±38.7 ng/mL, p = 0.015); COMP levels were unchanged. Immunohistochemical staining confirmed the presence of COMP in the submucosa and muscularis of resected fibrostenotic tissue.ConclusionsIn this biomarker discovery study, several serum glycoproteins, specifically COMP and HGFA, differ between between predominately inflammatory and fibrostenotic CD phenotypes. The development of blood-based biomarkers of fibrosis would provide an important complement to existing prognostic tools in IBD, aiding decisions on therapeutic intensity and mechanism selection, surgery, and the monitoring of future anti-fibrotic therapies for CD.
Highlights
Crohn’s disease (CD), an idiopathic inflammatory bowel disease, has a range of phenotypes resulting from the variation in the amount of accumulated bowel damage
Intra-individual changes of candidate biomarkers revealed hepatocyte growth factor activator (HGFA) levels significantly declined following the resection of all diseased intestine (152.7±66.5 vs. 107.1±38.7 ng/mL, p = 0.015); cartilage oligomeric matrix protein (COMP) levels were unchanged
Development of blood-based biomarkers of fibrosis would provide an important complement to existing prognostic tools in IBD, aiding decisions on therapeutic intensity and mechanism selection, surgery, and the monitoring of future anti-fibrotic therapies for CD
Summary
Crohn’s disease (CD), an idiopathic inflammatory bowel disease, has a range of phenotypes resulting from the variation in the amount of accumulated bowel damage. Inflammatory and fibrotic changes together contribute to progressive bowel wall thickening, stricture development, and subsequent obstructing and penetrating complications. Fibrostenotic CD complications are major mediators of disease morbidity with 60% of patients requiring surgery within 10 years of diagnosis. Escalation of therapeutic intensity and early use of biologics are associated with improved objective inflammatory disease control and reduction (or delay) of surgery and hospitalization [3,4]. Common management questions rely on estimations of the present and future contribution of intestinal fibrosis to overall CD-related bowel damage: Will therapeutic intensification durably avoid surgery? Is the existing therapeutic regimen sufficient to avoid fibrostenotic complications? These points highlight the need for methods to objectively measure the presence and ongoing accumulation of intestinal fibrosis and to quantify the relative contribution of inflammatory and fibrotic disease. We aimed to identify serum biomarkers which distinguish inflammatory from fibrostenotic phenotypes of CD using serum glycoproteome profiles
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