Trial discontinuation: lessons for future trial design?

Background: The current therapeutic arsenal still does not fulfill the therapeutic needs of inflammatory bowel disease patients. Although new drugs are constantly being developed, many will never reach the market. In this review we will search for reasons for discontinuing promising clinical trials and offer recommendation for future trials. Methods: The website clinicaltrials.gov was searched for interventional trials on novel inflammatory bowel disease therapies. Included were discontinued ‘Crohn’s disease’ and/or ‘colitis, ulcerative’ trials, started between July 1996 and October 2011 and discontinued. Pubmed was searched for publications to elucidate reasons for discontinuation. Results: One hundred and ninety one novel drug trials were published on clinicaltrials. gov, of which 24 (12.6%) were interrupted. The most common reason for discontinuation was lack of efficacy. Conclusion: Translation from bench to bedside is not always feasible, animal models come with restrictions. For better treatments, personalized medicine will be the future

Patients' preferences regarding shared decision-making in the treatment of inflammatory bowel disease: Results from a patient-empowerment study

Shared decision-making is gaining favor in clinical practice, although the extent to which patients want to be involved in choosing their treatment varies substantially. Because data are lacking on the preferences of patients with chronic diseases such as inflammatory bowel disease (IBD), we wanted to assess IBD patients' preferences about being involved in such decisions. Methods: Adult IBD patients were asked to anonymously complete an online survey on their preferences. Non-parametric tests (χ2) were used to determine the relationship between responses and respondents. Results: The questionnaire was completed by 1,067 patients, 617 with Crohn's disease and 450 with ulcerative colitis. Patients' mean age was 43 (SD 13.7) years; the majority were female (66%). In total, 866 patients (81%) reported it as 'very important' to be actively involved in the decision-making process, and another 177 (17%) rated it as 'quite important'. When asked how their treatment could be improved, 537 patients (50%) wanted close, equitable collaboration with their physician. This preference was significantly associated with a disease duration of ≤8 years (p = 0.03). Gender and type of IBD were not significantly associated with patients' preferences. Conclusions: This study demonstrates IBD patients' desire to be actively involved in the decision-making process. Further research is needed on physicians' perspectives on shared decision-making, and on finding predictive factors for developing a model for shared decision-making in IBD. Copyrigh

Effect of biologicals and JAK inhibitors during pregnancy on health-related outcomes in children of women with inflammatory bowel disease

Current guidelines advise to maintain immunomodulators and biologicals in pregnant patients because relapse of inflammatory bowel is associated with unfavourable pregnancy outcome. With the exception of Methotrexate, IBD therapy seems not to be related to an increase of congenital malformations or infections requiring hospitalisation of the babies, although the effect the on the developing immune system of the exposed infants remains unknown. In this review we will focus on the effect of IBD drugs on health-related outcomes in children taking into account possible long-term effects of biologicals and immunomodulators, which are transferred across the placenta

Local immune regulation of mucosal inflammation by Tacrolimus

PURPOSE: Tacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgroup of proctitis patients. This study aimed to evaluate whether colonic mucosal immune cells are susceptible to locally applied tacrolimus in vitro. Our in vivo studies aimed at evaluating whether local tacrolimus treatment in mice would bring about local immune suppression and to compare colonic and systemic tacrolimus levels after locally and systemically applied tacrolimus. RESULTS: In vitro tacrolimus inhibited the activation of multiple cell types present in colonic tissue; lamina propria T cells, NKT cells, and both classical- and non- classical antigen presenting cells. However, the cytokine production of epithelial cells was not inhibited by tacrolimus at these concentrations. After rectal administration in mice, tacrolimus blood levels were comparable to those obtained by oral intake. However, rectally treated mice exhibited a 14-fold higher concentration of tacrolimus within their colonic tissue than orally treated mice. Moreover, rectally applied tacrolimus resulted in a local but not a systemic immune suppression in mice. CONCLUSIONS: Tacrolimus inhibits activation of several pivotal immune cells of the intestinal mucosa. Murine studies indicate that colonic application of tacrolimus induces local rather than systemic immune suppression

Fecal calprotectin is a reliable marker of endoscopic response to vedolizumab therapy: A simple algorithm for clinical practice

Background and Aim: The association of fecal calprotectin (FC) and endoscopic response in inflammatory bowel disease patients during vedolizumab (VDZ) treatment is largely unknown. The aim of this study is to assess the diagnostic value of FC to predict endoscopic respo

A Direct Effect of Sex Hormones on Epithelial Barrier Function in Inflammatory Bowel Disease Models

Background: Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences of these pregnancy hormones on barrier cells and their function. Methods: We used IBD patient-derived inflammatory organoid models and 2D cell lines models. Epithelial barrier function was analyzed by measuring transepithelial electrica