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1.
Guidelines for best practices in monitoring established coeliac disease in adult patients.
Elli, L, Leffler, D, Cellier, C, Lebwohl, B, Ciacci, C, Schumann, M, Lundin, KEA, Chetcuti Zammit, S, Sidhu, R, Roncoroni, L, et al
Nature reviews. Gastroenterology & hepatology. 2024;(3):198-215
Abstract
Coeliac disease (CeD) is an immunological disease triggered by the consumption of gluten contained in food in individuals with a genetic predisposition. Diagnosis is based on the presence of small bowel mucosal atrophy and circulating autoantibodies (anti-type 2 transglutaminase antibodies). After diagnosis, patients follow a strict, life-long gluten-free diet. Although the criteria for diagnosis of this disease are well defined, the monitoring phase has been studied less and there is a lack of specific guidelines for this phase. To develop a set of clinical guidelines for CeD monitoring, we followed the Grading of Recommendations Assessment, Development and Evaluation methodology. Statements and recommendations with the level of evidence were developed and approved by the working group, which comprised gastroenterologists, pathologists, dieticians and biostatisticians. The proposed guidelines, endorsed by the North American and European coeliac disease scientific societies, make recommendations for best practices in monitoring patients with CeD based on the available evidence. The evidence level is low for many topics, suggesting that further research in specific aspects of CeD would be valuable. In conclusion, the present guidelines support clinicians in improving CeD treatment and follow-up and highlight novel issues that should be considered in future studies.
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2.
Follow-Up of Celiac Disease in Adults: "When, What, Who, and Where".
Mulder, CJJ, Elli, L, Lebwohl, B, Makharia, GK, Rostami, K, Rubio-Tapia, A, Schumann, M, Tye-Din, J, Zeitz, J, Al-Toma, A
Nutrients. 2023;(9)
Abstract
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. Ideally, celiac follow-up care includes a multidisciplinary approach, effective referral processes, improved access that leverages technological advances, and following guidelines with the identification of measurable quality indicators, ideally informed by evidence-based research. Face-to-face CeD care and telemedicine are considered the standards for this process, although published data are insufficient. Guidelines and statements on diagnosis are readily available. However, data are lacking on optimal clinic visit intervals and outcomes and quality indicators such as improvement of symptoms, function and quality of life, survival and disease control, and how to most effectively use healthcare resources. The results of future research should provide the basis for general recommendations for evidence-based standards of quality of care in CeD.
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3.
An Analysis of 5 Years of Randomized Trials in Gastroenterology and Hepatology Reveals 52 Medical Reversals.
Yopes, MC, Mozeika, AM, Liebling, S, Haslam, A, Prasad, V, Lebwohl, B
Digestive diseases and sciences. 2022;(6):2011-2018
Abstract
BACKGROUND AND AIMS One manifestation of low-value medical practice is the medical reversal, a practice in widespread use that, once subjected to a randomized controlled trial (RCT), is found to be no better-or worse-than a prior established standard of care. We aimed to determine the prevalence of medical reversals in gastroenterology (GI) journals and characterize these reversals. METHODS We searched the American Journal of Gastroenterology, Clinical Gastroenterology and Hepatology, Gastroenterology, Gut, Hepatology, and the Journal of Hepatology, reviewing studies published in 2015-2019. We identified RCTs that tested an established clinical practice and produced negative results, considered tentative reversals. Any systematic review or meta-analysis that included the article was categorized as confirming the reversal, refuting the reversal, or providing insufficient data. RESULTS During the 5-year period, we identified 5,898 original articles, of which 212 tested an established practice and 52 were categorized as unrefuted medical reversals (25% of articles testing standard of care). Of the reversals, 21 (40%) tested procedures and devices, 15 (29%) tested medications, and 8 (15%) tested vitamins/supplements/diet. Twenty-three (44%) considered the alimentary tract, 12 (23%) considered the liver, pancreas, or biliary tract, and 17 (33%) considered endoscopy. Thirty-eight (73%) were funded exclusively by non-industry sources. CONCLUSION This review reveals a total of 52 reversals across all subfields of GI and medical, procedural, screening, and diagnostic interventions, occurring in 25% of randomized trials testing an established practice. More research is needed to determine the optimal way to engage stakeholders and remove reversed practices from medical care.
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4.
Epidemiology, Presentation, and Diagnosis of Celiac Disease.
Lebwohl, B, Rubio-Tapia, A
Gastroenterology. 2021;(1):63-75
Abstract
The incidence of celiac disease is increasing, partly because of improved recognition of, and testing for, the disease. The rise in incidence is also due to a real increase of this immune-based disorder, independent of disease detection. The reasons for this true rise in recent decades are unknown but may be related to environmental factors that may promote loss of tolerance to dietary gluten. Strategies to reduce the development of celiac disease have not been proven successful in randomized trials, but the quantity of early-life gluten exposure has been a major focus of prevention efforts. The criteria for the diagnosis of celiac disease are changing, but in adults, diagnosis still depends on the presence of duodenal villous atrophy while the patient is on a gluten-containing diet, along with findings from serology analysis. Although guidelines in the United States continue to mandate a biopsy at all ages, some children receive a diagnosis of celiac disease without a biopsy. If proven accurate and scalable, assays that detect gluten-HLA tetramer complexes might be used in diagnosis to be made in the context of a gluten-free diet without intestinal biopsy.
