Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial.

Background: IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a protein that serves as a transcriptional regulator of bowel epithelium regeneration. We aimed to evaluate the safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856 in healthy participants and in patients with coeliac disease.

Methods: This study reports the results from a completed first-in-human, three-part, double-blind, randomised, placebo-controlled, clinical trial of IMU-856 in healthy participants and patients with coeliac disease done in Australia and New Zealand.

Environmental Determinants of Islet Autoimmunity (ENDIA) longitudinal prospective pregnancy to childhood cohort study of Australian children at risk of type 1 diabetes: parental demographics and birth information.

Introduction: The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes.

Research Design And Methods: Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D.

Evolution in coeliac disease diagnosis and management.

The traditional gut-centric view of coeliac disease is evolving as immune and genetic insights underscore the central importance of a systemic, T cell immune response to gluten in disease pathogenesis. As the field increasingly recognize the limitations of small intestinal histology as the diagnostic standard, data supporting the accuracy of an immune (serologic) diagnosis of coeliac disease - well demonstrated in children - are growing for adults. Novel biomarkers such as interleukin-2 that identify the gluten-specific T cell demonstrate high sensitivity and specificity for coeliac disease and offer the potential for a diagnostic approach that avoids the need for gluten challenge.

Budesonide Induces Favourable Histologic and Symptomatic Recovery in Patients with Non-responsive and Refractory Coeliac Disease When Given in an Open Capsule Format.

Introduction: Non-responsive coeliac disease (NRCD), where symptoms and enteropathy persist despite a prolonged gluten-free diet (GFD), is common. Refractory coeliac disease (RCD), characterised by malabsorption and extensive enteropathy, is rare but serious. In both, treatment options are limited.

Past, Present, and Future of Noninvasive Tests to Assess Gluten Exposure, Celiac Disease Activity, and End-Organ Damage.

Although many biomarkers have been proposed, and several are in widespread clinical use, there is no single readout or combination of readouts that correlates tightly with gluten exposure, disease activity, or end-organ damage in treated patients with celiac disease. Challenges to developing and evaluating better biomarkers include significant interindividual variability-related to immune amplification of gluten exposure and how effects of immune activation are manifest. Furthermore, the current "gold standard" for assessment of end-organ damage, small intestinal biopsy, is itself highly imperfect, such that a marker that is a better reflection of the "ground truth" may indeed appear to perform poorly.

Clinical Presentation and Spectrum of Gluten Symptomatology in Celiac Disease.

Views on the clinical presentation and symptomatology of celiac disease have evolved alongside advances in disease detection and understanding of disease pathogenesis. Although historically regarded as a pediatric illness characterized by malabsorption, it is now better viewed as an immune illness of gluten-specific T cells with systemic manifestations affecting all ages. Its broad presentation, including frequent extraintestinal manifestations and asymptomatic disease, contributes to suboptimal disease detection.

Development and validation of a brain fog scale for coeliac disease.

Background: Brain fog is a subjective cognitive impairment commonly reported in coeliac disease. A standardised tool to define and assess it is an important unmet need.

Aims: To develop a patient-informed tool to assess brain fog in coeliac disease to support clinical care, research and drug development.

Impaired IgM Memory B Cell Function Is Common in Coeliac Disease but Conjugate Pneumococcal Vaccination Induces Robust Protective Immunity.

Coeliac disease (CD) is associated with hyposplenism, an acquired impairment of spleen function associated with reduced IgM memory B cells and increased susceptibility to serious pneumococcal infection. Little is known about the immune implications of hyposplenism in CD or the optimal pneumococcal vaccination strategy. In this study, the immune effects of hyposplenism in CD, and the accuracy of screening approaches and protective responses induced by two different pneumococcal vaccines were examined.

Stool Gluten Peptide Detection Is Superior to Urinary Analysis, Coeliac Serology, Dietary Adherence Scores and Symptoms in the Detection of Intermittent Gluten Exposure in Coeliac Disease: A Randomised, Placebo-Controlled, Low-Dose Gluten Challenge Study.

Monitoring adherence to a gluten-free diet is an important goal of coeliac disease management. Urine and stool gluten immunogenic peptide (GIP) assays provide an objective readout of gluten ingestion, with the former favoured due to its convenience and acceptability. This study assessed stool GIP excretion after low-dose gluten challenge designed to mimic accidental gluten exposure.

Follow-Up of Celiac Disease in Adults: "When, What, Who, and Where".

For patients with celiac disease (CeD), a lifelong gluten-free diet is not a voluntary lifestyle choice-it is a necessity. The key end points in clinical follow-up are symptom resolution, the normalization of weight, prevention of overweight, seroconversion, and negation or minimization of increased long-term morbidity. For the latter, a surrogate endpoint is mucosal healing, which means the normalization of histology to Marsh 0-1.

Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with coeliac disease after bolus exposure to gluten (RESET CeD): an interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study.

Background: A gluten-free diet is insufficient to treat coeliac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy using immunodominant peptides recognised by gluten-specific CD4 T cells that might modify gluten-induced disease in coeliac disease. We aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with coeliac disease.

The mosaic oat genome gives insights into a uniquely healthy cereal crop.

Cultivated oat (Avena sativa L.) is an allohexaploid (AACCDD, 2n = 6x = 42) thought to have been domesticated more than 3,000 years ago while growing as a weed in wheat, emmer and barley fields in Anatolia. Oat has a low carbon footprint, substantial health benefits and the potential to replace animal-based food products.

Longitudinal assessment of the common sense model before and during the COVID-19 pandemic: A large coeliac disease cohort study.

Objective: Psychosocial factors likely play a substantial role in the well-being of those living with coeliac disease, especially during the COVID-19 pandemic, however, little research has examined well-being in this cohort using an integrated socio-cognitive model. This study had two aims: (1) Examine changes in gastrointestinal symptoms, psychosocial factors, and well-being outcomes (i.e.

Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells.

Although hydroxychloroquine (HCQ) has long been used to treat autoimmune diseases, its mechanism of action remains poorly understood. In CD4 T-cells, we found that a clinically relevant concentration of HCQ inhibited the mitochondrial antioxidant system triggered by TCR crosslinking, leading to increased mitochondrial superoxide, impaired activation-induced autophagic flux, and reduced proliferation of CD4 T-cells. In antigen-presenting cells, HCQ also reduced constitutive activation of the endo-lysosomal protease legumain and toll-like receptor 9, thereby reducing cytokine production, but it had little apparent impact on constitutive antigen processing and peptide presentation.

Quality of life in coeliac disease: relationship between psychosocial processes and quality of life in a sample of 1697 adults living with coeliac disease.

Background: Coeliac disease is a chronic gastrointestinal condition associated with an increased risk of psychiatric comorbidity, and diminished quality of life. Ongoing gastrointestinal symptomatology is frequently reported post-diagnosis, despite undertaking a gluten-free diet.

Purpose: To examine the role of psychosocial factors in mediating the relationship between gastrointestinal symptoms and quality of life, using a cross-sectional structural equation modelling mediation analysis guided by the Common-Sense Model.

A Sensitive Whole Blood Assay Detects Antigen-Stimulated Cytokine Release From CD4+ T Cells and Facilitates Immunomonitoring in a Phase 2 Clinical Trial of Nexvax2 in Coeliac Disease.

Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial ("RESET CeD") of Nexvax2, a peptide-based immunotherapy for CD.