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 & 23 others 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

Research output: Contribution to journalArticle

110 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1710-1718
Number of pages9
JournalThe Lancet
Volume389
Issue number10080
DOIs
StatePublished - Apr 29 2017

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Crohn Disease
Cohort Studies
Tumor Necrosis Factor-alpha
Serology
Ruminococcus
Veillonella
Implosive Therapy
Pediatrics
Genes
Propensity Score
Microbiota
Colitis
Therapeutics
Proportional Hazards Models
Health Care Costs
Canada
Extracellular Matrix
Genotype
Morbidity
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kugathasan, S., Denson, L. A., Walters, T. D., Kim, M. O., Marigorta, U. M., Schirmer, M., ... Dubinsky, M. C. (2017). Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study. The Lancet, 389(10080), 1710-1718. https://doi.org/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. / Kugathasan, Subra; Denson, Lee A.; Walters, Thomas D.; Kim, Mi Ok; Marigorta, Urko M.; Schirmer, Melanie; Mondal, Kajari; Liu, Chunyan; Griffiths, Anne; Noe, Joshua D.; Crandall, Wallace V.; Snapper, Scott; Rabizadeh, Shervin; Rosh, Joel R.; Shapiro, Jason M.; Guthery, Stephen; Mack, David R.; Kellermayer, Richard; Kappelman, Michael D.; Steiner, Steven; Moulton, Dedrick E.; Keljo, David; Cohen, Stanley; Oliva-Hemker, Maria; Heyman, Melvin B.; Otley, Anthony R.; Baker, Susan S.; Evans, Jonathan S.; Kirschner, Barbara S.; Patel, Ashish S.; Ziring, David; Trapnell, Bruce C.; Sylvester, Francisco A.; Stephens, Michael C.; Baldassano, Robert N.; Markowitz, James F.; Cho, Judy; Xavier, Ramnik J.; Huttenhower, Curtis; Aronow, Bruce J.; Gibson, Greg; Hyams, Jeffrey S.; Dubinsky, Marla C.

In: The Lancet, Vol. 389, No. 10080, 29.04.2017, p. 1710-1718.

