Safety and efficacy of the anti-TL1A monoclonal antibody tulisokibart for Crohn's disease: a phase 2a induction trial.

Background: TNF-like cytokine 1A (TL1A) is a key mediator of inflammation and fibrosis. The efficacy and safety of the anti-TL1A monoclonal antibody tulisokibart as induction treatment was assessed in adults with moderately to severely active Crohn's disease with a history of insufficient response, loss of response, or intolerance to conventional or approved biological therapies.

Methods: In the phase 2a, multicentre, open-label APOLLO-CD study, participants aged 18 years or older with moderately to severely active Crohn's disease, as defined by a Crohn's Disease Activity Index (CDAI) of 220-450 and a Simple Endoscopy Score for Crohn's Disease (SES-CD) of at least 6 for ileocolonic or colonic disease or at least 4 for isolated ileal disease, received intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10).

Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis.

Background: Tulisokibart is a tumor necrosis factor-like cytokine 1A (TL1A) monoclonal antibody in development for the treatment of moderately to severely active ulcerative colitis. A genetic-based diagnostic test was designed to identify patients with an increased likelihood of response.

Methods: We randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo.

A randomized, double-blind, placebo-controlled, phase 2b study of the efficacy and safety of velusetrag in subjects with diabetic or idiopathic gastroparesis.

Background: This study assessed the efficacy and safety of velusetrag-a 5-HT agonist with pan-gastrointestinal prokinetic activity-for gastroparesis symptom management and gastric emptying (GE).

Methods: In this multicenter, double-blind, randomized, placebo-controlled study, subjects with diabetic or idiopathic gastroparesis received velusetrag 5, 15, or 30 mg or placebo for 12 weeks. The primary efficacy outcome was a 7-day mean Gastroparesis Cardinal Symptom Index 24-h composite score (GCSI-24H) change from baseline at week 4; GE was evaluated using scintigraphy (GES) and breath tests, and safety from adverse events (AEs).

Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study.

Background: Gastroparesis is a serious gastrointestinal (GI) condition characterised by delayed gastric emptying (GE). Velusetrag-a potent, selective, pan-gastrointestinal 5-hydroxytryptamine type 4 receptor agonist-is under investigation for treatment of GI motility disorders including gastroparesis.

Aims: To assess the efficacy and safety of velusetrag for accelerating GE in subjects with diabetic or idiopathic gastroparesis.

Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme.

Background And Aims: Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473-an oral gut-selective pan-JAK inhibitor-from in vitro characterization through a Phase 1b study in patients with UC.

Methods: TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice.

Immunologic Alterations Associated With Oral Delivery of Anti-CD3 (OKT3) Monoclonal Antibodies in Patients With Moderate-to-Severe Ulcerative Colitis.

Aim: The aim of this study was to determine the immunologic effects and safety of oral anti-CD3 in patients with ulcerative colitis (UC).

Methods: An open-label pilot study of orally delivered anti-CD3 was performed in patients with moderate-to-severe UC. The primary end points were changes in immunologic parameters and evaluation for safety.

Antibiotic Treatment Induces Long-lasting Changes in the Fecal Microbiota that Protect Against Colitis.

Background: The interplay between host genetics, immunity, and microbiota is central to the pathogenesis of inflammatory bowel disease. Previous population-based studies suggested a link between antibiotic use and increased inflammatory bowel disease risk, but the mechanisms are unknown. The purpose of this study was to determine the long-term effects of antibiotic administration on microbiota composition, innate immunity, and susceptibility to colitis, as well as the mechanism by which antibiotics alter host colitogenicity.

Impact of Specialized Inpatient IBD Care on Outcomes of IBD Hospitalizations: A Cohort Study.

Background: The management of inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) is increasingly complex. Specialized care has been associated with improved ambulatory IBD outcomes.

Aims: To examine if the implementation of specialized inpatient IBD care modified short-term and long-term clinical outcomes in IBD-related hospitalizations.

Efficacy of Vedolizumab as Induction Therapy in Refractory IBD Patients: A Multicenter Cohort.

Background: Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients.

Methods: Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion.

High C-Reactive Protein Is Associated with Poor Sleep Quality Independent of Nocturnal Symptoms in Patients with Inflammatory Bowel Disease.

Background: Sleep disruption is common in inflammatory bowel diseases (IBD). However, studies demonstrating a similar prevalence in irritable bowel syndrome suggest that nighttime disruption due to diarrhea and abdominal pain may be key drivers of poor sleep quality. Whether inflammation is associated with poor sleep independently has not been examined previously.

