Alsoud, D.(1);Compernolle, G.(2);Tops, S.(2);Sabino, J.(1,3);Ferrante, M.(1,3);Thomas, D.(2);De Hertogh, G.(4);Vermeire, S.(1,3);Verstockt , B.(1,3);
(1)KU Leuven, Translational Research in Gastrointestinal Disorders- Department of Chronic Disease- Metabolism and Ageing, Leuven, Belgium;(2)KU Leuven, Laboratory for Therapeutic and Diagnostic Antibodies- Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium;(3)University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium;(4)University Hospitals Leuven, Laboratory of Morphology and Molecular Pathology, Leuven, Belgium;
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.
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.
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).
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.