Geboes Histopathology Score Grade 3 Subclassification Predicts Treatment Response in Active Ulcerative Colitis

<b>Background:</b> The growing number of ulcerative colitis (UC) treatments has complicated the selection process. We hypothesized that the degree of epithelial neutrophilic infiltration, which is a hallmark of interleukin-23 (IL-23) pathway activation, could guide personalized therapy. <b>Methods:</b> This single-center, prospective study included 42 patients with active UC who were treated between July 2024 and September 2025. The study was registered (NCT06626165) on 20 July 2024. Prior to treatment, all patients underwent colonoscopy with biopsy. Using a refined subclassification of the Geboes histopathology score, patients were stratified into two groups based on the percentage of crypts with neutrophilic infiltration: Grade ≥ 3.2 and Grade < 3.2. The primary outcome was clinical remission at four weeks. The secondary outcome was endoscopic remission at six months. <b>Results:</b> Of the 42 patients, 22 were classified as Grade ≥ 3.2, and 20 were classified as Grade < 3.2. Baseline clinical and endoscopic characteristics were similar between the two groups. All 22 patients in the Grade ≥ 3.2 group treated with mirikizumab achieved clinical remission within four weeks. Nineteen (86%) of the twenty-two patients achieved endoscopic remission within six months. All 20 patients in the Grade < 3.2 group who received vedolizumab (16) or upadacitinib (4) achieved clinical remission within the same timeframe. Both treatment strategies led to a statistically significant reduction in the inflammatory biomarker leucine-rich alpha-2-glycoprotein (LRG) (<i>p</i> < 0.001). <b>Conclusions:</b> Our findings suggest that UC patients with advanced epithelial neutrophil infiltration (Geboes Grade ≥ 3.2) may have a disease that is predominantly driven by the IL-23 pathway, making them potential candidates for selective IL-23p19 inhibitors. This histopathology-driven approach appears to be a useful strategy for tailoring treatment to patients with active UC, though further validation is required.