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

Abstract

Summary 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.

Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

“…We were specifically interested to know whether gene programs expressed in circulating neutrophils would reflect those that we recently reported in the gut. 12 The gene expression results with GMSI-Lo neutrophils were remarkably similar to those obtained in pretreatment ileal biopsies for CD patients who went on to develop strictures. 12 This included upregulation of an extracellular matrix production gene signature and suppression of a mitochondrial respiration gene signature in GMSI-Lo neutrophils relative to control neutrophils.…”

“…12 The gene expression results with GMSI-Lo neutrophils were remarkably similar to those obtained in pretreatment ileal biopsies for CD patients who went on to develop strictures. 12 This included upregulation of an extracellular matrix production gene signature and suppression of a mitochondrial respiration gene signature in GMSI-Lo neutrophils relative to control neutrophils. These data suggest an important role for GM-CSF in regulating these critical gene programs linked to patient outcomes, which will now be tested in purified ileal epithelial, myeloid, and myofibroblast cells.…”

“…12 However, we were not adequately powered to test for interactions between sex, race, CSF2RA A17G carriage, and neutrophil function and disease behavior in the current study. This will be the focus of a future multicenter study guided by the current results.…”

“…11,12 Clinical and demographic features are summarized in Supplementary Table 1. Genomic DNA was extracted from whole blood from 567 early-onset (age 0-18 years) IBD samples; 543 (95.8%) of these samples passed DNA quality control.…”

Early intervention in Crohn’s disease: towards disease modification trials

“…Given the limitations of this study (retrospective subgroup analysis, underpowered sample size), the authors concluded that the main explanation for the lack of benefit of early treatment in this cohort lies in the absence of clear criteria to select patients who could be expected to benefit from early anti-TNF therapy. Kugathasan et al recently showed that early anti-TNF use is associated with less penetrating complications (HR 0.30, 95% CI 0.10 to 0.89; p=0.0296) but not less stricturing complications (HR 1.13, 95% CI 0.51 to 2.51; p=0.76) 22. These data suggest that early intervention may not be appropriate in all patients, even though we do not have clear predictors to discriminate the right patient for the right strategy.…”