Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet

BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.

Gluten immunogenic peptide excretion detects dietary transgressions in treated celiac disease patients

BACKGROUND Life-long removal of gluten from the diet is currently the only way to manage celiac disease(CeD). Until now, no objective test has proven useful to objectively detect ingested gluten in clinical practice. Recently, tests that determine consumption of gluten by assessing excretion of gluten immunogenic peptides(GIP) in stool and urine have been developed. Their utility, in comparison with conventional dietary and analytical follow-up strategies, has not been fully established.AIM To assess the performance of enzyme-linked immunosorbent assay(ELISA) and point-of-care tests(PoCTs) for GIP excretion in CeD patients on gluten-free diet(GFD).METHODS We conducted an observational, prospective, cross-sectional study in patients following a GFD for at least two years. Using the Gastrointestinal Symptom Rating Scale questionnaire, patients were classified at enrollment as asymptomatic or symptomatic. Gluten consumption was assessed twice by 3-d dietary recall and GIP excretion(by ELISA in stool and PoCTs(commercial kits for stool and urine) in two consecutive samples. These samples and dietary reports were obtained 10 day apart one from the other. Patients were encouraged to follow their usual GFD during the study period.RESULTS Forty-four patients were enrolled, of which 19(43.2%) were symptomatic despite being on a GFD. Overall, 83 sets of stool and/or urine samples were collected.Eleven out of 44 patients(25.0%) had at least one positive GIP test. The occurrence of at least one positive test was 32% in asymptomatic patients compared with 15.8% in symptomatic patients. GIP was concordant with dietary reports in 65.9% of cases(Cohen′s kappa: 0.317). PoCT detected dietary indiscretions. Both ELISA and PoCT in stool were concordant(concomitantly positive or negative) in 67 out of 74(90.5%) samples. Excretion of GIP was detected in 7(8.4%) stool and/or urine samples from patients considered to be strictly compliant with the GFD by dietary reports.CONCLUSION GIP detects dietary transgressions in patients on long-term GFD, irrespective of the presence of symptoms. PoCT for GIP detection constitutes a simple homebased method for self-assessment of dietary indiscretions.

Risk of fracture in celiac disease:Gender,dietary compliance,or both?

AIM:To determine the incidence of peripheral fractures in patients with celiac disease (CD) and the effect of treatment on fracture risk.METHODS:We compared the incidence and risk of peripheral fractures before and after diagnosis between a cohort of 265 patients who had been diagnosed with CD at least 5 years before study entry and a cohort of 530 age-and sex-matched controls who had been diagnosed with functional gastrointestinal disorders.Data were collected through in-person interviews with an investigator.The overall assessment window for patients was 9843 patient-years (2815 patient-years after diagnosis).RESULTS:Compared with the control group,the CD cohort showed significantly higher incidence rate and risk of first peripheral fracture before diagnosis [adjusted hazard ratio (HR):1.78,95% CI:1.23-2.56,P < 0.002] and in men (HR:2.67,95% CI:1.37-5.22,P < 0.004).Fracture risk was significantly associated with the classic CD presentation with gastrointestinal symptoms (P < 0.003).In the time period after diagnosis,the risk of fractures was comparable between the CD cohort and controls in both sexes (HR:1.08,95% CI:0.55-2.10 for women;HR:1.57,95% CI:0.57-4.26 for men).CONCLUSION:CD patients have higher prevalence of fractures in the peripheral skeleton before diagnosis.This is associated with male sex and classic clinical presentation.The fracture risk was reduced after the treatment.

Determination of gluten immunogenic peptides for the management of the treatment adherence of celiac disease: A systematic review

BACKGROUND Gluten is a complex mixture of proteins with immunogenic peptide sequences triggering the autoimmune activity in patients with celiac disease(CeD).Gluten immunogenic peptides(GIP)are resistant to gastrointestinal digestion and are then excreted via the stool and urine.Most common detection methods applied in the follow-up visits for CeD patients such as serology tests,dietetic interviews,questionnaires,and duodenal biopsy have been proved to be inefficient,invasive,or inaccurate for evaluating gluten-free diet(GFD)compliance.Determination of excreted GIP in stool and urine has been developed as a non-invasive,direct,and specific test for GFD monitoring.AIM To summarize published literature about the clinical utility of GIP determination in comparison to the tools employed for GFD monitoring.METHODS PubMed and Web of Science searches were performed using the keywords“gluten immunogenic peptides”or“gluten immunogenic peptide”and a combination of the previous terms with“feces”,“stools”,“urine”,“celiac disease”,“gluten-free diet”,and“adherence”to identify relevant clinical studies published in English and Spanish between 2012 to January 2021.Reference lists from the articles were reviewed to identify additional pertinent articles.Published articles and abstracts reporting the clinical use of GIP determination in stool and/or urine for the follow-up of patients with CeD in comparison with other tools in use were included.Case reports,commentaries,reviews,conference papers,letters,and publications that did not focus on the aims of this review were excluded.RESULTS Total of 15 publications were found that involved the use of GIP determination in stool and/or urine to monitor the adherence to the GFD in comparison to other tools.Studies included both children and adults diagnosed with CeD and healthy volunteers.Overall,these preliminary studies indicated that this novel technique was highly sensitive for the detection of GFD transgressions and therefore could facilitate the follow-up of patients with CeD.Tools identified in this work included the CeD-specific serology,dietetic questionnaires,symptomatology,and the duodenal biopsy.Review of the literature revealed that the rates of GFD adherence may vary between 30%-93%using either stool or urine GIP determination,49%-96%by the serology,59%-94%using the dietetic questionnaires,56%-95%by the reported symptoms and 44%-76%with the duodenal biopsy.In addition,the association between the different methods and histological abnormalities(Marsh II-III)was found to be 33%-100%for GIP determination(stool and urine),25%-39%for CeD-specific serology,3%-50%for dietetic questionnaires,and 22%-28%for the symptomatology.CONCLUSION Excreted GIP detection is the precise approach for determining voluntary or involuntary gluten consumption in CeD patients preventing future complications arising from gluten exposure.

