P0809 Higher Ustekinumab Concentrations in Induction are associated With Better Endoscopic Outcomes in Inflammatory Bowel Disease

Abstract Background Ustekinumab (UST) is a monoclonal antibody targeting the p40 subunit of interleukin-12/23. Evidence suggests a relationship between UST concentrations and therapeutic outcomes. This study aimed to evaluate the association between UST trough concentrations during the induction phase and clinical and especially endoscopic outcomes at week 24 in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Methods Patients with CD and UC were included from the start of UST treatment. Intensification and maintenance regimens were based on standard clinical practice. UST trough concentrations were measured at weeks 8,16, and 24 after induction. The primary objective was to assess endoscopic remission at week 24, defined as a simple-endoscopic-score (SES-CD) ≤2 for CD and a Mayo endoscopic score (MES) ≤1 for UC. Secondary endpoints included clinical remission, and endoscopic improvement. Quartile analysis and logistic regression assessed the relationship between UST concentrations and endoscopic outcomes, while logistic and Cox proportional hazards regressions identified variables associated with endoscopic remission and treatment discontinuation, respectively. The diagnostic performance of UST concentrations was assessed with receiver operating characteristic (ROC) curve analysis. Results Seventy patients (45 with CD) were enrolled. Those achieving endoscopic response and remission at week 24 had higher UST levels at week 8 (4.0 μg/mL vs. 2.5 μg/mL, p=0.002; 3.9 μg/mL vs. 2.9 μg/mL, p=0.047). Patients with UST concentrations in the fourth quartile (Q4) at week 8 (> 4.5 μg/mL) had higher rates of endoscopic remission (69% [Q4] vs. 23% [Q1], p=0.014; 24% [Q2], p=0.003; 31% [Q3], p=0.024). A UST concentration threshold of 4.5 μg/mL at week 8 was the best predictor of endoscopic remission (AUC=0.678, sensitivity 52.5%, specificity 84.6%), while 3.5 μg/mL predicted endoscopic response (AUC=0.732, sensitivity 63.6 %, specificity 73.1 %). Logistic regression did not reveal other predictive factors for endoscopic response/remission other than higher through concentrations at week 8. Longer disease duration correlated with a higher risk of UST discontinuation (OR 1.034, 95% CI 1.002-1.068, p=0.035). Fourteen (20%) patients discontinued UST after a median of 15.50 months. Higher UST concentrations in Q4 did not result in greater drug persistence (p=0.319). Conclusion UST concentrations at week 8 were positively associated with endoscopic outcomes at week 24, with a threshold of 4.5 μg/mL reliably predicting endoscopic remission. Further randomized clinical trials are warranted to explore whether optimizing UST treatment based on post-induction concentrations can enhance therapeutic outcomes. References K. Papamichael, E.H. Vogelzang, J. Lambert, G. Wolbink, A.S. Cheifetz, Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases, Expert Rev Clin Immunol 15 (2019) 837–848. https://doi.org/10.1080/1744666X.2019.1630273. D. Alsoud, G. De Hertogh, G. Compernolle, S. Tops, J. Sabino, M. Ferrante, D. Thomas, S. Vermeire, B. Verstockt, Real-world Endoscopic and Histological Outcomes Are Correlated with Ustekinumab Exposure in Patients with Ulcerative Colitis, J Crohns Colitis 16 (2022) 1562–1570. https://doi.org/10.1093/ECCO-JCC/JJAC067. C. Mcdonald, H. Kerr, E. Gibbons, T. Lukose, D. Cheriyan, G. Harewood, S. Patchett, A. O’toole, O. Kelly, K. Boland, Higher Ustekinumab Levels in Maintenance Therapy are Associated with Greater Mucosal Healing and Mucosal Response in Crohn’s Disease: An Experience of 2 IBD Centers, Inflamm Bowel Dis 30 (2024) 423–428. https://doi.org/10.1093/ibd/izad073. T. Straatmijer, V.B.C. Biemans, D.J.A.R. Moes, F. Hoentjen, R. ter Heine, P.W.J. Maljaars, R. Theeuwen, M. Pierik, M. Duijvestein, A.E. van der Meulen-de Jong, Ustekinumab Trough Concentrations Are Associated with Biochemical Outcomes in Patients with Crohn’s Disease, Dig Dis Sci 68 (2023) 2647. https://doi.org/10.1007/S10620-023-07822-7.