Murray, J A

ABSTRACT Background Immune checkpoint inhibitors (ICIs) enhance anti‐tumour immunity by modulating immune pathways but can also trigger immune‐related adverse events. We aimed to evaluate the risk of developing coeliac disease (CeD) among patients with malignancy treated with ICIs. Methods Using the TriNetX US Collaborative Network, we identified adults (≥ 18 years) diagnosed with malignancies for which ICIs are routinely used between January 2010 and December 2024 and stratified them by exposure to immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, tremelimumab, or avelumab). Patients with pre‐existing celiac disease (CeD) were excluded. Cohorts were propensity score matched for demographics and autoimmune comorbidities. The primary outcome was incident CeD occurring ≥ 90 days after the index event. Adjusted hazard ratios (aHRs) were calculated, with subgroup analyses by age and sex. Statistical significance was defined as p < 0.05. Results After propensity score matching, 158,208 patients were included in each cohort. CeD was diagnosed more frequently among patients exposed to ICIs than among matched controls (0.152% vs. 0.071%; aHR 3.95, 95% CI 3.11–5.03; p < 0.001), corresponding to a number needed to harm (NNH) of 1235. The increased risk persisted across sex and age subgroups, including females (aHR 3.43, 95% CI 2.55–4.62), males (aHR 5.36, 95% CI 3.53–8.12), with the risk being highest among patients older than 60 years (0.14% vs. 0.06%; aHR 4.24, 95% CI 3.17–5.67; p < 0.001). Conclusion In this large real‐world cohort, ICI exposure was associated with nearly a fourfold increase in the risk of being diagnosed with CeD compared with matched controls.

ABSTRACT Background Coeliac disease is due to an acquired, lifelong gluten‐specific immune response resulting in a gluten‐dependent chronic immune‐mediated enteropathy associated with gastrointestinal and extraintestinal morbidity. Strictly avoiding dietary gluten is the only available management but has never been subjected to rigorous efficacy assessment now required for a pharmaceutical agent. Gluten‐free diet (GFD) is partially and inconsistently effective, but it places a high burden on patients, families, the food industry, and regulators and is defined inconsistently around the world, highlighting the need for effective and convenient adjunctive pharmacological therapies. Aims To summarize key patient, scientific, and regulatory considerations for coeliac disease drug development based on a multi‐stakeholder meeting focused on accelerating clinical trials. Methods A pre‐competitive meeting convened by the Beyond Celiac Coalition (May 2024) included patients with coeliac disease, academic experts, pharmaceutical industry representatives, and participants from the US Food and Drug Administration. Moderated panel addressed patient priorities, symptom and histologic endpoints, biopsy and histology methods, gluten challenge design, clinical trial duration, and regulatory expectations. Themes were synthesized qualitatively with focus on trial design implications and unresolved questions. Results Participants described high symptom burden and psychosocial impact despite gluten‐free diet adherence underscoring unmet therapeutic need in coeliac disease. Regulatory perspectives emphasized the need for clinically meaningful improvement and evidence of intestinal benefit, framed as symptom and histology co‐primary endpoints in clinical trials. These expectations were discussed as most applicable to trial populations with both clinically meaningful symptoms and active histologic injury at baseline; for other phenotypes, it was emphasized that endpoint strategy, the role of gluten exposure, and trial duration should be tailored case by case to the population and mechanism of action. Practical challenges identified included endpoint selection and definition, discordance between symptoms and histology, selecting fit‐for‐purpose symptom measures; standardizing biopsy acquisition and central histology reads to address patchiness and variability, pre‐specifying definitions of meaningful histologic change given ongoing uncertainty about healing, and trial feasibility. Controlled gluten exposure was discussed as a tool to improve interpretability of efficacy outcomes, with careful consideration of dose, duration, patient burden and safety. Discussion addressed the ideal length of the double‐blind period, including a shorter 24‐week double‐blind study with an open‐label extension versus a 52‐week double‐blind design. Trial duration should balance scientific rigour, patient retention, and the need for longer‐term safety and durability data, with flexibility to tailor the approach to context. Conclusions Progress in coeliac disease drug development will require patient‐centred, scientifically robust but feasible trial designs with appropriate endpoints, justified use of gluten exposure, consideration of improved biomarkers to reduce patient burden and early regulatory engagement. Continued multi‐stakeholder collaboration, including dedicated consideration of paediatric drug development, is essential to advance effective therapies.

