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.
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.
Aims Controversies regarding infliximab treatment in elderly patients with inflammatory bowel diseases remain. We evaluated the effect of patient's age on infliximab exposure, efficacy and safety. Methods Retrospective case‐control data of patients receiving infliximab induction treatment were analysed. A population pharmacokinetic model was developed to estimate individual pharmacokinetic parameters. A logistic regression model was used to investigate the effect of exposure on endoscopic remission. Repeated time‐to‐event models were developed to describe the hazard of safety events over time. Results A total of 104 patients (46 elderly, ≥65 years) were included. A two‐compartment population pharmacokinetic model with linear elimination adequately described the data. Infliximab clearance decreased with older age, higher serum albumin, lower fat‐free mass, lower C‐reactive protein and absence of immunogenicity. Yet, infliximab exposure was not significantly different between elderly and nonelderly. Regardless of age, an infliximab trough concentration at week (w)14 of 15.6 mg/L was associated with a 50% probability of attaining endoscopic remission between w6 and w22. Infliximab exposure during induction treatment was not a risk factor of (severe) adverse events. The hazard of severe adverse events and malignancy increased by 2% and 7%, respectively, with increasing year of age. Concomitant immunomodulator use increased the hazard of infection by 958%, regardless of age. Conclusions Elderly patients attained infliximab exposure and endoscopic remission similarly to nonelderly patients. Therefore, the same infliximab trough concentration target can be used in therapeutic drug monitoring. The hazards of severe adverse events and malignancy increased with age, but not with infliximab exposure.
The past decades witnessed a significant stride in deciphering the pathophysiology of inflammatory bowel disease, which further advanced drug development adding several new biologicals and small molecules to the arsenal of available therapies. Surprisingly, this wealth in therapeutic options did not yield the aspired high durable response rates. In addition, the increase in therapeutic availabilities ignited an increase in research toward biomarkers that could help assign therapies to patients with the highest probability of response. Luckily, major steps have been undertaken in this domain which resulted in the discovery of some interesting biomarkers that are still under validation. However, the pace in which this domain is progressing, the discordance between short-term endpoints in biomarker discovery studies and the ambition of the disease community in modifying disease course, and the uncertainties about the validity of discovered biomarkers highlight the need for a critical appraisal of research conduct in this domain. In this review, we shed light on areas of improvement in biomarker discovery studies that will help optimize the use of available therapies and break the current therapeutic ceiling.
Background Therapeutic options for Crohn’s disease are growing, making the choice of first-line therapy relevant. Both adalimumab and ustekinumab are effective in moderate-to-severe Crohn’s disease. The Safety and Efficacy of Adalimumab Versus Ustekinumab for One Year trial suggested no difference in clinical or endoscopic remission at week 52 in biological-naive Crohn’s disease patients. We explored if results withstand in the real world. Methods We included bio-naive Crohn’s disease patients starting adalimumab or ustekinumab between 2017 and 2020. Patients had endoscopy-proven moderate-to-severe disease [Simple Endoscopic Score for Crohn’s disease (SES-CD) ≥3]. Clinical remission was defined as Harvey Bradshaw Index (HBI) <5 or physician global assessment. Endoscopic remission (SES-CD <3) and improvement (≥50% reduction in SES-CD from baseline) were assessed at W26-52. Propensity score matching was used. Results A total of 68 biological-naive Crohn’s disease patients were included (32 adalimumab and 32 ustekinumab) and followed for median of (IQR) 60 (33–104) weeks. Patients had significantly higher odds of achieving endoscopic remission with adalimumab than ustekinumab [adjusted odds ratio (aOR), 2.73; confidence interval (CI), 1.12–7.36; P = 0.03]. Also, more adalimumab-treated patients achieved endoscopic response, clinical remission at week 26 and 52 (aOR, 2.24; CI, 0.94–5.71; P = 0.07; aOR, 1.26; CI, 0.36–4.51; P = 0.72; aOR, 1.58; CI, 0.54–4.88; P = 0.41, respectively). Treatment persistence was not different between groups (P = 0.44). The number of adverse events was similar. Conclusion In a real-world cohort of biological-naive Crohn’s disease patients, adalimumab was superior to ustekinumab in achieving endoscopic remission. No differences in clinical remission at W26-52 or treatment persistence were observed. Both adalimumab and ustekinumab remain good options as first-line biologicals in moderate-to-severe Crohn’s disease.
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