P442 Real-world endoscopic and histologic outcomes are linked to ustekinumab exposure in Ulcerative Colitis

Abstract

Background Histologic healing is being proposed as new treatment target in ulcerative colitis (UC), and the concept of histo-endoscopic mucosal improvement was introduced in the UNIFI study with ustekinumab (UST) in moderate–to-severe UC. Very little is known about the Pk-PD relationship of ustekinumab in UC patients, and especially whether serum UST concentrations correlate well with colonic tissue drug exposure and with histologic healing. The aim of this study is to provide real-world data including histology, and to study UST serum concentrations and its relation to tissue levels and drug efficacy. Methods UC patients starting UST in standard dosage at our referral centre were prospectively followed by clinical and endoscopic assessments at week, 16 or week, 24, and colonic biopsies were taken for histopathologic scoring. Histologic remission was defined as Nancy histology index (NHI) of, 0. Other collected outcomes were clinical response, clinical remission, endoscopic improvement, endoscopic remission and mucosal healing (definitions in Figure, 1). Paired trough serum sample and colonic mucosal biopsy were collected for UST levels measurement using a CE marked in-house developed ELISA. Results A total of, 42 UC patients started ustekinumab between June, 2019 and May, 2021, allowing a follow-up of at least, 6 months (Table, 1). By week, 24, clinical response, clinical remission, endoscopic improvement, endoscopic remission, and mucosal healing were observed in, 31 (74%), 24 (57%), 22 (52%), 11 (26%) and, 10 (24%) patients, respectively (Figure, 1). Histologic remission was observed in, 19 (45%) patients, of whom, 10 and, 9 with endoscopic Mayo, 0 and, 1, respectively. Multivariate analysis identified clinical response at week, 8 as a predictor for histologic remission at week, 24 [OR, 8.84, p = 0.024], and inversely correlated with therapy discontinuation [OR, 0.10, p = 0.006]. A trend of higher UST serum trough levels was observed in patients achieving histologic and endoscopic outcomes in comparison with patients who did not reach these outcomes, with a significant statistical difference at week, 8 for endoscopic outcomes (Figure, 2). UST concentrations from paired serum and biopsy samples revealed a strong positive correlation (Spearman r=0.88, p<0.001, n=17), both in inflamed (mayo endoscopic score >1) (r=0.89, p<0.001, n=10) and uninflamed (mayo endoscopic score ≤, 1) tissue (r=0.88, p<0.008, n=7) (Figure, 3). Conclusion In this real-word cohort of UC patients initiating UST, more than a third of the patients achieved histologic remission. Serum UST levels were furthermore strongly correlated with tissue levels of UST. A drug exposure-response relationship was observed for histologic and endoscopic outcomes.

Efficacy, Effectiveness, and Safety of Ustekinumab for the Treatment of Ulcerative Colitis: A Systematic Review

“…The percentage of patients with endoscopic remission at induction was similar in the RCTs and in 2 of the observational studies that reported it. 20 , 23 In another observational study, 24 this percentage was much higher, possibly due to its smaller sample size (23 patients). Another similarity between efficacy results (from RCTs) and effectiveness results (from observational studies) was clinical remission in maintenance, with the percentage of patients achieving remission ranging from 38% to 68% in RCTs and 33% to 79% in observational studies.…”

“…The median disease duration was between 5 and 9 years. Of the studies that reported data on UC extension, approximately half of the patients had extensive colitis, except for 1 study 23 that reported only 26%. The Supplementary Material shows the characteristics of included studies in detail ( Table S2 ).…”

“…On the contrary, there were 2 studies with a significantly low-quality rating (a score of 2 out of 9), indicating a large risk of bias. 20 , 23 The results of the quality assessments are presented in Tables 2 and 3 for RCTs and observational studies, respectively. Furthermore, the Supplementary Material shows the results of the risk of bias assessment in detail ( Tables S3 and S4 ).…”

Comparative effectiveness and safety of ustekinumab at different intervals of maintenance phase in inflammatory bowel disease: a systematic review and meta-analysis

“…Studies have shown that approximately 50% of CD patients who undergo intensive UST dose adjustments experience positive outcomes, but data on this approach in UC patients is limited [37]. A multivariate analysis based on real-world data found that clinical response to UST induction therapy at 8 weeks is a predictor of histologic remission at 24 weeks (OR, 8.84, P = 0.024) [38]. Direct comparison and evaluation of the therapeutic effects of the two maintenance intervals on IBD patients can better inform clinicians in the management of subsequent UST therapy, particularly for patients who respond well after the induction phase.…”

Constrained Multiple Instance Learning for Ulcerative Colitis Prediction Using Histological Images

“…However, incorporating histology into clinical practice remains challenging. This is due to: (1) the lack of a universal definition of HR that varies depending on the histological score/index applied, (2) the complexity of most scores and (3) the high inter-observer variability between pathologists [4,[7][8][9] .…”