A subset of patients with Crohn's disease (CD) rapidly progress to a stricturing or internal penetrating phenotype that requires surgery. Despite great strides in therapy, there have not been population-level declines in the rates of these serious complications or need for surgery in CD. Effective risk stratification models to predict progression to such complications in pediatric CD are presently lacking. We aimed to develop and test a prognostic model incorporating clinical and host biology and integrated the comparative effectiveness of anti-TNF in preventing stricturing or perforating complications.Methods:
In this inception cohort of CD, 28 sites have recruited a total of 1096 pediatric patients at diagnosis before any therapy was started. The patients were followed prospectively for 36 months and clinical, genetic, serologic and mucosal gene expression data was collected at baseline and progression to stricturing and/or internal penetrating complication was recorded. A competing risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-Tumor Necrosis Factor (anti-TNF) therapy within 3 months of diagnosis on complication risk.Results:
Of the 1096 total recruited patients, 913 were newly diagnosed uncomplicated pediatric CD patients. Seventy-eight (9%) out of those experienced CD complication within 36 months. Neither isolated ileal disease nor ASCA IgA were associated with stricturing behavior but CBir1 (HR: 2.30 [95% CI, 1.26–4.20], P = 0.007) seropositivity was. Older age at diagnosis (HR: 1.45 [95% CI, 1.17–1.8], P < 0.001), African American race (HR: 3.19 [95% CI, 1.39–7.31], P = 0.006), ASCA IgA (HR: 2.68 [95% CI, 1.19–6.04], P = 0.02) and CBir1 (HR: 3.01 [95% CI, 1.31–6.93], P = 0.010) seropositivity were associated with internally penetrating behavior. The validated competing risk model included age, race, disease location, and anti-microbial serologies and provided a sensitivity of 66% (95% CI, 51%–82%) and specificity of 63% (95% CI, 55%–71%), with a negative predictive value of 95% (95% CI, 94%–97%). With 16 baseline characteristics balanced via propensity-score matching, we found that the patients who received early anti-TNF (n = 191) were less likely to experience a penetrating (hazard ratio [HR]: 0.30 [95% CI, 0.10–0.89], P = 0.03), but not stricturing (HR: 1.13 [95% CI, 0.51–2.51, P = 0.76]), complication. Distinct organisms were implicated in the development of complications; Rothia and Ruminococcus with strictures, and Collinsella and Veillonella with penetrating lesions. Twelve out of 70 ileal genes controlling extra-cellular matrix (ECM) production were up-regulated at diagnosis. This ECM gene signature was found to be associated with stricturing behavior in the risk model (HR: 1.7 [95% CI, 1.12–2.57], P = 0.01), improving the specificity of the model to 71%.Conclusions:
We have identified predictable signatures for future development of stricturing and internal penetrating disease at diagnosis when they present with inflammatory phenotype. Our results advance our understanding of the pathogenesis of CD complications, and inform more personalized approaches to the approach of children presenting with a new diagnosis of Crohn's disease.