No Superiority of Tacrolimus Suppositories vs Beclomethasone Suppositories in a Randomized Trial of Patients With Refractory Ulcerative Proctitis.

BACKGROUND & AIMS: Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP. METHODS: We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test. RESULTS: Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups. CONCLUSIONS: In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.

Patient sex does not affect endoscopic outcomes of biologicals in inflammatory bowel disease but is associated with adverse events.

PURPOSE: Biological therapies are currently the mainstay in the treatment of patients with inflammatory bowel diseases (IBD). Several factors are known to influence the efficacy and tolerability of biologicals, such as CRP levels or previous biological use. Whether patient sex affects the efficacy or tolerability is unclear but would help with better risk and benefit stratification. This systematic review assesses patient sex on the efficacy and tolerability of biological therapies in IBD patients. METHODS: A systematic literature review was performed using Embase (including MEDLINE), MEDLINE OvidSP, Cochrane Central Register of Controlled Trials, Web of Science and PubMed. The primary outcome was the influence of patient sex on endoscopic outcomes in IBD patients treated with biologicals. The secondary outcome was the influence of patient sex on adverse events. Studies were included in the assessment regardless of study type or setting. RESULTS: The search yielded 19,461 citations; after review, 55 studies were included in the study, involving 28,465 patients treated with adalimumab, certolizumab pegol, infliximab, or vedolizumab. There was no significant association between patient sex and endoscopic efficacy in 41 relevant studies. Increased adverse events were associated with female sex in 7 out of 14 relevant studies. CONCLUSIONS: There is no evidence for a sex difference in endoscopically measured response to biological therapies in IBD patients. However, there is an influence of sex on the occurrence of adverse events.

Low dose Naltrexone for induction of remission in inflammatory bowel disease patients.

BACKGROUND: Around 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function. METHODS: Patients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples. RESULTS: Low dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers. Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN. Cytokine levels in neither epithelial cells nor serum from IBD patients were affected. CONCLUSIONS: Naltrexone directly improves epithelial barrier function by improving wound healing and reducing mucosal ER stress levels. Low dose Naltrexone treatment is effective and safe, and could be considered for the treatment of therapy refractory IBD patients.

Low-dose naltrexone for the induction of remission in patients with mild to moderate Crohn's disease: protocol for the randomised, double-blinded, placebo-controlled, multicentre LDN Crohn study.

INTRODUCTION: Crohn's disease (CD) is an inflammatory bowel disease (IBD). Several drugs exist to induce and maintain remission, but a significant part of the patients is refractory to current IBD drugs or experiences side effects. Whether low-dose naltrexone (LDN) is a safe and easily accessible alternative treatment option for these patients needs to be investigated. The aim of this study is to assess the efficacy of LDN for the induction of remission in patients with mild to moderate CD. METHODS AND ANALYSIS: The LDN Crohn study is a randomised, double-blinded, placebo-controlled multicentre trial. Patients with CD are randomised 1:1 to receive treatment with either LDN 4.5 mg once daily or placebo for 12 weeks. The primary objective is endoscopic remission at week 12, defined as Simple Endoscopic Score-CD≤2 and ulcerated surface subscore ≤1 in all five segments. Secondary aims include clinical and endoscopic response, changes in laboratory measures of inflammation, adverse events and patient-reported outcomes. To have 85% power to detect a true difference in the primary outcome measure between placebo and LDN, 61 patients will be needed in both groups. ETHICS AND DISSEMINATION: The study is approved by the Medical Ethics Committee of the Erasmus MC, Rotterdam, the Netherlands (registration number NL69149.078.19, MEC-2019-0602). Results will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBERS: EudraCT2019-000852-32; NL9259.

Sex Is Associated with Adalimumab Side Effects and Drug Survival in Patients with Crohn's Disease.

BACKGROUND: Adalimumab (ADA) is an effective treatment for Crohn's disease (CD). In rheumatology, sex differences concerning the response to ADA therapy have been described. However, such differences have not yet been reported for patients with CD. As such, the aim of this study was to compare ADA treatment outcomes in male and female patients with CD. METHODS: A clinical cohort was formed of consecutive patients with CD starting ADA in a single tertiary center between March 2006 and February 2011. The cohort was followed up to August 2015. Clinical outcomes were primary nonresponse, secondary nonresponse, and drug survival (ongoing ADA use). Reasons for stopping ADA were recorded. Kaplan-Meier analysis and Cox regression were used to assess drug survival. RESULTS: The cohort consisted of 107 female and 81 male patients. Median follow-up was 6.0 years (range 0.3-9.2). Drug survival was higher in male than female patients (48.1% versus 30.8%, P = 0.016). Side effects were reported more often by female patients (81.3% versus 64.2%, P = 0.008), and female patients ceased ADA more often due to side effects (35.4% versus 18.4%, P = 0.017). In survival analysis, female sex was associated with higher cessation rates (P = 0.006). Cox regression also identified female sex (P = 0.020), along with higher baseline CD Activity Index (P = 0.003), as predictors of ADA cessation. CONCLUSIONS: Female sex is negatively associated with ADA drug survival. Female patients report more side effects and cease ADA because of side effects more often. A more personalized and sex-specific approach seems warranted to increase drug survival in female patients.

A red-shifted photochromic sulfonylurea for the remote control of pancreatic beta cell function.

Azobenzene photoresponsive elements can be installed on sulfonylureas, yielding optical control over pancreatic beta cell function and insulin release. An obstacle to such photopharmacological approaches remains the use of ultraviolet-blue illumination. Herein, we synthesize and test a novel yellow light-activated sulfonylurea based on a heterocyclic azobenzene bearing a push-pull system.

Drug therapies for ulcerative proctitis: systematic review and meta-analysis.

BACKGROUND: Patients with ulcerative colitis limited to the proctum are considered to have ulcerative proctitis (UP). In patients with more extensive ulcerative colitis, treatment occurs in a step-up fashion (5-ASA, corticosteroids, thiopurines, anti-TNF-α agents), a strategy which has proven effective. Although treatment of UP occurs using the same step-up design, the efficacy of these therapies in UP is scarcely studied. The objectives were to systematically review the literature for randomized controlled trials studying drug therapies for induction and maintenance of remission in patients with UP. METHODS: Electronic databases and reference lists of review articles were searched. The primary outcomes were clinical remission induction rate and the maintained clinical remission rate. Secondary outcomes were induction and maintenance of endoscopic and histological remission. Relative risks (RR) and 95% confidence intervals (CI) for were calculated. RESULTS: Twenty-three studies (1834 patients) were included. Eighteen trials investigated induction and 5 studied maintenance of remission. Topical 5-ASA was significantly superior to placebo for induction (RR, 2.39; 95% CI, 1.63-3.51) and maintenance (RR, 2.80; 95% CI, 1.21-6.45) of clinical remission, regardless of dose or formulation. Subgroup analysis of 5-ASA suppositories also showed superiority over placebo for induction of clinical (RR, 3.07; 95% CI, 1.70-5.55) and endoscopic remission (RR, 2.64; 95% CI, 1.85-3.77). CONCLUSIONS: Topical 5-ASA is superior to placebo for the induction and maintenance of clinical remission and for the induction of endoscopic remission. The efficacy of corticosteroids, thiopurines, and anti-TNFα has been insufficiently studied in patients with UP.