Phenotypic Heterogeneity in Crohn’s Disease-Associated Intestinal Strictures: An Exploratory Retrospective Cohort Study

Background: Crohn’s disease-associated intestinal strictures represent a major source of morbidity and frequently require endoscopic or surgical intervention. However, patients with stricturing Crohn’s disease demonstrate substantial clinical heterogeneity regarding disease localization, penetrating complications, systemic manifestations, metabolic alterations, and treatment exposure. This study aimed to explore phenotypic heterogeneity within patients with Crohn’s disease-associated intestinal strictures. Methods: In this retrospective exploratory cohort study, 96 patients with Crohn’s disease-associated intestinal strictures treated at a tertiary referral center between 2014 and 2024 were included. Clinical, structural, metabolic, and treatment-related variables were analyzed. Univariate analyses were performed using chi-square, Fisher’s exact test, Student’s t-test, or Mann–Whitney U test as appropriate. Exploratory multivariable logistic regression models were constructed to explore relationships between different clinical phenotypes and disease-related characteristics, including extraintestinal manifestations (EIMs), smoking status, penetrating disease manifestations, hepatic steatosis, stenosis localization, and abscess formation. Given the limited sample size and event numbers in several subgroup analyses, all multivariable analyses were considered exploratory and hypothesis-generating. Results: The cohort demonstrated a heterogeneous clinical presentation with a high prevalence of perianal disease, penetrating complications, prior intestinal surgery, and biologic therapy exposure. Female sex (OR 4.63, p = 0.044), autoimmune disease (OR 23.5, p = 0.049), rectal stenosis (inverse association; OR 0.08, p = 0.041), and exposure to multiple biologic therapies (OR 20.11, p = 0.036) remained associated with EIMs after multivariable adjustment. Smoking status was associated with anastomotic stenosis (OR 3.16, p = 0.023) and inversely associated with female sex (OR 0.35, p = 0.036). Phenotype-oriented analyses further suggested clustering of penetrating disease manifestations, including associations between intestinal fistulas, perianal fistulas, and abscess formation. Hepatic steatosis demonstrated exploratory associations with intestinal fistulas, intestinal resection, and appendectomy. Several analyses demonstrated wide confidence intervals and should therefore be interpreted cautiously. Conclusions: This exploratory retrospective cohort study highlights the substantial clinical heterogeneity observed among patients with Crohn’s disease-associated intestinal strictures. Different structural, systemic, penetrating, behavioral, and metabolic disease manifestations may indicate potentially overlapping phenotypic patterns within stricturing Crohn’s disease. Given the retrospective design, limited sample size, and exploratory statistical approach, these findings should be interpreted cautiously and require validation in larger prospective studies.