-
1.
The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development.
Smithson, G, Siegelman, J, Oki, T, Maxwell, JR, Leffler, DA
Frontiers in immunology. 2021;:665756
Abstract
Celiac disease is a common immune-mediated disease characterized by abnormal T-cell responses to gluten. For many patients, symptoms and intestinal damage can be controlled by a gluten-free diet, but, for some, this approach is not enough, and celiac disease progresses, with serious medical consequences. Multiple therapies are now under development, increasing the need for biomarkers that allow identification of specific patient populations and monitoring of therapeutic activity and durability. The advantage of identifying biomarkers in celiac disease is that the underlying pathways driving disease are well characterized and the histological, cellular, and serological changes with gluten response have been defined in gluten challenge studies. However, there is room for improvement. Biomarkers that measure histological changes require duodenal biopsies and are invasive. Less invasive peripheral blood cell and cytokine biomarkers are transient and dependent upon gluten challenge. Here, we discuss established biomarkers and new approaches for biomarkers that may overcome current limitations.
-
2.
Current and emerging therapies for coeliac disease.
Kivelä, L, Caminero, A, Leffler, DA, Pinto-Sanchez, MI, Tye-Din, JA, Lindfors, K
Nature reviews. Gastroenterology & hepatology. 2021;(3):181-195
Abstract
Coeliac disease is a common enteropathy that occurs in genetically susceptible individuals in response to the ingestion of gluten proteins present in wheat, rye and barley. Currently, the only available treatment for the condition is a strict, life-long gluten-free diet that, despite being safe and often effective, is associated with several challenges. Due to the high cost, particularly restrictive nature and perception of decreased quality of life associated with the diet, some patients are continuously exposed to gluten, which prevents an adequate disease control. Moreover, a subgroup of patients does not respond to the diet adequately, and healing of the small-bowel mucosa can be incomplete. Thus, there is a need for alternative treatment forms. The increasingly understood pathogenetic process of coeliac disease has enabled the identification of various targets for future therapies. Multiple investigational therapies ranging from tolerogenic to immunological approaches are in the pipeline, and several drug candidates have entered phase II/III clinical trials. This Review gives a broad overview of the different investigative treatment modalities for coeliac disease and summarizes the latest advances in this field.
-
3.
Concepts and Instruments for Patient-Reported Outcome Assessment in Celiac Disease: Literature Review and Experts' Perspectives.
Clifford, S, Taylor, AJ, Gerber, M, Devine, J, Cho, M, Walker, R, Stefani, I, Fidel, S, Drahos, J, Leffler, DA
Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2020;(1):104-113
Abstract
BACKGROUND In diseases where there is a large subjective component, such as celiac disease (CD), patient reported-outcomes (PRO) endpoints are highly relevant. However, there is a gap in knowledge about which PRO endpoints and instruments should be used for clinical trials for treatment of celiac disease. OBJECTIVES To identify patient-centered symptom, impact, and health-related quality of life (HRQoL) concepts in CD and relevant PRO instruments, and to gather expert input on concepts and instruments to inform selection of PRO endpoints for use in clinical trials of new CD treatments. METHODS A targeted literature review was conducted to identify symptom, impact, and HRQoL concepts, including those captured in PROs further reviewed against U.S. Food and Drug Administration standards for development and validation as endpoints. US and European clinicians, payers, and a patient advocate (n = 21) were interviewed to assess the identified concepts' relative importance in measuring treatment benefit and to gauge the value of potential PROs as endpoints for market access/reimbursement. RESULTS Thirty-four published studies were identified: 27 elucidated patient-centered concepts and 7 detailed the development or validation of PRO instruments. The Celiac Disease Symptom Diary and Celiac Disease Patient Reported Outcome instrument were deemed most appropriate for use as endpoints; however, each had limitations related to conceptual coverage, evidence for measurement properties, and feasibility for use in clinical trials. Experts reported gastrointestinal symptoms as most important to treat, with extra-intestinal symptoms burdensome from the patient perspective as well. Payers emphasized measuring both frequency and severity of symptoms and targeting patients nonresponsive to the gluten-free diet for treatment. CONCLUSIONS With emerging treatment options for CD, further work is needed to operationalize PRO symptom endpoints that are meaningful to patients, valued by payers, and acceptable to regulators in demonstrating efficacy.
-
4.
Angiotensin II receptor blockers and gastrointestinal adverse events of resembling sprue-like enteropathy: a systematic review.