Abstract Genome-resolved virome analysis remains inaccessible for many samples, including those with clinical relevance, because viral nucleic acid recovered after enrichment is often too scarce to support de novo genome assembly. As a result, many analyses are limited to sparse read-level detection, which cannot recover divergent viruses, resolve strains, or interpret gene-level variation. Here, we developed Low Biomass Viral Sequencing (LBV-Seq), a workflow that couples low-input viral sample handling with modified primary template-directed amplification and short- or long-read sequencing to enable de novo reconstruction of DNA and RNA viral genomes from sub-femtogram to nanogram inputs. LBV-Seq reproducibly captures the same relative community composition, amplifies diverse viruses, and achieved broad genome coverage across nearly all targets regardless of viral genome structure, Baltimore class, abundance, or input mass. Short-read assemblies recovered near-complete genomes from femtogram-scale inputs. Long-read sequencing provided orthogonal support for genome structure, with PacBio HiFi reads spanning large portions of viral genomes and, in some cases, complete small viral genomes. Applied to virus-enriched human duodenal biopsy eluates, LBV-Seq provided proof-of-feasibility for recovering both bacteriophage and eukaryotic viral genomes from low-input biopsy-derived material. In the eluates tested, LBV-Seq recovered co-occurring Alphatorquevirus and Betatorquevirus genomes estimated to be present at roughly 10 copies/µL and at viral masses below 0.1 fg/µL. LBV-Seq enables genome-resolved virome analysis in samples previously limited to detection-based viromics, supporting viral discovery and strain-resolved analyses in settings where viral mass is low, including viruses enriched from human tissue biopsies.

Coeliac disease is characterised by immune-mediated damage to the small intestine in response to dietary gluten in genetically predisposed individuals. Increased intestinal permeability is a central component to its pathophysiology. This review explores the evidence for increased permeability in coeliac disease and the underlying mechanisms, including the roles of zonulin, inflammatory cytokines, microbial alterations and immune responses to gliadin peptides. We also review comprehensively the therapies targeting barrier integrity and normalising intestinal permeability, including particular diets and supplements, and experimental and improved medications including larazotide acetate and IMU-856. Finally, we highlight the need for reliable biomarkers for evaluating increased permeability in coeliac disease and advocate for further research on therapies which normalise barrier function, particularly as a strategy to maintain remission.

SummaryBackgroundThe Th2 allergic pathway in eosinophilic oesophagitis (EoE) responds to food antigen exposure.AimTo compare the presence and temporal pattern of food antigen penetration in oesophageal mucosa in active and inactive EoE and controlsMethodsThirty‐two patients with EoE (20 active) and 10 controls were asked to eliminate all wheat and/or dairy 12, 24, 48, 72 or 96 hours before endoscopy. Immunostaining on endoscopic biopsies was performed for gliadin, casein and whey.ResultsGluten, casein and whey were detected by positive staining in 17/32 (53.1%), 21/32 (65.6%), and 30/32 (92.0%) of patients, respectively. In active vs inactive EoE, 70.0% vs 25.0% (P < 0.05), 80.0% vs 41.5%, and 90.0% vs 90.9% patients had detectable gliadin, casein and whey, respectively. Casein and whey (20.0% and 100%, respectively) but not gliadin, were present in controls. The gliadin staining density was greater in active compared to inactive disease at ≤ 24 vs >24 hours after exposure (P = 0.05) but no differences were detected when comparing active and inactive patients for casein and whey. There was greater staining density for whey than casein for all patients at ≤24 hours (mean 2.14 ± 0.91 and 1.07 ± 1.33, P = 0.02). In active EoE, IgG4 was present in 14/20 compared to one inactive patient.ConclusionThe oesophageal epithelium is selectively permeable and has relatively long dwell times for food antigens known to trigger EoE. The precise mechanism of antigen‐specific mucosal entry and the factors that determine the induction or effector trigger of the Th2 pathway activation merit further study.

