Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review

Abstract

Background and aims: Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures.

Methods: We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal).

Results: Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties.

Conclusions: There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.

Keywords: Biomarker; Crohn’s Disease; Fibrosis; Fibrostenosis; IBD; Inflammatory Bowel Disease; Stenosis; Stricture.

Figure 1.

Key markers associated with or predictive of Crohn’s disease associated strictures. Abbreviations: ASCA = anti-saccharomyces cerevisiae antibody; Anti-GP2 = anti-zymogen granule glycoprotein 2; anti flagellin (A4-Fla2, and anti Fla-X, anti-CBir1); anti-I2 = anti-CD-associated bacterial sequence; anti-OmpC = anti-Escherichia coli outer membrane porin C; LL-37 = human cathelicidin; MBL = mannan binding lectin; Pro-C3 = pro-collagen 3, C3M = matrix metallopeptidase degradation product of collagen 3; COMP = cartilage oligomeric matrix protein; HGFA = and hepatocyte growth factor activator; IL12B = interleukin 12B; TNFSF 15 = tumor necrosis factor ligand superfamily member 15; aPCR (factor V Leiden) = activated protein C resistance; IL10 = interleukin 10; WWOX = WW domain containing oxidoreductase; TAK1 = TGFβ-activated kinase; OGR1 = pH-sensing ovarian cancer G-protein coupled receptor 1; CH25H = cholesterol 25-hydroxylase; TNF = tumor necrosis factor; IL6 = interleukin 6.

Figure 2:

Suggested study design for the clinical scenarios of future investigation of biomarkers of intestinal stricture in CD.