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Pancreatic enzyme supplementation versus placebo for improvement of gastrointestinal symptoms in non-responsive celiac disease: A cross-over randomized controlled trial.
Yoosuf, S, Barrett, CG, Papamichael, K, Madoff, SE, Kurada, S, Hansen, J, Silvester, JA, Therrien, A, Singh, P, Dennis, M, et al
Frontiers in medicine. 2022;:1001879
Abstract
BACKGROUND Pancreatic Exocrine Insufficiency (PEI) is a possible cause of recurrent/persistent symptoms in celiac disease. Although pancreatic enzyme supplementation may be used to treat non-responsive celiac disease (NRCD) in clinical practice, clinical outcomes are variable and there is limited and low quality evidence to support this practice. The aim of this study was to assess the efficacy of pancreatic enzyme supplements (PES) for improvement of gastrointestinal symptoms in NRCD. METHODS Prospective, randomized, placebo-controlled, double-blind, cross-over trial in adults with NRCD examining Celiac Disease-Gastrointestinal Symptom Rating Scale (CeD-GSRS) scores on PES (pancrelipase co-administered with omeprazole) versus placebo (omeprazole only) during a 10-day treatment period. The study was registered under the clinical trials registry (https://clinicaltrials.gov/ number, NCT02475369) on 18 Jun 2015. RESULTS Twelve participants (nine female) were included in the per-protocol analysis; one participant had low fecal elastase-1. Pancrelipase was not associated with significant change in CeD-GSRS compared to placebo (-0.03 versus -0.26; P = 0.366). There was a significant decrease in mean values of total CeD-GSRS scores (3.58 versus 2.90, P = 0.004), abdominal pain (2.92 versus 2.42, P = 0.009), and diarrhea sub-scores (3.44 versus 2.92, P = 0.037) during the run-in period with omeprazole. CONCLUSION In this prospective, cross-over randomized, placebo-controlled study, PES did not improve symptoms in patients with NRCD. It is unclear whether this is a trial effect or related to administration of omeprazole.
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Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial.
Leonard, MM, Silvester, JA, Leffler, D, Fasano, A, Kelly, CP, Lewis, SK, Goldsmith, JD, Greenblatt, E, Kwok, WW, McAuliffe, WJ, et al
Gastroenterology. 2021;(3):720-733.e8
Abstract
BACKGROUND & AIMS Gluten challenge is used to diagnose celiac disease (CeD) and for clinical research. Sustained gluten exposure reliably induces histologic changes but is burdensome. We investigated the relative abilities of multiple biomarkers to assess disease activity induced by 2 gluten doses, and aimed to identify biomarkers to supplement or replace histology. METHODS In this randomized, double-blind, 2-dose gluten-challenge trial conducted in 2 US centers (Boston, MA), 14 adults with biopsy-proven CeD were randomized to 3 g or 10 g gluten/d for 14 days. The study was powered to detect changes in villous height to crypt depth, and stopped at planned interim analysis on reaching this end point. Additional end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with HLA-DQ2-gluten tetramers and enzyme-linked immune absorbent spot, gut-homing CD8 T cells, interleukin-2, symptoms, video capsule endoscopy, intraepithelial leukocytes, and tissue multiplex immunofluorescence. RESULTS All assessments showed changes with gluten challenge. However, time to maximal change, change magnitude, and gluten dose-response relationship varied. Villous height to crypt depth, video capsule endoscopy enteropathy score, enzyme-linked immune absorbent spot, gut-homing CD8 T cells, intraepithelial leukocyte counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten only; symptoms were significant at 3 g. Symptoms and plasma interleukin-2 levels increased significantly or near significantly at both doses. Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure. CONCLUSIONS Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion. This work provides a preliminary framework for rational design of gluten challenge for CeD research. ClinicalTrials.gov number, NCT03409796.
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Enteric-Release Budesonide May Be Useful in the Management of Non-Responsive Celiac Disease.
Therrien, A, Silvester, JA, Leonard, MM, Leffler, DA, Fasano, A, Kelly, CP
Digestive diseases and sciences. 2021;(6):1989-1997
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Abstract
BACKGROUND Non-responsive celiac disease (NRCD) has many aetiologies, including gluten exposure. Budesonide may be used for refractory celiac disease (RCD) and celiac crisis. AIMS We reviewed the effectiveness of budesonide to induce clinical and histologic response in NRCD with villous atrophy (VA). METHODS Case series of adult cases with NRCD and VA prescribed budesonide at two celiac centers. Clinical variables and mucosal recovery (i.e., normal villous architecture within 1 year of treatment) were evaluated. RESULTS Forty-two cases [77% female, median age 45.0 (IQR 28.3-60.0) years] were included. Most common symptoms were diarrhea (64%) and abdominal pain (62%). Budesonide was initiated at 9 mg (83%) for a median duration of 16.0 weeks (IQR 6.8-25.0 weeks). In total, 57% exhibited a clinical response, positively associated with diarrhea (adjusted OR 6.08 95% CI 1.04-35.47) and negatively with fatigue (adjusted OR 0.18 95% CI 0.03-0.98). Clinical response was higher among those with dietitian counseling prior to budesonide (n = 29, 70 vs. 23%, p < 0.01). Mucosal recovery was observed in 11/24 with follow-up duodenal biopsies. There was no association between clinical response and mucosal recovery, and 79% of clinical responders had a symptomatic relapse. RCD (48%) and chronic gluten exposure (24%) were the main suspected aetiologies of NRCD. Most individuals without a clinical response subsequently received an IBS-related diagnosis. CONCLUSIONS Budesonide may be effective to induce clinical response in NRCD presenting with diarrhea and VA, but clinical recurrence and lack of mucosal recovery are frequent after tapering. Other diagnoses, including coexisting IBS, may be considered in non-responders to budesonide therapy.