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5.
Celiac disease: clinical update.
Uche-Anya, E, Lebwohl, B
Current opinion in gastroenterology. 2021;(6):619-624
Abstract
PURPOSE OF REVIEW This review highlights literature from the past year and explores the impact on current understanding of celiac disease pathogenesis, diagnosis, and management. RECENT FINDINGS In contrast to earlier clinical trials, recent data suggests that early gluten introduction may protect against the development of celiac disease. Celiac disease is underdiagnosed, associated with high burden of disease and linked to excess mortality risk, yet, there remains considerable uncertainty regarding the utility of mass screening in asymptomatic individuals. The gut microbiome is increasingly implicated in celiac disease pathogenesis, although the exact mechanism is undefined. Probiotics have been proposed as a disease-modifying option for celiac disease but most studies assessing efficacy are of low-quality. Patients with celiac disease do not appear to be at increased risk of contracting or developing adverse outcomes from COVID-19. Little is known about the pathogenesis of nonceliac gluten sensitivity; however, recent findings suggest an autoimmune basis for the condition. SUMMARY Current understanding of celiac disease continues to advance, though significant knowledge gaps remain. Large, rigorous, prospectively designed studies are needed to further characterize celiac disease pathogenesis, management and therapeutic options.
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6.
AGA Clinical Practice Update on the Evaluation and Management of Seronegative Enteropathies: Expert Review.
Leonard, MM, Lebwohl, B, Rubio-Tapia, A, Biagi, F
Gastroenterology. 2021;(1):437-444
Abstract
DESCRIPTION Our aim was to provide a consensus statement for the best approaches for diagnosis and management of patients with suspected enteropathy, but negative results from serologic tests for celiac disease (seronegative enteropathy). METHODS We collected findings from published cohort, case-control, and cross-sectional studies of diagnosis and case series and descriptive studies of management of patients believed to have celiac disease or other enteropathies unrelated to gluten, but negative results from serologic tests. BEST PRACTICE ADVICE 1: Review histologic findings with experienced pathologists who specialize in gastroenterology. BEST PRACTICE ADVICE 2: Serologic tests are essential for an accurate diagnosis of celiac disease. For patients with suspected celiac disease but negative results from serologic tests, total IgA level should be measured; patients should also be tested for anti-tissue transglutaminase, IgA against deamidated gliadin peptide, and endomysial antibody (IgA). Patients with total IgA levels below the lower limit of detection and IgG against tissue transglutaminase or deamidated gliadin peptide, or endomysial antibody, should be considered to have celiac disease with selective IgA deficiency rather than seronegative celiac disease. BEST PRACTICE ADVICE 3: Patients' diets should be carefully reviewed and duodenal biopsies should be collected and analyzed at the time of serologic testing to determine exposure to gluten and accuracy of test results. BEST PRACTICE ADVICE 4: Thorough medication histories should be collected from patients, with attention to angiotensin II receptor blockers, such as olmesartan, along with travel histories to identify potential etiologies of villous atrophy. This will guide additional testing. BEST PRACTICE ADVICE 5: Patients should be analyzed for disease-associated variants in human leukocyte antigen genes; results must be carefully interpreted. Negative results can be used to rule out celiac disease in seronegative patients. BEST PRACTICE ADVICE 6: Patients with suspected celiac disease who are seronegative but have villous atrophy and genetic risk factors for celiac disease must undergo endoscopic evaluation after 1-3 years on a gluten-free diet to evaluate improvements in villous atrophy. A diagnosis of seronegative celiac disease can then be confirmed based on clinical and histologic markers of improvement on the gluten-free diet. BEST PRACTICE ADVICE 7: Seronegative patients with an identified cause for enteropathy should be treated accordingly; a follow-up biopsy might or might not be necessary. BEST PRACTICE ADVICE 8: Patients with persistent signs and symptoms who do not respond to a gluten-free diet, and for whom no etiology of enteropathy is ultimately identified, should be treated with budesonide. CONCLUSIONS These best practice guidelines will aid in diagnosis and management of patients with suspected celiac disease, but negative results from serologic tests.
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7.
Diagnosis and Treatment Patterns in Celiac Disease.
