Abstract Background Crohn’s disease (CD) is a chronic inflammatory bowel disease with heterogeneous clinical behaviour and severity. Approximately 20–30% of patients have a mild course, but evidence on the natural history of newly diagnosed mild CD is limited. We aimed to estimate the risk of progression of a large cohort of mild CD and to identify baseline predictors thereof. Methods We conducted a retrospective, multicentre cohort study across six Italian IBD centers, enrolling patients with mild CD at diagnosis between 2005 and 2020 with at least 5 years of follow-up. Mild CD was defined in case of single-segment involvement (ileal, colonic or ileocaecal) without large/deep ulcers, upper-GI or rectal disease, strictures, fistulas or perianal disease and systemic illness (fever, 10% weight loss, inability to take oral nutrition). Demographic, clinical, endoscopic, therapeutic and follow-up data were abstracted at diagnosis, 1 and 5 years, and at last follow-up available. Disease progression was defined as the need for immunosuppressants or biologics, CD-related surgery, progression to stricturing or penetrating disease, or onset of perianal disease. Results A total of 181 patients were included, of whom 53% were female, with a mean age of 40.9±15.5 years; 45.3% were 40 years and 28.1% active smokers. Median follow-up was 9.2 years (IQR 6.0–14.9). According to the Montreal classification, 80.1% had ileal disease, 7.1% colonic, and 12.9% ileocolonic.Low-bioavailability steroids and mesalamine were prescribed at diagnosis to 40.9% and 70.7% of patients, respectively. At diagnosis, the median SES-CD was 4 (IQR 3–6). Over the entire follow-up, disease progression occurred in 41% of patients. Five-year risk of progression was 24% (95% CI 18.4–31.0) (Figure 1). Five-year cumulative incidence (competing risks) was 21% (95% CI 15.6–27.6) for advanced therapies (biologics/immunosuppressants), and 3.4% for surgery. In multivariable stepwise logistic regression, active smoking was the only independent risk factor for progression (OR 2.05, 95% CI 1.03–4.06; p = 0.040), whereas age 40 years at diagnosis was independently associated with a reduced risk (OR 0.52, 95% CI 0.28–0.98; p = 0.044). Conclusion Progression risk in mild CD at diagnosis was relatively low and aligned with the lower range reported in the literature. Active smoking was associated with higher risk of progression, whereas age 40 years was protective. References: 1. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical 448 Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. Apr 449 2018;113(4):481-517. doi:10.1038/ajg.2018.27 2. Feuerstein JD, Ho EY, Shmidt E, et al. AGA Clinical Practice Guidelines on the Medical 460 Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Disease. 461 Gastroenterology. Jun 2021;160(7):2496-2508. doi:10.1053/j.gastro.2021.04.022 3. Gomoll.n F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management. J Crohns Colitis. 2017;11:3–25 4. Hannah Gordon et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment Journal of Crohn’s and Colitis 2024 18, 1531–1555 5. Peraza J. et al. A Simple Endoscopic Score for Crohn’s disease (SES-CD) ≥ 7 predicts disease progression in patients with Crohn’sdisease Aliment Pharmacol Ther 2025 Mar;61(6):1011-1018. 6. Claytor J. et al. Mild Crohn’s Disease: Definition and Management Current Gastroenterology Reports (2023) 25:45–51 7. Jacobsen H. A. et al. Prevalence and Prognosis of Mild Inflammatory Bowel Q1 Disease: A Population-based Cohort Study, 1997–2020 Clinical Gastroenterology and Hepatology 2025 (in press) 8. Elmasry S. et al. Evidence-Based Approach to the Management of Mild Crohn’s Disease. Clinical Gastroenterology and Hepatology 2024;22:480–483 9. C. Reenaers et al. Long-term evolution and predictive factors of mild inflammatory bowel disease. Scand J Gastroenterol 2016;51(6):712-9 10. Sandborn W.J. Crohn’s Disease Evaluation and Treatment: Clinical Decision Tool Gastroenterology 2014;147:702–705 Conflict of interest: Dr. Mendolaro, Marco: No conflict of interest Viola, Anna: No conflict of interest Dragoni, Gabriele: Grant: ECCO Grant 2020 ECCO/AOCC Travel Grant 2021 ECCO IIS Registry Grant 2023 ECCO/IBUS Research Grant 2023 Personal Fees: - Speaker’s fees from: 2020: Novartis 2022: Janssen 2023: Alfasigma, Janssen, Pfizer, and Takeda 2024: Ferring, Johnson & Johnson, Eli Lilly, Pfizer, and Takeda 2025: Abbvie, Alfasigma, Ferring, Eli Lilly, LionHealth, Pfizer, Takeda - Advisory board fees from: 2023: Celltrion Healthcare and Pfizer 2024: AbbVie 2025: AbbVie, Johnson & Johnson Pugliese, Daniela: Consultant/Lectures fees from: AbbVie, Takeda, Johnson, Pfizer, Alfasigma, MSD, Lilly, Celltrion. Testa, Anna: Consultant /Advisory board for Abbvie, J & J, Takeda, Ferring Barberio, Brigida: Brigida Barberio: has served as speaker for Abbvie, Agave, Alfasigma, AGpharma, Johnson & Johnson, Eli Lilly, MSD, Pfizer, Procise, Sofar, Takeda, Unifarco. BB has served as consultant for Abbvie, Eli Lilly, ohnson & Johnson. Miccichè, Niccolò: No conflict of interest Cuccia, Giuseppe: No conflict of interest Savarino, Edoardo Vincenzo: Personal Fees: Takeda, Abbvie, MSD, Janssen, Sofar Castiglione, Fabiana: No conflict of interest Fries, Walter: research grant (Pfizer) speaker fees (Abbvie, Takeda) advisory board (Pfizer, Lilly) non finanvcal support (Ferring, Lilly, Pfizer, Janssen, Takeda, Alpha-Wassermann) Daperno, Marco: None
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