Kamal, A, Fain, C, Park, A, Wang, P, Gonzalez-Velez, E, Leffler, DA, Hutfless, SM
Gastroenterology report. 2019;(3):162-167
-
-
Free full text
-
Abstract
BACKGROUND Olmesartan, an angiotensin II receptor blocker (ARB), is associated with gastrointestinal symptoms resembling sprue-like enteropathy. Some have proposed that enteropathy may be a class effect rather than olmesartan-specific. We performed a systematic review to identify literature of sprue-like enteropathy for all ARBs. METHODS Case reports, case series and comparative studies of ARBs were searched on PubMed and Embase databases through 21 November 2018 and then assessed. RESULTS A total of 82 case reports and case series as well as 5 comparative studies, including 248 cases, were selected and analysed. The ARBs listed in the case reports were olmesartan (233 users; 94.0%), telmisartan (5 users; 2.0%), irbesartan (4 users; 1.6%), valsartan (3 users; 1.2%), losartan (2 users; 0.8%) and eprosartan (1 user; 0.4%). The periods between ARB initiation and onset of symptoms ranged from 2 weeks to 13 years. Histologic results were reported in 218 cases, in which 201 cases (92.2%) were villous atrophy and 131 cases (60.1%) were intraepithelial lymphocytosis. Human leucocyte antigen (HLA) testing was performed in 147 patients, among whom 105 (71.4%) had HLA-DQ2 or HLA-DQ8 haplotypes. Celiac-associated antibodies were tested in 169 patients, among whom 167 (98.8%) showed negative results. Gluten exclusion from the diet failed to relieve symptoms of enteropathy in 127 (97.7%) of 130 patients with information. Complete remission of symptoms after discontinuation of ARB was reported in 233 (97.4%) of the 239 patients with information. Seven cases (2.8%) reported recurrence of symptoms after restarting olmesartan; rechallenge was not reported for the non-olmesartan ARBs. The retrospective studies conducted worldwide had inconsistent study designs (e.g. differences in periods of study and case definition) and findings. CONCLUSIONS Although enteropathy is rare, clinicians should remain vigilant of this potential adverse event even years after medication initiation.
-
5.
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.
-
6.
Celiac disease: a comprehensive current review.
Caio, G, Volta, U, Sapone, A, Leffler, DA, De Giorgio, R, Catassi, C, Fasano, A
BMC medicine. 2019;(1):142
Abstract
BACKGROUND Celiac disease remains a challenging condition because of a steady increase in knowledge tackling its pathophysiology, diagnosis, management, and possible therapeutic options. MAIN BODY A major milestone in the history of celiac disease was the identification of tissue transglutaminase as the autoantigen, thereby confirming the autoimmune nature of this disorder. A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota). Its prevalence in the general population is of approximately 1%, with female predominance. The disease can occur at any age, with a variety of symptoms/manifestations. This multifaceted clinical presentation leads to several phenotypes, i.e., gastrointestinal, extraintestinal, subclinical, potential, seronegative, non-responsive, and refractory. Although small intestinal biopsy remains the diagnostic 'gold standard', highly sensitive and specific serological tests, such as tissue transglutaminase, endomysial and deamidated gliadin peptide antibodies, have become gradually more important in the diagnostic work-up of celiac disease. Currently, the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma. CONCLUSIONS The present review is timely and provides a thorough appraisal of various aspects characterizing celiac disease. Remaining challenges include obtaining a better understanding of still-unclear phenotypes such as slow-responsive, potential (minimal lesions) and seronegative celiac disease. The identification of alternative or complementary treatments to the gluten-free diet brings hope for patients unavoidably burdened by diet restrictions.
-
7.
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.
-
8.
Tests for Serum Transglutaminase and Endomysial Antibodies Do Not Detect Most Patients With Celiac Disease and Persistent Villous Atrophy on Gluten-free Diets: a Meta-analysis.