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Celiac Disease: Fallacies and Facts.
Silvester, JA, Therrien, A, Kelly, CP
The American journal of gastroenterology. 2021;(6):1148-1155
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Abstract
Our understanding of the pathophysiology of celiac disease has progressed greatly over the past 25 years; however, some fallacies about the clinical characteristics and management persist. Worldwide epidemiologic data are now available showing that celiac disease is ubiquitous. An elevated body mass index is common at the time of the diagnosis. The gluten-free diet (GFD) is an imperfect treatment for celiac disease; not all individuals show a response. This diet is widely used by people without celiac disease, and symptomatic improvement on a GFD is not sufficient for diagnosis. Finally, the GFD is burdensome, difficult to achieve, and thus has an incomplete efficacy, opening exciting opportunities for novel, nondietary treatments.
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Prevalence of celiac disease in China: Meta-analysis and serological survey in high-risk populations.
Zhou, WY, Liu, XY, Wang, MM, Liang, LP, Liu, L, Zheng, K, Silvester, JA, Ma, WJ, Wu, W, Ji, GY, et al
Journal of digestive diseases. 2021;(11):645-655
Abstract
OBJECTIVE To summarize data from a serological survey of high-risk populations in Guangdong Province, China, and to perform a meta-analysis to investigate the prevalence and seroprevalence of celiac disease (CD) in the Chinese general and high-risk populations. METHODS We collected data from the serological survey of high-risk population of CD in Guangdong Province, China (N = 1390) by testing their serum tissue transglutaminase immunoglobulin A (tTG-IgA), deamidated gliadin peptides immunoglobulin A (DGP-IgA) and deamidated gliadin peptides immunoglobulin G (DGP-IgG). Additionally, a literature search was performed on PubMed, EMBASE, Cochrane Library and three Chinese databases for articles published up to 20 December 2020 to estimate the pooled prevalence and seroprevalence of CD in China. RESULTS In the serological survey, 0.94% (13/1390) of individuals were positive for CD antibodies. In a meta-analysis of 18 studies, the seroprevalence of CD in the general Chinese population was 0.27% (95% confidence interval [CI] 0.02%-0.71%). While that in the high-risk population was 8.34% (95% CI 4.90%-12.54%) (odds ratio 7.27, 95% CI 4.06-13.04). The prevalence of biopsy-confirmed CD in high-risk Chinese populations was 4.44% (95% CI 1.53%-8.58%). The seroprevalence of CD varied with patients' geographical origin, being higher in northern China than in southern China. CONCLUSIONS Early diagnosis of CD by serological screening in high-risk population and generous serological testing in those with vague symptoms, especially in northern China, are recommended.
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Probiotics for Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Seiler, CL, Kiflen, M, Stefanolo, JP, Bai, JC, Bercik, P, Kelly, CP, Verdu, EF, Moayyedi, P, Pinto-Sanchez, MI
The American journal of gastroenterology. 2020;(10):1584-1595
Abstract
INTRODUCTION Many patients with celiac disease (CD) experience persistent symptoms despite adhering to the gluten-free diet. Different studies have assessed the use of probiotics as an adjuvant treatment for CD. We performed a systematic review and meta-analysis to evaluate the efficacy of probiotics in improving gastrointestinal (GI) symptoms and quality of life (QOL) in patients with CD. METHODS We searched EMBASE, MEDLINE, CINAHL, Web of Science, CENTRAL, and DARE databases up to February 2019 for randomized controlled trials (RCTs) evaluating probiotics compared with placebo for treating CD. We collected data on GI symptoms, QOL, adverse events, serum tumor necrosis factor-α, intestinal permeability, and microbiota composition. RESULTS We screened 2,831 records and found that 7 articles describing 6 RCTs (n = 279 participants) were eligible for quantitative analysis. Probiotics improved GI symptoms when assessed by the GI Symptoms Rating Scale (mean difference symptom reduction: -28.7%; 95% confidence interval [CI] -43.96 to -13.52; P = 0.0002). There was no difference in GI symptoms after probiotics when different questionnaires were pooled. The levels of Bifidobacteria increased after probiotics (mean difference: 0.85 log colony-forming units (CFU) per gram; 95% CI 0.38-1.32 log CFU per gram; P = 0.0003). There were insufficient data on tumor necrosis factor-a levels or QOL for probiotics compared with placebo. No difference in adverse events was observed between probiotics and placebo. The overall certainty of the evidence ranged from very low to low. DISCUSSION Probiotics may improve GI symptoms in patients with CD. High-quality clinical trials are needed to improve the certainty in the evidence (see Visual abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B595).
