Abstract Background Advanced therapies are crucial in Ulcerative Colitis(UC). Anti-TNFa agents recommended as first-line therapy1 are switched to second-line when patients lose response or develop adverse effects. In practice, vedolizumab2, JAK inhibitors(JAKi)3, and IL-12/23 inhibitors are used sequentially4, with IL-12/23 or JAKi often reserved for third-line therapy4. However, no comparative data exist for outcomes of third line agents. Methods We conducted a retrospective, international, multi-centre study that compared anti-IL12/23 and JAKi as third line therapy in UC patients with prior anti-TNFa and vedolizumab failure, between 01/2022 and 09/2025. The primary outcome was clinical response at week 12 defined as a decrease of SCCAI or pMayo score ≥3 points from baseline. The secondary outcomes were: clinical remission(SCCAI score≤2 or pMayo≤2), biochemical remission(faecal calprotectin150 ug/g and CRP 5mg/L) and endoscopic remission(UCEIS = 0 or Mayo = 0) at week 12, 24, 52. Treatment persistence and adverse events up to week 52 were documented. Statistical analyses were conducted using SPSS. This study received ethics approval. Results We recruited 178 participants from 8 tertiary centres. Patients were treated with mirikizumab, ustekinumab, upadacitinib, filgotinib and tofacitinib. The median age was 41.5 years(IQR 26), with a median disease duration of 8 years(IQR 8) and 46.6% were female. 58 patients received anti-IL12/23 and 120 received JAKi. Clinical response at week 12 was 56.3% in anti-IL12/23 versus 78.7% in JAKi(p = 0.005). Clinical remission at week 12 was 61.2% in anti-IL12/23 versus 75% in JAKi(p = 0.086). Biochemical remission was 50% and 61.8% in anti-IL12/23 and JAKi respectively(p = 0.43). Endoscopic remission was 40% in anti-IL12/23 versus 33.3% in JAKi (p = 0.61)(Figure 1). In the subgroup analysis (Figure 2), clinical remission at week 12 was higher for upadacitinib(81%) compared to filgotinib(64.3%) and tofacitinib (72.5%,p = 0.41), while among anti-IL12/23, ustekinumab presented higher clinical remission rates (67.5%), versus mirikizumab (33.3%,p = 0.57). Biochemical remission was similar among upadacitinib, filgotinib and tofacitinib (61.5%, 33.3% and 73.3% respectively, p = 0.23), and among anti-IL12/23 (20% with mirikizumab versus 63.6% with ustekinumab, p = 0.1). Treatment persistence at week 52 was 68.8% for ustekinumab, 76.3% for upadacitinib, 64.7% for filgotinib, 66.7% for tofacitinib. In the anti-IL12/23 cohort, 1 patient developed infectious endocarditis, while 2 cases of lymphoma and basal cell carcinoma were reported among JAKi. Conclusion JAKi demonstrated superior clinical response rates at week 12 as third line therapy versus anti-IL12/23, with upadacitinib achieving higher, but not statistically significant, remission rates. References: 1. Raine T, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis. 2022;16(1):2-17. doi:10.1093/ecco-jcc/jjab178Frontline Gastroenterol. 2022;13(5):392-401. doi:10.1136/flgastro-2021-101906Am J Gastroenterol. 2025;120(6):1187-1224. doi:10.14309/ajg.0000000000003463Clin Gastroenterol Hepatol. 2023;21(10):2629-2638. doi:10.1016/j.cgh.2023.01.038 2. Miller C, Kwok H, Harrow P, et al. Comparative effectiveness of a second-line biologic in patients with ulcerative colitis: vedolizumab followed by an anti-TNF versus anti-TNF followed by vedolizumab. Frontline Gastroenterol. 2022;13(5):392-401. doi:10.1136/flgastro-2021-101906 3. Rubin DT, Ananthakrishnan AN, Siegel CA, Barnes EL, Long MD. ACG Clinical Guideline Update: Ulcerative Colitis in Adults. Am J Gastroenterol. 2025;120(6):1187-1224. doi:10.14309/ajg.0000000000003463 4. Ibing S, Cho JH, Böttinger EP, Ungaro RC. Second–Line Biologic Therapy Following Tumor Necrosis Factor Antagonist Failure: A Real–World Propensity Score–Weighted Analysis. Clin Gastroenterol Hepatol. 2023;21(10):2629-2638. doi:10.1016/j.cgh.2023.01.038 Conflict of interest: Manti, Magdalini: M. Manti has received support for educational activities from J & J. Ramos-Belinchon, Clara: No conflict of interest Lees, Charlie: Consultancy and lecture fees: Abbvie, Oshi Health, Gilead, Pfizer, Takeda, Janssen, Shire, Samsung Bioepis, Dr Falk, GSK, Galapagos, Trellus Health, Iterative Scopes, Fresnius Kabi Argyriou, Konstantinos: No conflict of interest Kapsoritakis, Andreas: No conflict of interest Zoabi, Narmin: No conflict of interest Kopylov, Uri: Grant: Takeda, Janssen,Abbvie, Medtronic, Ely Lilly Other: Takeda, Janssen, Ely Lilly, Roche, Celtrion, Abbvie, Medtronic, CTS, Pfizer, BMS- speaker and advisory fees Compot, Elisabeta-Luminita: No conflict of interest Johnston, Emma: No conflict of interest Vasilakis, Thomas: No conflict of interest Alahmad, Maryam: No conflict of interest Quraishi, Mohammed Nabil: Speaker fees from Johnson and Johnson, Takeda, Abbvie, Hikma and Lilly and consultancy fees from Johnson and Johnson and Lilly. Rubín De Célix, Cristina: Cristina Rubín de Célix has received education funding from Ferring, Tillotts Pharma, AbbVie, Sandoz, Alfasigma, Lilly, Norgine, MSD, Pfizer, Takeda, and Janssen Bermejo San Jose, Fernando: F. Bermejo has been a speaker, consultant and advisory member or has received research funding from Abbvie, Takeda, Janssen, Pfizer, MSD, Biogen, Amgen, Galapagos, Ferring, Faes Farma, Tillotts Pharma, Chiesi, Vifor Pharma, Lilly. Toskas, Alexandros: No conflict of interest Misra, Ravi: No conflict of interest Arebi, Naila: Personal Fees: Janssen,Lilly, Pfizer and Takeda Non-financial Support: Janssen (J & J), Novonesis Kamperidis, Nikolaos: Abbvie, Tillots, Takeda and J & J
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