Abstract Background Upadacitinib, a selective JAK1 inhibitor, is approved for the treatment of ulcerative colitis and Crohn’s disease. Its real-world safety profile, particularly in combination with other advanced therapies such as ustekinumab, requires further investigation. Methods This study integrated data from two sources: the FDA Adverse Event Reporting System (FAERS) (2004Q1–2024Q4) and a single-center retrospective cohort from Chongqing General Hospital (2023–2025). Disproportionality analyses (reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and empirical Bayes geometric mean) were applied to FAERS data to detect adverse event (AE) signals. Descriptive statistics were used to analyze clinical data from 127 patients. Subgroup analyses were stratified by sex, age, and body weight. Results • FAERS Database: Among 4,571 upadacitinib-related inflammatory bowel disease reports, the most frequent AEs involved gastrointestinal disorders, general disorders, and infections. Strong disproportionality signals were observed for discoloration of semen, dyslipidemia, and cystic acne. • Clinical Cohort: Of the 127 patients, 69 (54.3%) experienced at least one AE, totaling 89 events. The most common AEs were hematological abnormalities, skin and subcutaneous tissue disorders, and infections. No deaths, malignancies, or hepatitis B reactivation were reported. • Combination Therapy: FAERS contained 29 reports of upadacitinib-ustekinumab co-therapy, with significant signals for headache and panic attacks. In the clinical cohort, 4 out of 17 patients receiving combination therapy experienced AEs, primarily elevated lipids and infections. Subgroup Analysis • Sex: Acne was common in both sexes, with herpes zoster more frequent in females and hemorrhagic events in males. • Age: Acne was predominant across all age groups, while pulmonary embolism and cataracts were more common in older patients. • Weight: Infections and elevated inflammatory markers were more frequent in lower-weight patients, whereas thrombotic events were increased in higher-weight patients. Conclusion The real-world safety profile of upadacitinib aligns with its mechanism of action, including infections, dyslipidemia, and hematological abnormalities. Discrepancies between FAERS and clinical data highlight the complementary roles of spontaneous reporting and active surveillance. Combination therapy with ustekinumab may increase the risk of neurological events, warranting further investigation. References: 1. Drugan S, Keers J, Upadacitinib First Approval. Drugs, 2019, 79: 819-828. 2. Sammar M, R, Crommelin H, Upadacitinib for Patients with Rheumatoid Arthritis: A Comprehensive Review. J Clin Med, 2023, 12(25): 734. 3. Roskoski Jr R. Properties of FDA-approved small molecule pro- tein kinase inhibitors: A 2023 update J. Pharmacol Res, 2022: 106552. 4. Loftus Jr EV, Panés J, Lacerda AP, et al. Upadacitinib In- duction and Maintenance Therapy for Crohn’s Disease J. N Engl J Med, 2023, 388(21): 1966-1980. 5 Raine T, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical TreatmentJ. J Crohns Colitis, 2022,16(1): 2-17. 6 中华医学会消化病学分会炎症性肠病学组, 中国炎症性肠病诊疗质量控制评估中心. 中国溃疡性结肠炎诊治指南（2023年·西安）J. 中华炎性肠病杂志（中英文）, 2024,1(8): 33-58. 7 乌帕替尼说明书20230621版Z. 8 Sandborn WJ, Feagan BG, Kornbluth A, et al. Efficacy and safety of upadacitinib in patients with moderate-to-severe active ulcerative colitis: 52-week results from the phase 3 U-ACHIEVE maintenance study. Gut. 2024 Oct;73(10):1886-1897. 9 Smith J, Brown A, Upadacitinib for the treatment of inflammatory bowel disease: a systematic review and meta-analysis. Journal of Crohn’s and Colitis. 2023, 17(3), 456-467. 10 Sandborn WJ, et al. Tofacitinib for the treatment of ulcerative colitis: a randomized trial. Ann Intern Med. 2015;162(10):663-672. 11 FDA Adverse Event Reporting System (FAERS). Analysis of CDI reports in patients using JAK inhibitors. Available at: FAERS Database. 12 Feagan BG, et al. Upadacitinib for the treatment of Crohn’s disease: a randomized trial. Ann Intern Med. 2023;178(3):345-356. 13 Smith J, et al. Upadacitinib and the risk of Clostridium difficile infection in IBD patients: a single-center retrospective study. Journal of Crohn’s and Colitis. 2024;18(4):456-467. Conflict of interest: Dr. Wei, Tan: Non-financial support guo, hong: Non-financial support Song, Xiaomei: Non-financial support Liu, Yan: Non-financial support
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