Risk perception and knowledge of COVID-19 in patients with celiac disease

BACKGROUND We recently demonstrated that the odds of contracting coronavirus disease 2019(COVID-19)in patients with celiac disease(CeD)is similar to that of the general population.However,how patients with CeD perceive their COVID-19 risk may differ from their actual risk.AIM To investigate risk perceptions of contracting COVID-19 in patients with CeD and determine the factors that may influence their perception.METHODS We distributed a survey throughout 10 countries between March and June 2020 and collected data on demographics,diet,COVID-19 testing,and risk perceptions of COVID-19 in patients with CeD.Participants were recruited through various celiac associations,clinic visits,and social media.Risk perception was assessed by asking individuals whether they believe patients with CeD are at an increased risk of contracting COVID-19 when compared to the general population.Logistic regression was used to determine the influencing factors associated with COVID-19 risk perception,such as age,sex,adherence to a gluten-free diet(GFD),and comorbidities such as cardiac conditions,respiratory conditions,and diabetes.Data was presented as adjusted odds ratios(aORs)RESULTS A total of 10737 participants with CeD completed the survey.From them,6019(56.1%)patients with CeD perceived they were at a higher risk or were unsure if they were at a higher risk of contracting COVID-19 compared to the non-CeD population.A greater proportion of patients with CeD perceived an increased risk of contracting COVID-19 when compared to infections in general due to their CeD(56.1%vs 26.7%,P<0.0001).Consequently,34.8%reported taking extra COVID-19 precautions as a result of their CeD.Members of celiac associations were less likely to perceive an increased risk of COVID-19 when compared to non-members(49.5%vs 57.4%,P<0.0001).Older age(aOR:0.99;95%CI:0.99 to 0.99,P<0.001),male sex(aOR:0.84;95%CI:0.76 to 0.93,P=0.001),and strict adherence to a GFD(aOR:0.89;95%CI:0.82 to 0.96,P=0.007)were associated with a lower perception of COVID-19 risk and the presence of comorbidities was associated with a higher perception of COVID-19 risk(aOR:1.38;95%CI:1.22 to 1.54,P<0.001).CONCLUSION Overall,high levels of risk perceptions,such as those found in patients with CeD,may increase an individual’s pandemic-related stress and contribute to negative mental health consequences.Therefore,it is encouraged that public health officials maintain consistent communication with the public and healthcare providers with the celiac community.Future studies specifically evaluating mental health in CeD could help determine the consequences of increased risk perceptions in this population.

Upper gastrointestinal endoscopic findings in celiac disease at diagnosis:A multicenter international retrospective study

BACKGROUND Gastroduodenal endoscopy and biopsy following positive specific serology is considered the gold standard to diagnose celiac disease(CeD)in adults.Whether upper endoscopy helps detect comorbid conditions is unknown.AIM To investigate the prevalence of non-celiac endoscopic findings in patients in whom endoscopy was performed to confirm CeD diagnosis.METHODS This is an observational,descriptive,multicenter,retrospective study that reports endoscopic findings obtained in adult patients enrolled in local registries from four tertiary centers.We collected data reported on first endoscopy,indicated for investigation of CeD.Diagnosis of CeD was performed by histology(≥Marsh 2type mucosal damage)and specific serology.Two European and one North American center included biopsy-confirmed CeD following positive serology.A fourth center(South America)included symptomatic patients undergoing endoscopy,irrespective of CeD serology.The latter cohort included a non-CeD control group.RESULTS A total of 1328 patients(80%female;35 years median age)were enrolled,of whom 95.6%had positive specific serology.In 135 patients,endoscopy revealed 163 abnormalities unrelated to CeD(prevalence:10.1%).Erosive reflux esophagitis(6.4%),gastric erosions(2.0%),and suspicion of esophageal metaplasia(1.2%)were the most common findings.Biopsy-confirmed Barrett’s esophagus was infrequent(0.2%).No endoscopic cancer was detected.Older patients(≥51 years of age)had a higher prevalence of endoscopic findings than those≤50(P<0.01).Within the South American cohort,CeD was associated with a lower rate(8.2%)of comorbid endoscopic findings compared with controls(29.1%;P<0.001).In the adjusted multivariate analysis of this cohort,having CeD was associated with a 72%reduction in the risk of any endoscopic abnormality(P<0.0001),and having alarm symptoms was associated with a 37%reduction in the risk of finding at least one endoscopic lesion(P<0.02).CONCLUSION In this large multicenter study,young adults with positive CeD serology had few comorbid endoscopic findings.Although patients over 51 years had a high prevalence of non-CeD gastroduodenal mucosal damage,no malignancy or premalignant lesions were found.