Cichewicz, AB, Mearns, ES, Taylor, A, Boulanger, T, Gerber, M, Leffler, DA, Drahos, J, Sanders, DS, Thomas Craig, KJ, Lebwohl, B
Digestive diseases and sciences. 2019;(8):2095-2106
Abstract
Celiac disease (CD) is an immune-mediated gastrointestinal (GI) disorder driven by innate and adaptive immune responses to gluten. Presentation of CD has changed over time, with non-GI symptoms, such as anemia and osteoporosis, presenting more commonly. With improved screening and diagnostic methods, the reported prevalence of CD has increased globally, and there is considerable global variation in diagnostic and treatment practices. The objective of this study was to describe the current state of CD diagnosis and treatment patterns. A targeted review of literature from MEDLINE, Embase, the Cochrane Library, and screening of relevant conference abstracts was performed. The generally recommended diagnostic approach is GI endoscopy with small bowel biopsy; however, in selected patients, biopsy may be avoided and diagnosis based on positive serology and clinical symptoms. Diagnosis often is delayed; the average diagnostic delay after symptom onset is highly variable and can last up to 12 years. Barriers to accurate and timely diagnosis include atypical presentation, lack of physician awareness about current diagnostic criteria, misdiagnosis, and limited access to specialists. Currently, strict adherence to a gluten-free diet (GFD) is the only recommended treatment, which is not successful in all patients. Only one-third of patients are monitored regularly following diagnosis. Unmet needs for CD include improvements in the accuracy and timeliness of diagnosis, and the development of treatments for both refractory CD and GFD nonresponsive CD. Further research should investigate the impact of education about gluten-free eating and the availability of gluten-free foods support adherence and improve outcomes in patients with CD.
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8.
Disease activity indices in coeliac disease: systematic review and recommendations for clinical trials.
Hindryckx, P, Levesque, BG, Holvoet, T, Durand, S, Tang, CM, Parker, C, Khanna, R, Shackelton, LM, D'Haens, G, Sandborn, WJ, et al
Gut. 2018;(1):61-69
Abstract
OBJECTIVE Although several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials. DESIGN MEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA). RESULTS Of 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy. CONCLUSIONS Current best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.
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9.
Prevalence of Celiac Disease in Patients With Iron Deficiency Anemia-A Systematic Review With Meta-analysis.
Mahadev, S, Laszkowska, M, Sundström, J, Björkholm, M, Lebwohl, B, Green, PHR, Ludvigsson, JF
Gastroenterology. 2018;(2):374-382.e1
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Abstract
BACKGROUND & AIMS Anemia is common in patients with celiac disease (CD) and a frequent mode of presentation. Guidelines recommend screening patients with iron-deficiency anemia (IDA) for CD. However, the reported prevalence of CD in patients with IDA varies. We performed a systematic review to determine the prevalence of biopsy-verified CD in patients with IDA. METHODS We performed a systematic review of articles published in PubMed Medline or EMBASE through July 2017 for the term "celiac disease" combined with "anemia" or "iron deficiency." We used fixed-effects inverse variance-weighted models to measure the pooled prevalence of CD. Meta-regression was used to assess subgroup heterogeneity. RESULTS We identified 18 studies composed of 2998 patients with IDA for inclusion in our analysis. Studies originated from the United Kingdom, United States, Italy, Turkey, Iran, and Israel. The crude unweighted prevalence of CD was 4.8% (n = 143). Using a weighted pooled analysis, we found a prevalence of biopsy-confirmed CD of 3.2% (95% confidence interval = 2.6-3.9) in patients with IDA. However, heterogeneity was high (I2 = 67.7%). The prevalence of CD was not significantly higher in studies with a mean participant age older or younger than 18 years or in studies with a mixed-sex vs female-predominant (≥60%) population. On meta-regression, year of publication, female proportion, age at CD testing, and prevalence in the general population were not associated with the prevalence of CD in patients with IDA. In the 8 studies fulfilling all our quality criteria, the pooled prevalence of CD was 5.5% (95% confidence interval = 4.1-6.9). CONCLUSIONS In a systematic review and meta-analysis, we found that approximately 1 in 31 patients with IDA have histologic evidence of CD. This prevalence value justifies the practice of testing patients with IDA for CD.
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10.
Coeliac disease.
Lebwohl, B, Sanders, DS, Green, PHR
Lancet (London, England). 2018;(10115):70-81
Abstract
Coeliac disease occurs in about 1% of people in most populations. Diagnosis rates are increasing, and this seems to be due to a true rise in incidence rather than increased awareness and detection. Coeliac disease develops in genetically susceptible individuals who, in response to unknown environmental factors, develop an immune response that is subsequently triggered by the ingestion of gluten. The disease has many clinical manifestations, ranging from severe malabsorption to minimally symptomatic or non-symptomatic presentations. Diagnosis requires the presence of duodenal villous atrophy, and most patients have circulating antibodies against tissue transglutaminase; in children, European guidelines allow a diagnosis without a duodenal biopsy provided that strict symptomatic and serological criteria are met. Although a gluten-free diet is an effective treatment in most individuals, a substantial minority develop persistent or recurrent symptoms. Difficulties adhering to a gluten-free diet have led to the development of non-dietary therapies, several of which are undergoing trials in human beings.