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Background Histo-endoscopic outcomes are being proposed as new treatment targets in ulcerative colitis (UC). Little is known about the PK-PD relationship of ustekinumab (UST) in UC patients, and whether serum UST concentrations reflect tissue drug exposure. We aimed to study UST serum concentrations and its relation to tissue exposure and drug effectiveness in a real-world setting. Methods Forty-two UC patients starting UST were prospectively followed by clinical, endoscopic and histological assessments at week 16. Histologic remission was defined as Nancy histology index of 0. Analogous to the UNIFI program, histo-endoscopic mucosal improvement was defined as a combination of histologic improvement (Geboes ≤3.1) and endoscopic improvement (MES ≤1). Paired trough serum sample and colonic mucosal biopsies were collected for UST levels measurement. Results After 16 weeks [IQR 15.8 - 16.4] of therapy, histologic remission and histo-endoscopic mucosal improvement were observed in 19 (45%) and 18 (43%) patients, respectively. Patients who achieved these outcomes had higher serum UST levels than those who didn’t. Patients with shorter disease duration and clinical response at week 8 had higher odds to achieve histologic remission. UST concentrations from paired serum and biopsy samples revealed a strong positive correlation (r = 0.88, p < 0.001), both in inflamed and uninflamed tissue. Conclusion In this real-word cohort of refractory UC patients initiating UST, more than a third of the patients achieved histologic remission. A drug exposure-response relationship was observed for histo-endoscopic outcomes, with no added value of measuring tissue exposure given the strong correlation with serum exposure.

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Inflammatory Bowel Disease (IBD) has a multifactorial origin and originates from a complex interplay of environmental factors with the innate immune system at the intestinal epithelial interface in a genetically susceptible individual. All these factors make its etiology intricate and largely unknown. Multi-omic datasets obtained from IBD patients are required to gain further insights into IBD biology. We here review the landscape of multi -omic data availability in IBD and identify barriers and gaps for future research. We also outline the various technical and non-technical factors that influence the utility and interpretability of multi -omic datasets and thereby the study design of any research project generating such datasets. Co-ordinated generation of multi-omic datasets and their systemic integration with clinical phenotypes and environmental exposures will not only enhance understanding of the fundamental mechanisms of IBD but also improve therapeutic strategies. Finally, we provide recommendations to enable and facilitate generation of multi -omic datasets.

Background In recent phase 3 trials, risankizumab (RZB), a humanised monoclonal IgG1 antibody targeting the interleukin 23 p19 subunit, proved to be superior to placebo in inducing and maintaining clinical remission and endoscopic response in patients with moderate-to-severe Crohn’s disease. In this study, we aimed to evaluate the effectiveness and safety of RZB in a real-world cohort of multi-refractory CD patients. Methods Adult CD patients from six Belgian IBD centres who initiated RZB prior to May 2021 as part of a medical need program were prospectively followed. Patients with an ostomy were excluded for the main analyses. The primary endpoint was steroid-free clinical remission at week 24 (average daily liquid stool frequency [SF] ≤2.8 and average abdominal pain [AP] score ≤1, both not worse than baseline). Secondary endpoints included clinical response, endoscopic remission, endoscopic response, biological remission, biological response, need for CD-related hospitalisation or surgery, and serious adverse events (definitions in Figure 1). Given that a follow-up endoscopy has not yet been performed in some patients, results are shown for both “all patients” (with non-responder imputation) and “as observed”. Results A total of 27 patients started RZB of whom 19 patients were eligible for this study with a minimal follow-up of 24 weeks (Table 1). Eight patients were excluded as they had an ostomy at time of RZB initiation. Eighteen patients (95%) had been exposed to more than 3 biologicals and 13 (68%) previously underwent a CD-related intestinal resection. By week 24, 7/19 (37%) and 7/19 (37%) patients achieved steroid-free clinical remission and endoscopic response, respectively (Figure 1). In the “as observed” analyses, these rates were 7/18 (39%) and 7/9 (78%), respectively (Figure 2). Five patients used concomitant steroids at baseline and were all able to stop it after a median of 10 weeks. Eventually, three patients had to be hospitalized for bowel resection (2 with placement of an ostomy) after a median of 24 weeks, two of them required earlier an emergent hospitalization due to flares of abdominal pain and bloody diarrhea. None of the patients experienced serious infections or intolerance. Based on physician global assessment, three out of eight patients with an ostomy did achieve clinical remission, and two other achieved clinical response. Endoscopic follow-up data were available in six patients, and three of them experienced endoscopic response. Conclusion In this real-world, multi-refractory cohort, clinical remission and endoscopic response were both observed by week 24 in more than one third of CD patients initiating RZB. RZB was well tolerated with no safety issues.