Abstract
Background: Progression of inflammatory bowel disease (IBD) follows distinct epidemiologic stages: Stage 1 (Emergence), characterized by low incidence and prevalence; Stage 2 (Acceleration in Incidence), characterized by rapidly increasing incidence and low prevalence; Stage 3 (Compounding Prevalence), characterized by stabilizing incidence and rapidly increasing prevalence. Studies have observed that when IBD emerges in a population, ulcerative colitis (UC) incidence is higher than Crohn’s disease (CD) incidence. Over time, the UC:CD incidence ratio approximates 1. Aim: To examine changes in UC:CD incidence ratios across epidemiologic stages of IBD.
Methods: Epidemiologic stage classifications were previously determined by a machine-learning classifier on data from 522 population-based studies on incidence and prevalence of UC and CD comprising 82 countries from 1920-2024. Population-weighted mean incidence was used to calculate annual, country-specific UC:CD ratios. Incidence values of zero were excluded. These ratios were analyzed using a generalized additive model for location, scale, and shape (GAMLSS), which accommodates overdispersion and skewness. Post-hoc pairwise Wilcoxon rank sum tests with Bonferroni correction were performed to assess differences between epidemiologic stages. Average annual percent changes (AAPC) with 95% confidence intervals (CI) of UC:CD incidence ratios per country within a stage were calculated across time. AAPCs were pooled by meta-analysis within each epidemiologic stage.
Results: The GAMLSS model, adjusted for country, demonstrated significant effects of epidemiologic stage on the UC:CD ratio (p<0.001), showing a progressive shift toward 1:1 across stages (Figures 1, 2). Post-hoc testing found significant differences between the stages: Stage 1: Median: 3.62 (1QR: 3.9 [1.66-5.56]); Stage 2: Median: 1.8 (IQR: 2 [1.12-3.12]); Stage 3: Median: 1.56 (1QR: 1 [1.08-2.08]); all comparisons: p<0.001. Meta-analyses demonstrated narrowing of the UC:CD ratio within each stage across time. For stage 1, 13 countries contributed to the meta-analysis spanning 1954-2022 showing a significant decrease in the ratio (AAPC: -4.77; 95%CI: -8.59, -0.95). For stage 2,42 countries contributed to the meta-analysis spanning 1952-2022 showing a significant decrease in the ratio (AAPC: -2.55; 95%CI: -4.04, -1.06). For stage 3, 24 countries contributed to the meta-analysis spanning 1970-2023 showing a stable ratio (AAPC: -0.12; 95%CI: -0.66, 0.42).
Discussion: The UC:CD incidence ratio significantly decreases during stage 1 and 2, then stabilizes in stage 3. Understanding the relevance of the UC:CD incidence ratio could help researchers differentiate periods of increasing CD incidence and focus investigations on determinants driving these changes, including advancements in diagnosis and environmental factors contributing to disease development.