Objective Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. Design An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. Results Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. Conclusion This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

AbstractBackgroundThe popularity of the gluten‐free diet and sales of gluten‐free products have increased immensely.AimsTo investigate whether gluten induces gastrointestinal symptoms, measured by self‐reported questionnaires, as well as mental health symptoms in adolescents from a population‐based cohort.MethodsThe eligible participants (n = 273) were recruited from a population‐based cohort of 1266 adolescents and had at least four different gastrointestinal symptoms. Phase one (n = 54) was a run‐in phase where the participants lived gluten‐free for 2 weeks. If they improved they continued to phase 2 (n = 33), a blinded randomised cross‐over trial. Participants were blindly randomised either to start with 7 days of gluten, eating two granola bars containing 10 g of gluten or to 7 days on placebo, eating two granola bars without gluten, followed by the reverse and separated by a 7‐day washout period. The effects of the intervention on gastrointestinal symptoms and mental health symptoms were assessed.ResultsIn total, 54/273 participants entered the run‐in phase and 35 were eligible for randomization. A total of 33 were randomised and 32 completed the trial. The median age was 20.3 (IQR 19.2–20.9) and 32/33 participants were females. Compared with a placebo, gluten did not induce gastrointestinal symptoms. The difference in the average VAS was −0.01 (95% confidence interval −2.07 to 2.05). Nor did we find a difference in the outcomes measuring mental health.ConclusionCompared with placebo, adding gluten to the diet did not induce gastrointestinal symptoms or worsened mental health in adolescents recruited from a population‐based cohort. The trial registration number is NCT04639921.

SummaryBackgroundRumination syndrome is a functional gastroduodenal disorder characterised by effortless regurgitation of recently ingested food. Emerging evidence reports duodenal eosinophilic inflammation in a subset, suggesting a shared pathophysiology with functional dyspepsia (FD).AimTo assess the clinical features of rumination syndrome and FD in a community‐based study.MethodsWe mailed a survey assessing gastrointestinal symptoms, diet and psychological symptoms to 9835 residents of Olmsted County, MN, USA in 2017‐2018; diagnostic codes were obtained from linked clinical records. The two disorders were assessed as mutually exclusive in ‘pure’ forms with a separate overlap group, all compared to a control group not meeting criteria for either. Prevalence of associations, and univariate and independent associations with predictors were assessed by logistic regression.ResultsPrevalence of rumination syndrome and FD were 5.8% and 7.1%, respectively; the overlap was 3.83‐times more likely than expected by chance. Independent predictors for rumination (odds ratio (OR), 95% confidence interval (CI)) were female gender (1.79, 1.21‐2.63), smoking (1.89, 1.28‐2.78), gluten‐free diet (1.58, 1.14‐2.19), allergic rhinitis (1.45, 1.01‐2.08) and depression (1.10, 1.05‐1.16). FD was independently associated with female gender, depression, non‐coeliac wheat sensitivity, migraine, irritable bowel syndrome and somatic symptoms. A similar reported efficacy (≥54%) of low fat or dairy‐free diets was found with both disorders (P = 0.53 andP = 1.00, respectively). The strongest independent associations with overlapping FD and rumination syndrome were a history of rheumatoid arthritis (3.93, 1.28‐12.06) and asthma (3.02, 1.44‐6.34).ConclusionRumination syndrome overlaps with FD with a shared risk factor profile, suggesting a common pathophysiology.