Silvester, JA, Kurada, S, Szwajcer, A, Kelly, CP, Leffler, DA, Duerksen, DR
Gastroenterology. 2017;(3):689-701.e1
-
-
Free full text
-
Abstract
BACKGROUND & AIMS Tests to measure serum endomysial antibodies (EMA) and antibodies to tissue transglutaminase (tTG) were developed to screen for celiac disease in patients consuming gluten. However, they are commonly used to monitor patients on a gluten-free diet (GFD). We conducted a meta-analysis to assess the sensitivity and specificity of tTG IgA and EMA IgA assays in identifying patients with celiac disease who have persistent villous atrophy despite a GFD. METHODS We searched PUBMED, EMBASE, BIOSIS, SCOPUS, clinicaltrials.gov, Science Citation Index, and Cochrane Library databases through November 2016. Inclusion criteria were studies of subjects with biopsy-confirmed celiac disease, follow-up biopsies, and measurement of serum antibodies on a GFD, biopsy performed on subjects regardless of symptoms, or antibody test results. Our analysis excluded subjects with refractory celiac disease, undergoing gluten challenge, or consuming a prescribed oats-containing GFD. Tests were considered to have positive or negative findings based on manufacturer cut-off values. Villous atrophy was defined as a Marsh 3 lesion or villous height:crypt depth ratio below 3.0. We constructed forest plots to determine the sensitivity and specificity of detection for individual studies. For the meta-analysis, a bivariate random effects model was used to jointly model sensitivity and specificity. RESULTS Our search identified 5408 unique citations. Following review of abstracts, 442 articles were reviewed in detail. Only 26 studies (6 of tTG assays, 15 of EMA assays, and 5 of tTG and EMA assays) met our inclusion criteria. The most common reason studies were excluded from our analysis was inability to cross-tabulate histologic and serologic findings. The serum assays identified patients with persistent villous atrophy with high levels of specificity: 0.83 for the tTG IgA assay (95% CI, 0.79-0.87) and 0.91 for the EMA IgA assay (95% CI, 0.87-0.94). However, they detected villous atrophy with low levels of sensitivity: 0.50 for the tTG IgA assay (95% CI, 0.41-0.60) and 0.45 for the EMA IgA assay (95% CI, 0.34-0.57). The tests had similar levels of performance in pediatric and adult patients. CONCLUSIONS In a meta-analysis of patients with biopsy-confirmed celiac disease undergoing follow-up biopsy on a GFD, we found that tests for serum tTG IgA and EMA IgA levels had low sensitivity (below 50%) in detection of persistent villous atrophy. We need more-accurate non-invasive markers of mucosal damage in children and adults with celiac disease who are following a GFD.
-
9.
Diagnosis and Updates in Celiac Disease.
Shannahan, S, Leffler, DA
Gastrointestinal endoscopy clinics of North America. 2017;(1):79-92
Abstract
Celiac disease is an autoimmune disorder induced by gluten in genetically susceptible individuals. It can result in intraintestinal and extraintestinal manifestations of disease including diarrhea, weight loss, anemia, osteoporosis, or lymphoma. Diagnosis of celiac disease is made through initial serologic testing and then confirmed by histopathologic examination of duodenal biopsies. Generally celiac disease is a benign disorder with a good prognosis in those who adhere to a gluten-free diet. However, in refractory disease, complications may develop that warrant additional testing with more advanced radiologic and endoscopic methods. This article reviews the current strategy to diagnose celiac disease and the newer modalities to assess for associated complications.
-
10.
Safety of Adding Oats to a Gluten-Free Diet for Patients With Celiac Disease: Systematic Review and Meta-analysis of Clinical and Observational Studies.
Pinto-Sánchez, MI, Causada-Calo, N, Bercik, P, Ford, AC, Murray, JA, Armstrong, D, Semrad, C, Kupfer, SS, Alaedini, A, Moayyedi, P, et al
Gastroenterology. 2017;(2):395-409.e3
-
-
Free full text
-
Abstract
BACKGROUND & AIMS Patients with celiac disease should maintain a gluten-free diet (GFD), excluding wheat, rye, and barley. Oats might increase the nutritional value of a GFD, but their inclusion is controversial. We performed a systematic review and meta-analysis to evaluate the safety of oats as part of a GFD in patients with celiac disease. METHODS We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases for clinical trials and observational studies of the effects of including oats in GFD of patients with celiac disease. The studies reported patients' symptoms, results from serology tests, and findings from histologic analyses. We used the GRADE approach to assess the quality of evidence. RESULTS We identified 433 studies; 28 were eligible for analysis. Of these, 6 were randomized and 2 were not randomized controlled trials comprising a total of 661 patients-the remaining studies were observational. All randomized controlled trials used pure/uncontaminated oats. Oat consumption for 12 months did not affect symptoms (standardized mean difference: reduction in symptom scores in patients who did and did not consume oats, -0.22; 95% CI, -0.56 to 0.13; P = .22), histologic scores (relative risk for histologic findings in patients who consumed oats, 0.24; 95% CI, 0.01-4.8; P = .35), intraepithelial lymphocyte counts (standardized mean difference, 0.21; 95% CI, reduction of 1.44 to increase in 1.86), or results from serologic tests. Subgroup analyses of adults vs children did not reveal differences. The overall quality of evidence was low. CONCLUSIONS In a systematic review and meta-analysis, we found no evidence that addition of oats to a GFD affects symptoms, histology, immunity, or serologic features of patients with celiac disease. However, there were few studies for many endpoints, as well as limited geographic distribution and low quality of evidence. Rigorous double-blind, placebo-controlled, randomized controlled trials, using commonly available oats sourced from different regions, are needed.