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Celiac Disease: Extraintestinal Manifestations and Associated Conditions.
Therrien, A, Kelly, CP, Silvester, JA
Journal of clinical gastroenterology. 2020;(1):8-21
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Abstract
Celiac disease is a common form of enteropathy with frequent extraintestinal manifestations (EIM). Misrecognition of these presentations may lead to significant delays in diagnosis. Any organ may be involved, either through an immune/inflammatory phenomenon, or nutritional deficiencies. Some EIM, such as gluten ataxia, may be irreversible if left untreated, but most will improve with a gluten-free diet. Knowledge of the various EIM, as well as the associated conditions which do not improve on a gluten-free diet, will avoid delays in the diagnosis and management of celiac disease and associated manifestations.
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Nondietary Therapies for Celiac Disease.
Serena, G, Kelly, CP, Fasano, A
Gastroenterology clinics of North America. 2019;(1):145-163
Abstract
Celiac disease (CD) is an autoimmune enteropathy triggered by gluten. Gluten-free diets can be challenging because of their restrictive nature, inadvertent cross-contaminations, and the high cost of gluten-free food. Novel nondietary therapies are at the preclinical stage, clinical trial phase, or have already been developed for other indications and are now being applied to CD. These therapies include enzymatic gluten degradation, binding and sequestration of gluten, restoration of epithelial tight junction barrier function, inhibition of tissue transglutaminase-mediated potentiation of gliadin oligopeptide immunogenicity or of human leukocyte antigen-mediated gliadin presentation, induction of tolerance to gluten, and antiinflammatory interventions.
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Novel Nondietary Therapies for Celiac Disease.
Alhassan, E, Yadav, A, Kelly, CP, Mukherjee, R
Cellular and molecular gastroenterology and hepatology. 2019;(3):335-345
Abstract
Celiac Disease (CeD) is defined as a chronic small intestinal immune-mediated enteropathy that is precipitated by exposure to dietary gluten in genetically predisposed individuals. CeD is one of the most common autoimmune disorders affecting around 1% of the population worldwide. Currently, the only acceptable treatment for CeD is strict, lifelong adherence to a gluten-free diet (GFD) which can often present a challenging task. A GFD alone is not sufficient to control symptoms and prevent mucosal damage that can result from unintentional gluten exposure. Moreover, long-term complications can occur in many patients. Consequently, there is an unmet need for non-dietary therapies for the management of CeD. Such therapies could serve as an adjunct to the GFD but eventually may replace it. This review will focus on and discuss non-dietary therapies currently in clinical development for the management of CeD. METHODOLOGY We searched clinicaltrials.gov and PubMed to extract articles about celiac disease. We used keywords including, but not limited to, "celiac disease," "non-dietary," "therapeutics," "pathophysiology," "Endopeptidases," "tight junction modulators," "vaccine," and "Nexvax2". We focused mainly on articles that conducted pathophysiologic and therapeutic research in human trials.
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Diagnostic Accuracy of Point of Care Tests for Diagnosing Celiac Disease: A Systematic Review and Meta-Analysis.
Singh, P, Arora, A, Strand, TA, Leffler, DA, Mäki, M, Kelly, CP, Ahuja, V, Makharia, GK
Journal of clinical gastroenterology. 2019;(7):535-542
Abstract
GOALS To perform a systematic review and meta-analysis to estimate the overall diagnostic accuracy of point of care tests (POCTs) for diagnosing celiac disease (CD). BACKGROUND Recently, POCTs for CD have been developed and are commercially available. Studies have reported significant variability in their sensitivity (70% to 100%) and specificity (85% to 100%). STUDY We searched MEDLINE, EMBASE databases, and the Cochrane library through June 2017. Positive reference test was defined as villous atrophy along with positive celiac-specific serology and/or clinical improvement after gluten-free diet. Normal duodenal biopsy was defined as negative reference test. Bivariate random-effect model was used to present the summary estimates of sensitivities and specificities along with 95% confidence regions We assessed methodologic quality using the quality assessment of diagnostic accuracy studies-2 tool. RESULTS The pooled sensitivity and specificity of all POCTs (based on tTG or DGP or tTG+Anti-gliadin antibodies) for diagnosing CD were 94.0% [95% confidence interval (CI), 89.9-96.5] and 94.4% (95% CI, 90.9-96.5), respectively. The pooled positive and negative likelihood ratios for POCTs were 16.7 and 0.06, respectively. The pooled sensitivity and specificity for IgA-tTG-based POCTs were 90.5% (95% CI, 82.3-95.1) and 94.8% (95% CI, 92.5-96.4), respectively. CONCLUSIONS The pooled sensitivity and specificity of POCTs in diagnosing CD are high. POCTs may be used to screen for CD, especially in areas with limited access to laboratory-based testing. Further research assessing the diagnostic accuracy of individual POCTs and comparing it with other available POCTs is needed.