Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

Subra Kugathasan; Lee A Denson; Thomas D Walters; Mi-Ok Kim; Urko M Marigorta; Melanie Schirmer; Kajari Mondal; Chunyan Liu; Anne Griffiths; Joshua D Noe; Wallace V Crandall; Scott Snapper; Shervin Rabizadeh; Joel R Rosh; Jason M Shapiro; Stephen Guthery; David R Mack; Richard Kellermayer; Michael D Kappelman; Steven Steiner; Dedrick E Moulton; David Keljo; Stanley Cohen; Maria Oliva-Hemker; Melvin B Heyman; Anthony R Otley; Susan S Baker; Jonathan S Evans; Barbara S Kirschner; Ashish S Patel; David Ziring; Bruce C Trapnell; Francisco A Sylvester; Michael C Stephens; Robert N Baldassano; James F Markowitz; Judy Cho; Ramnik J Xavier; Curtis Huttenhower; Bruce J Aronow; Greg Gibson; Jeffrey S Hyams; Marla C Dubinsky

doi:10.1016/S0140-6736(17)30317-3

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

Lancet. 2017 Apr 29;389(10080):1710-1718. doi: 10.1016/S0140-6736(17)30317-3. Epub 2017 Mar 2.

Authors

Subra Kugathasan¹, Lee A Denson², Thomas D Walters³, Mi-Ok Kim⁴, Urko M Marigorta⁵, Melanie Schirmer⁶, Kajari Mondal⁷, Chunyan Liu⁴, Anne Griffiths³, Joshua D Noe⁸, Wallace V Crandall⁹, Scott Snapper¹⁰, Shervin Rabizadeh¹¹, Joel R Rosh¹², Jason M Shapiro¹³, Stephen Guthery¹⁴, David R Mack¹⁵, Richard Kellermayer¹⁶, Michael D Kappelman¹⁷, Steven Steiner¹⁸, Dedrick E Moulton¹⁹, David Keljo²⁰, Stanley Cohen²¹, Maria Oliva-Hemker²², Melvin B Heyman²³, Anthony R Otley²⁴, Susan S Baker²⁵, Jonathan S Evans²⁶, Barbara S Kirschner²⁷, Ashish S Patel²⁸, David Ziring²⁹, Bruce C Trapnell³⁰, Francisco A Sylvester¹⁷, Michael C Stephens³¹, Robert N Baldassano³², James F Markowitz³³, Judy Cho³⁴, Ramnik J Xavier³⁵, Curtis Huttenhower⁶, Bruce J Aronow³⁶, Greg Gibson⁵, Jeffrey S Hyams³⁷, Marla C Dubinsky³⁴

Affiliations

¹ Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA; Children's Healthcare of Atlanta, Atlanta, GA, USA. Electronic address: skugath@emory.edu.
² Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁴ Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁵ Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA, USA.
⁶ The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biostatistics, Harvard T H Chan School of Public Health, Boston, MA, USA.
⁷ Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA, USA.
⁸ Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA.
⁹ Department of Pediatric Gastroenterology, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA.
¹⁰ Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
¹¹ Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹² Department of Pediatrics, Goryeb Children's Hospital, Morristown, NJ, USA.
¹³ Department of Pediatrics, Hasbro Children's Hospital, Providence, RI, USA.
¹⁴ Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
¹⁵ Department of Pediatrics, Children's Hospital of Eastern Ontario IBD Centre and University of Ottawa, ON, Canada.
¹⁶ Section of Pediatric Gastroenterology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
¹⁷ Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁸ Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁹ Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA.
²⁰ Department of Gastroenterology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
²¹ Children's Healthcare of Atlanta, Atlanta, GA, USA; Children's Center for Digestive Health Care, Atlanta, GA, USA.
²² Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²³ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
²⁴ Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
²⁵ Department of Digestive Diseases and Nutrition Center, University at Buffalo, Buffalo, NY, USA.
²⁶ Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL, USA.
²⁷ Department of Pediatrics, University of Chicago, Chicago, IL, USA.
²⁸ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²⁹ Department of Pediatrics, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
³⁰ Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³¹ Department of Pediatric Gastroenterology, Mayo Clinic, Rochester, MN, USA.
³² Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.
³³ Department of Pediatrics, Northwell Health, New York, NY, USA.
³⁴ Department of Pediatrics, Mount Sinai Hospital, New York, NY, USA.
³⁵ The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Computational and Integrative Biology, Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
³⁶ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
³⁷ Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA.

Abstract

Background: Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown.

Methods: We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk.

Findings: Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%.

Interpretation: Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy.

Funding: Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.

Publication types

Clinical Trial
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adalimumab / therapeutic use
Adolescent
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Child
Cohort Studies
Crohn Disease / complications*
Crohn Disease / diagnosis
Crohn Disease / drug therapy
Crohn Disease / microbiology
Disease Progression
Female
Gastrointestinal Microbiome
Humans
Infliximab / therapeutic use
Intestinal Obstruction / etiology
Male
Prognosis
Propensity Score
Prospective Studies
Risk Assessment / methods
Severity of Illness Index
Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

Anti-Inflammatory Agents, Non-Steroidal
Tumor Necrosis Factor-alpha
Infliximab
Adalimumab

Abstract

Publication types

MeSH terms

Substances

Grants and funding