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

Jing Wu, David M. Lubman, Subra Kugathasan, Lee A. Denson, Jeffrey S. Hyams, Marla C. Dubinsky, Anne M. Griffiths, Robert N. Baldassano, Joshua D. Noe, Shervin Rabizadeh, Ajay S. Gulati, Joel R. Rosh, Wallace V. Crandall, Peter D.R. Higgins, Ryan W. Stidham

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)777-785
Number of pages9
JournalThe American journal of gastroenterology
Volume114
Issue number5
DOIs
StatePublished - May 1 2019

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Crohn Disease
Blood Proteins
Extracellular Matrix Proteins
Fibrosis
Biomarkers
Phenotype
Delayed Diagnosis
Immunogenetics
Validation Studies
Serology
Proteomics
Immunoglobulin A
Disease Progression
Enzyme-Linked Immunosorbent Assay
Prospective Studies
Pediatrics
Pediatric Crohn's disease
Serum

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Wu, Jing ; Lubman, David M. ; Kugathasan, Subra ; Denson, Lee A. ; Hyams, Jeffrey S. ; Dubinsky, Marla C. ; Griffiths, Anne M. ; Baldassano, Robert N. ; Noe, Joshua D. ; Rabizadeh, Shervin ; Gulati, Ajay S. ; Rosh, Joel R. ; Crandall, Wallace V. ; Higgins, Peter D.R. ; Stidham, Ryan W. / Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease. In: The American journal of gastroenterology. 2019 ; Vol. 114, No. 5. pp. 777-785.
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abstract = "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.",
author = "Jing Wu and Lubman, {David M.} and Subra Kugathasan and Denson, {Lee A.} and Hyams, {Jeffrey S.} and Dubinsky, {Marla C.} and Griffiths, {Anne M.} and Baldassano, {Robert N.} and Noe, {Joshua D.} and Shervin Rabizadeh and Gulati, {Ajay S.} and Rosh, {Joel R.} and Crandall, {Wallace V.} and Higgins, {Peter D.R.} and Stidham, {Ryan W.}",
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Wu, J, Lubman, DM, Kugathasan, S, Denson, LA, Hyams, JS, Dubinsky, MC, Griffiths, AM, Baldassano, RN, Noe, JD, Rabizadeh, S, Gulati, AS, Rosh, JR, Crandall, WV, Higgins, PDR & Stidham, RW 2019, 'Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease', The American journal of gastroenterology, vol. 114, no. 5, pp. 777-785. https://doi.org/10.14309/ajg.0000000000000237

Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease. / Wu, Jing; Lubman, David M.; Kugathasan, Subra; Denson, Lee A.; Hyams, Jeffrey S.; Dubinsky, Marla C.; Griffiths, Anne M.; Baldassano, Robert N.; Noe, Joshua D.; Rabizadeh, Shervin; Gulati, Ajay S.; Rosh, Joel R.; Crandall, Wallace V.; Higgins, Peter D.R.; Stidham, Ryan W.

In: The American journal of gastroenterology, Vol. 114, No. 5, 01.05.2019, p. 777-785.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease

AU - Wu, Jing

AU - Lubman, David M.

AU - Kugathasan, Subra

AU - Denson, Lee A.

AU - Hyams, Jeffrey S.

AU - Dubinsky, Marla C.

AU - Griffiths, Anne M.

AU - Baldassano, Robert N.

AU - Noe, Joshua D.

AU - Rabizadeh, Shervin

AU - Gulati, Ajay S.

AU - Rosh, Joel R.

AU - Crandall, Wallace V.

AU - Higgins, Peter D.R.

AU - Stidham, Ryan W.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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