Impact of mode of delivery on outcomes in patients with perianal Crohn's disease.

Background: Crohn's disease (CD) often affects women during the reproductive years. Although several studies have examined the impact of pregnancy on luminal disease, limited literature exists in those with perianal CD. Decision regarding mode of delivery is a unique challenge in such patients due to concerns regarding the effect of pelvic floor trauma during delivery on preexisting perianal involvement.

Impaired innate immune function associated with fecal supernatant from Crohn's disease patients: insights into potential pathogenic role of the microbiome.

Background: Although a dysbiosis of the intestinal microbiome plays a role in the pathogenesis of Crohn's disease (CD), the functional implication is unclear. We sought to determine the influence of fecal supernatant from patients with CD on innate immune function in neutrophil, macrophage, and epithelial cells. Metabolomic analysis was subsequently performed in an attempt to identify potential compounds responsible for the effects identified.

Natural history of Crohn's disease following total colectomy and end ileostomy.

Background: Crohn's disease (CD) requires surgical management in up to two-thirds of patients. Few studies have addressed the issue of ileal recurrence after colectomy and permanent ileostomy. The aims of our study were to assess the rate and predictors of postoperative recurrence of CD in patients with permanent ileostomy.

Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells.

Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases.

Background: Cigarette smoking is a well-established environmental risk factor for Crohn's disease (CD) and ulcerative colitis (UC). The exact mechanism of its effect remains unexplained. Genetic polymorphisms in metabolizing enzymes may influence susceptibility to the effect of smoking and shed light on its mechanism of action.

Venous thromboembolism in patients with inflammatory bowel diseases: a case-control study of risk factors.

Background: Inflammatory bowel disease (IBD) is a well-known risk factor for venous thromboembolism (VTE). Existing guidelines for thromboprophylaxis in hospitalized patients do not extend to other clinical scenarios that may also be associated with VTE risk. Our aim was to estimate the fraction of VTE events in patients with IBD that could be prevented.

Differential effect of genetic burden on disease phenotypes in Crohn's disease and ulcerative colitis: analysis of a North American cohort.

Objectives: Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown.

Animal models of ulcerative colitis and their application in drug research.

The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn's disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy.

Pretreatment 25-hydroxyvitamin D levels and durability of anti-tumor necrosis factor-α therapy in inflammatory bowel diseases.

Introduction: Emerging evidence supports an immunologic role for 25-hydroxyvitamin D (25(OH)D) in inflammatory bowel disease (IBD). Here we examined if pretreatment vitamin D status influences durability of anti-tumor necrosis factor (TNF)-α therapy in patients with Crohn's disease (CD) or ulcerative colitis (UC).

Methods: All IBD patients who had plasma 25(OH)D level checked <3 months prior to initiating anti-TNF-α therapy were included in this retrospective single-center cohort study.

β7 integrins are required to give rise to intestinal mononuclear phagocytes with tolerogenic potential.

Background And Objective: While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin α4β7 is required for this process.

Methods: We used a T cell-mediated colitis model to study the role of α4β7 in the innate immune compartment.

Colitis and colon cancer in WASP-deficient mice require helicobacter species.

Background: Wiskott-Aldrich syndrome protein-deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which Helicobacter spp. have been implicated in disease pathogenesis.

The microbiota and inflammatory bowel disease: insights from animal models.

Inflammatory bowel disease (IBD) is thought to result from a dysregulated immune response to intestinal microbial flora in individuals with genetic predisposition(s). Genome-wide association studies (GWAS) in human IBD have identified more than 150 associated loci, some of which are key players in innate immunity and bacterial handling, reflecting the importance of the microbiota in disease pathogenesis. In fact, the presence of a microbial flora is not only crucial to the development of a normal murine immune system but also critical for the development of disease in the majority of animal models of IBD.

Impact of coexistent celiac disease on phenotype and natural history of inflammatory bowel diseases.

Objectives: Inflammatory bowel disease (IBD) and celiac disease are the two most common immune-mediated gastrointestinal diseases. There is limited knowledge regarding the course of IBD in those with coexisting celiac disease. We conducted this study to determine whether patients with coexisting celiac disease present a unique phenotype of IBD and to examine the frequency of co-occurrence of celiac disease and IBD in comparison with other autoimmune disorders.