Progression of Pediatric Crohn's Disease Is Associated With Anti–Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization

Background & Aims: The evolution of complicated pediatric Crohn's disease (CD) in the era of anti–tumor necrosis factor (aTNF) therapy continues to be described. Because CD progresses from inflammatory to stricturing (B2) and penetrating (B3) disease behaviors in a subset of patients, we aimed to understand the risk of developing complicated disease behavior or undergoing surgery in relation to aTNF timing and body mass index z-score (BMIz) normalization. Methods: Multicenter, 5-year longitudinal data from 1075 newly diagnosed CD patients were analyzed. Descriptive statistics, univariate and stepwise multivariate Cox proportional hazard regression (CPHR), and log-rank analyses were performed for risk of surgery and complicated disease behaviors. Differential gene expression from ileal bulk RNA sequencing was correlated with outcomes. Results: Stricturing complications had the largest increase: from 2.98% to 10.60% over 5 years. Multivariate CPHR showed aTNF exposure within 3 months from diagnosis (hazard ratio [HR], 0.33; 95% CI, 0.15–0.71) and baseline L2 disease (HR, 0.29; 95% CI, 0.09–0.92) to be associated with reduced B1 to B2 progression. For children with a low BMIz at diagnosis (n = 294), multivariate CPHR showed BMIz normalization within 6 months of diagnosis (HR, 0.47; 95% CI, 0.26–0.85) and 5-aminosalicyclic acid exposure (HR, 0.32; 95% CI, 0.13–0.81) were associated with a decreased risk for surgery while B2 (HR, 4.20; 95% CI, 1.66–10.65) and B2+B3 (HR, 8.24; 95% CI, 1.08–62.83) at diagnosis increased surgery risk. Patients without BMIz normalization were enriched for genes in cytokine production and inflammation. Conclusions: aTNF exposure up to 3 months from diagnosis may reduce B2 progression. In addition, lack of BMIz normalization within 6 months of diagnosis is associated with increased surgery risk and a proinflammatory transcriptomic profile.