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Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease

Wu, Jing PhD1; Lubman, David M. PhD1; Kugathasan, Subra MD2; Denson, Lee A. MD3; Hyams, Jeffrey S. MD4; Dubinsky, Marla C. MD5; Griffiths, Anne M. MD6; Baldassano, Robert N. MD7; Noe, Joshua D. MD8; Rabizadeh, Shervin MD, MBA9; Gulati, Ajay S. MD10; Rosh, Joel R. MD11; Crandall, Wallace V. MD12; Higgins, Peter D.R. MD, PhD, MSc13; Stidham, Ryan W. MD, MS13

American Journal of Gastroenterology: May 2019 - Volume 114 - Issue 5 - p 777–785
doi: 10.14309/ajg.0000000000000237
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OBJECTIVES: Avoiding fibrostenotic complications is of paramount concern in the management of Crohn's disease (CD). We sought to investigate the association of candidate biomarkers of fibrosis collected at diagnosis with the future development of fibrostenotic CD.

METHODS: Using the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort, a multicenter prospective observational pediatric inception cohort, subjects with an inflammatory phenotype (B1) at diagnosis who later converted to a stricturing phenotype (B2) within 3 years were compared with those who remained B1. Serum collected at diagnosis underwent both parallel reaction monitoring–targeted proteomic analysis and conventional enzyme-linked immunosorbent assay for 10 candidate biomarkers of intestinal fibrosis. Cox proportional hazard regression was used for multivariable analysis of time-dependent outcomes.

RESULTS: In 116 subjects 58 subjects with verified B1 phenotype at diagnosis who later converted to B2 disease were compared with 58 subjects who remained B1 over 3 years of follow-up. Extracellular matrix protein 1 (ECM1) levels in the upper quartile (hazard ratio [HR] 3.43, 95% confidence limit [CL] 1.33, 8.42) were associated with future fibrostenotic disease. ASCA IgA (HR 4.99, 95% CL 1.50, 16.68) and CBir levels (HR 5.19, 95% CL 1.83, 14.74) were also associated with future intestinal fibrostenosis, although ECM1 continued to demonstrate independent association with conversion to B2 even with adjustment for serologies in multivariable analysis (HR 5.33, 95% CL 1.29, 22.13).

CONCLUSIONS: ECM1 and other biomarkers of fibrosis may aid in determining the risk of uncomplicated inflammatory disease converting to B2 stricturing phenotypes in children with CD. Prospective validation studies to verify test performance and optimize clinical utilization are needed before clinical implementation.

1Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA;

2Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA;

3Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA;

4Division of Digestive Diseases, Hepatology, and Nutrition, Department of Pediatrics, Connecticut Children's Medical Center, Hartford, Connecticut, USA;

5Department of Pediatrics, Division of Gastroenterology and Nutrition, Icahn School of Medicine, Mount Sinai New York, New York, USA;

6Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, the Hospital for Sick Children, University of Toronto, Toronto, Canada;

7Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital of Pennsylvania, Philadelphia, Pennsylvania, USA;

8Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA;

9Division of Pediatric Gastroenterology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA;

10Division of Pediatric Gastroenterology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA;

11Department of Pediatrics, Goryeb Children's Hospital, Morristown, New Jersey, USA;

12Division of Pediatric Gastroenterology, Department of Pediatrics, Nationwide Children's Hospital, the Ohio State University College of Medicine, Columbus, Ohio, USA;

13Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Correspondence: Ryan W. Stidham, MD, MS. E-mail: ryanstid@med.umich.edu.

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/A173

Received May 11, 2018

Accepted March 04, 2019

© The American College of Gastroenterology 2019. All Rights Reserved.
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