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

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.

Figure 1. Development of stricturing or penetrating complications during follow-up in the competing-risk analysis in the whole cohort (A) and in the propensity-matched cohort (B)

B2 refers to stricturing behaviour, and B3 to penetrating behaviour. (A) includes 35 patients with Crohn’s disease who either developed complications during the first 90 days after diagnosis, or did not have complete information for disease location at diagnosis, and were therefore excluded from the primary analysis. 97 patients developed complications, 63 with stricturing behaviour and 34 with penetrating behaviour. In (B), early anti-TNFα therapy was defined as exposure within 90 days of diagnosis, and the survival probabilities were computed among those staying complication free by 90 days. Among those treated with early anti-TNFα therapy, 18 patients developed complications, 14 with stricturing behaviour and four with penetrating behaviour. 23 patients developed complications, 12 with stricturing behaviour and 11 with penetrating behaviour, among the matched group not treated with early anti-TNFα therapy. TNFα=tumour necrosis factor α.

Figure 2. Ileal gene signatures associated with development of disease complications

(A) shows the proportion of ileal genes upregulated in patients who developed stricturing (B2, blue bars) versus penetrating (B3, red bars) complications for 19 gene ontology pathways significantly enriched for genes upregulated in pairwise comparisons between the subgroups (appendix). Names of pathways are shown, along with the total number of genes included in each pathway in parentheses.* (B) is a combined scatterplot and density plot of log₂ fold changes in ileal gene expression for patients who exhibited stricturing (B2) versus complication-free (B1, x-axis) and stricturing (B2) versus penetrating (B3, y-axis) behaviour, with higher mean expression in B2 either to the right or to the top (and correspondingly, higher expression in B1 to the left, or B3 to the bottom). Genes involved in ECM remodelling (n=70, gene ontology pathway 0005201) are depicted with blue filled dots and blue lines. Background values for all genes (n=17 081) are shown with grey dots and black lines. (C) shows a volcano plot of significance (negative logarithm of the p value on the y-axis) against difference in average ileal gene expression (log₂ scale, x-axis) between patients with Crohn’s disease with low risk for complications who nonetheless developed stricturing behaviour (B2 low probability†) and patients with Crohn’s disease with high risk for complications who nonetheless remained complication free (B1 protected‡). Genes involved in the mitochondrial respiratory chain (n=179, gene ontology pathways 0022900 and 0045333, in dark red) are almost all upregulated in B1 protected, whereas genes involved in remodelling of the ECM (n=68, gene ontology pathway 0005201, in light blue) are upregulated in B2 low probability. TNFα=tumour necrosis factor α. ECM=extracellular matrix. LPS=lipopolysaccharide. *Sample sizes were n=18 (B2), n=11 (B3), and n=214 (B1). The pathways were selected as highly significant in the enrichment analyses of B2 vs B1 or B3 vs B1 (appendix). †Refers to nine patients who developed B2 despite a 3-year probability of complication from the competing-risk model below the median of all B2 (mean 0·048, range 0·029–0·072). ‡Refers to 22 patients who did not develop any complications despite being among the top 10% of 3-year probability of complication according to the competing-risk model (mean 0·152, range 0·121–0·241). The small sample size results in slight significance values, but the coherence of the two pathways is strongly indicated by the polarity of the genes in the two signatures on either side of zero.