Research output: Contribution to journalArticle

Kugathasan, S, Denson, LA, Walters, TD, Kim, MO, Marigorta, UM, Schirmer, M, Mondal, K, Liu, C, Griffiths, A, Noe, JD, Crandall, WV, Snapper, S, Rabizadeh, S, Rosh, JR, Shapiro, JM, Guthery, S, Mack, DR, Kellermayer, R, Kappelman, MD, Steiner, S, Moulton, DE, Keljo, D, Cohen, S, Oliva-Hemker, M, Heyman, MB, Otley, AR, Baker, SS, Evans, JS, Kirschner, BS, Patel, AS, Ziring, D, Trapnell, BC, Sylvester, FA, Stephens, MC, Baldassano, RN, Markowitz, JF, Cho, J, Xavier, RJ, Huttenhower, C, Aronow, BJ, Gibson, G, Hyams, JS & Dubinsky, MC 2017, 'Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study', The Lancet, vol. 389, no. 10080, pp. 1710-1718. https://doi.org/10.1016/S0140-6736(17)30317-3
Kugathasan, Subra ; Denson, Lee A. ; Walters, Thomas D. ; Kim, Mi Ok ; Marigorta, Urko M. ; Schirmer, Melanie ; Mondal, Kajari ; Liu, Chunyan ; Griffiths, Anne ; Noe, Joshua D. ; Crandall, Wallace V. ; Snapper, Scott ; Rabizadeh, Shervin ; Rosh, Joel R. ; Shapiro, Jason M. ; Guthery, Stephen ; Mack, David R. ; Kellermayer, Richard ; Kappelman, Michael D. ; Steiner, Steven ; Moulton, Dedrick E. ; Keljo, David ; Cohen, Stanley ; Oliva-Hemker, Maria ; Heyman, Melvin B. ; Otley, Anthony R. ; Baker, Susan S. ; Evans, Jonathan S. ; Kirschner, Barbara S. ; Patel, Ashish S. ; Ziring, David ; Trapnell, Bruce C. ; Sylvester, Francisco A. ; Stephens, Michael C. ; Baldassano, Robert N. ; Markowitz, James F. ; Cho, Judy ; Xavier, Ramnik J. ; Huttenhower, Curtis ; Aronow, Bruce J. ; Gibson, Greg ; Hyams, Jeffrey S. ; Dubinsky, Marla C. / Prediction of complicated disease course for children newly diagnosed with Crohn's disease : a multicentre inception cohort study. In: The Lancet. 2017 ; Vol. 389, No. 10080. pp. 1710-1718.
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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.",
author = "Subra Kugathasan and Denson, {Lee A.} and Walters, {Thomas D.} and Kim, {Mi Ok} and Marigorta, {Urko M.} and Melanie Schirmer and Kajari Mondal and Chunyan Liu and Anne Griffiths and Noe, {Joshua D.} and Crandall, {Wallace V.} and Scott Snapper and Shervin Rabizadeh and Rosh, {Joel R.} and Shapiro, {Jason M.} and Stephen Guthery and Mack, {David R.} and Richard Kellermayer and Kappelman, {Michael D.} and Steven Steiner and Moulton, {Dedrick E.} and David Keljo and Stanley Cohen and Maria Oliva-Hemker and Heyman, {Melvin B.} and Otley, {Anthony R.} and Baker, {Susan S.} and Evans, {Jonathan S.} and Kirschner, {Barbara S.} and Patel, {Ashish S.} and David Ziring and Trapnell, {Bruce C.} and Sylvester, {Francisco A.} and Stephens, {Michael C.} and Baldassano, {Robert N.} and Markowitz, {James F.} and Judy Cho and Xavier, {Ramnik J.} and Curtis Huttenhower and Aronow, {Bruce J.} and Greg Gibson and Hyams, {Jeffrey S.} and Dubinsky, {Marla C.}",
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TY - JOUR

T1 - Prediction of complicated disease course for children newly diagnosed with Crohn's disease

T2 - a multicentre inception cohort study

AU - Kugathasan, Subra

AU - Denson, Lee A.

AU - Walters, Thomas D.

AU - Kim, Mi Ok

AU - Marigorta, Urko M.

AU - Schirmer, Melanie

AU - Mondal, Kajari

AU - Liu, Chunyan

AU - Griffiths, Anne

AU - Noe, Joshua D.

AU - Crandall, Wallace V.

AU - Snapper, Scott

AU - Rabizadeh, Shervin

AU - Rosh, Joel R.

AU - Shapiro, Jason M.

AU - Guthery, Stephen

AU - Mack, David R.

AU - Kellermayer, Richard

AU - Kappelman, Michael D.

AU - Steiner, Steven

AU - Moulton, Dedrick E.

AU - Keljo, David

AU - Cohen, Stanley

AU - Oliva-Hemker, Maria

AU - Heyman, Melvin B.

AU - Otley, Anthony R.

AU - Baker, Susan S.

AU - Evans, Jonathan S.

AU - Kirschner, Barbara S.

AU - Patel, Ashish S.

AU - Ziring, David

AU - Trapnell, Bruce C.

AU - Sylvester, Francisco A.

AU - Stephens, Michael C.

AU - Baldassano, Robert N.

AU - Markowitz, James F.

AU - Cho, Judy

AU - Xavier, Ramnik J.

AU - Huttenhower, Curtis

AU - Aronow, Bruce J.

AU - Gibson, Greg

AU - Hyams, Jeffrey S.

AU - Dubinsky, Marla C.

PY - 2017/4/29

Y1 - 2017/4/29

N2 - 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.

AB - 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.

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