Is it Possible to Change Phenotype Progression in Crohn's Disease in the Era of Immunomodulators? Predictive Factors of Phenotype Progression

OBJECTIVES: Crohn's disease (CD) induces cumulative structural damage, initially characterized by a non-stenosing non-penetrating behavior (B1) with progression over time to a fibro-stenosing (B2) and/or penetrating phenotype (B3). Our aim was to assess the long-term evolution of disease behavior of CD and determine what factors predict phenotype progression. METHODS: This was a study based on prospectively collected data from a CD database in an inflammatory bowel disease outpatient clinic. B1 corresponds to a non-stenosing non-penetrating disease, B2 to a stenosing behavior, and B3 to a penetrating one. RESULTS: Seven hundred and thirty-six patients with CD (368 female) were followed up for 12.3 years (+/- 8.4), with 87.0% of them exhibiting B1 phenotype at diagnosis. Of these patients, 28.5% progressed to B2 phenotype and 23.5% to B3. Fifty percent of the patients started azathioprine treatment before phenotype change and 13.9% started anti-tumor necrosis factor-alpha (anti-TNF alpha) treatment before phenotype change. Monotherapy with azathioprine before phenotype change as well as combination therapy with azathioprine /anti-TNF alpha before phenotype change delayed disease progression (B1-B2 or B3) in comparison with patients who did not receive treatment (P < 0.001). The hazard ratio (HR) for disease progression was lower for both monotherapy with azathioprine (HR: 0.15, P < 0.001) or combination therapy with anti-TNF alpha (HR: 0.33, P < 0.001). Upper gastrointestinal tract involvement, male gender, and steroid use were associated with an early progression of phenotype from B1 to B2 or B3 (P < 0.001). The HR for disease progression was higher in patients who used steroids without criteria of dependence or resistance (HR: 2.67, P < 0.001) and was even higher in patients with criteria of dependence or resistance (HR: 6.44, P < 0.001). Longer delays between CD diagnosis and beginning of therapy with azathioprine and/or anti-TNF alpha were associated with disease progression. The longer the duration of treatment, the less likely the disease progression. CONCLUSIONS: Monotherapy with azathioprine before behavior change as well as combination therapy with azathioprine and anti-TNF alpha before behavior change delays phenotype progression of CD, whereas upper gastrointestinal tract involvement, male gender, and steroid use with or without criteria of steroid dependence are associated with a higher risk for disease progression.