Celiac Disease: New Approaches to Therapy
Celiac Disease: New Approaches to Therapy
Background Coeliac disease is managed by life-long gluten withdrawal from the diet. However, strict adherence to a gluten-free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.
Aim To review recent advances in new therapeutic options for coeliac disease.
Methods A literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrials.gov for English articles and abstracts. The search terms used included, but not limited to, 'Celiac disease', 'new', 'novel', 'Advances', 'alternatives' and 'Drug therapy'. The cited articles were selected based on the relevancy to the review objective.
Results Several new therapeutic approaches for coeliac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.
Conclusions Gluten-free diet is still the only practical treatment for patients with coeliac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.
Sensitivity to gluten results in a wide spectrum of manifestations triggered by ingestion of the gluten-containing grains – wheat, barley and rye. As the most common presentation of this disorder in genetically predisposed individuals, coeliac disease presents with a set of diverse clinical features, which typically includes fatigue, weight loss, diarrhoea, anaemia, osteoporosis and depression. Intestinal damage is the main component of coeliac disease and is characterised by intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy. These pathological changes develop in the intestinal mucosa of sensitive individuals in response to gluten or the other related peptides and improvement is usually observed by gluten withdrawal from the diet. Currently, the prevalence of coeliac disease is estimated to be approximately 1% in western countries and increasing incidence of both diagnosed and undiagnosed cases has been reported. Coeliac disease is also commonly seen in association with extraintestinal manifestations, such as the typical skin lesions known as Dermatitis Herpetiformis, and the neurological disorders that primarily present with ataxia or neuropathy. In addition, patients with longstanding untreated coeliac disease may develop serious complications such as osteoporosis, refractory sprue and malignant lymphoma that are potentially preventable with early diagnosis and treatment. However, due to the broad spectrum of presenting symptoms, the diagnosis may not be so obvious or easy. Thus, it is important to have a greater awareness and lower threshold for testing for this disorder. When coeliac disease is suspected, serological testing and subsequently duodenal biopsies are required to confirm the diagnosis. Antibodies to tissue transglutaminase of the IgA isotype (IgA anti tTg) and anti endomysial antibody testing have been repeatedly shown to be highly sensitive and specific for identification of coeliac disease; however, as assay performance is mainly dependent on pretest probability of the disease, histological studies are still being considered as the gold standard for establishing the diagnosis.
Currently, adherence to a gluten-free diet is considered as the first line and indeed only therapy for coeliac disease, which has been proven to relieve the symptoms in most cases and effectively prevent potential complications. The availability of a readily applicable and safe therapy in the gluten-free diet has reduced the impetus for alternative therapies. However, the costly and restrictive aspect of complying with a life-long gluten-free regimen may have a significant adverse impact upon the quality of life of the patients. Human nature in dealing with temptation, motivation to resume regular diet especially with milder disease, and the hidden gluten in the diet are the main issues. In many cases, what should be naturally considered as gluten-free foods are widely contaminated with wheat. Moreover, even with achieving and maintaining a truly gluten-free diet, especially in adults, there might be a lack of complete recovery in the intestine which may impact survival. All these concerns along with ineffectiveness in some cases have warranted the development of alternative and complementary approaches to dietary treatment. Improved understanding of pathogenic pathways that underlie coeliac disease has led to development of multiple new therapeutic approaches, some of which have reached clinical studies. It may be especially important to provide optimum aids and eventually alternatives to the gluten-free diet for those with mild or no symptoms for whom the motivation to be gluten-free may be less.
As a chronic autoimmune disorder, both adaptive and innate immune responses are involved in pathogenesis of coeliac disease. In genetically susceptible individuals who express HLA DQ2 or DQ8, gluten consumption leads to the recognition of gliadin by T lymphocytes through antigen presentation process. At the intestine level, tissue transglutaminase interacts with gliadin proteins, resulting in selective deamidation of certain glutamine residues. The deamidated gliadin peptide-TTG complexes presented by antigen presenting B cells provoke augmented activation of specific gluten-responsive T cells. Similarly, transient T-cell response has been shown with gluten challenge in the peripheral blood of patients with coeliac disease. Interaction between activated T cells and the B cell response together lead to stimulation of antibody-secreting cells and produce an inflammatory process that results in destruction of intestinal mucosa and presentations of the disease.
It is well recognised that the role of the T cell-based adaptive immunity, i.e. HLA restricted, is required for coeliac disease and also specific to the disease. However, the innate response to gluten, which may not be specific to coeliac disease, is nonetheless required. Hence, approaches that target either arm of the immune system may be helpful in the containment of their response to gluten. Although directed at the specific T cell, responses to gluten are more likely to have a degree of specificity not seen with blocking the innate response. It is also important to preserve particularly innate responses to infections within the intestine.
In this article, we aim to review the recent advances in novel therapeutic options that have been suggested as adjuvant therapy for dietary restriction as well as the potential true alternatives to gluten-free diet in coeliac disease. Therapies that focus on detoxification of gluten are briefly discussed as they have been recently reviewed elsewhere.
An extensive literature search through August 2011 for English articles and abstracts was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrials.gov. A combination of controlled vocabulary (MeSH, EMTREE) was used for MEDLINE and EMBASE. The terms 'Celiac disease', 'Coeliac disease', 'diet therapy', 'drug therapy', 'prevention and control', as well as text-words; 'new', 'novel', 'strategies', 'developments', 'advances', 'alternatives', 'compared', 'comparison', 'comparative' and 'gluten-free' were applied in the searching process. Subject headings and publication types, including 'clinical trials', 'case reports', 'case series', 'controlled trials', 'randomised controlled trials', 'cohort studies', 'retrospective/prospective studies', 'major clinical studies', 'meta-analysis', and 'systematic review', were used to identify the relevant literature. Cited articles were selected based on the novelty and the relevancy to the purpose of this review.
Abstract and Introduction
Abstract
Background Coeliac disease is managed by life-long gluten withdrawal from the diet. However, strict adherence to a gluten-free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.
Aim To review recent advances in new therapeutic options for coeliac disease.
Methods A literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrials.gov for English articles and abstracts. The search terms used included, but not limited to, 'Celiac disease', 'new', 'novel', 'Advances', 'alternatives' and 'Drug therapy'. The cited articles were selected based on the relevancy to the review objective.
Results Several new therapeutic approaches for coeliac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.
Conclusions Gluten-free diet is still the only practical treatment for patients with coeliac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.
Introduction
Sensitivity to gluten results in a wide spectrum of manifestations triggered by ingestion of the gluten-containing grains – wheat, barley and rye. As the most common presentation of this disorder in genetically predisposed individuals, coeliac disease presents with a set of diverse clinical features, which typically includes fatigue, weight loss, diarrhoea, anaemia, osteoporosis and depression. Intestinal damage is the main component of coeliac disease and is characterised by intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy. These pathological changes develop in the intestinal mucosa of sensitive individuals in response to gluten or the other related peptides and improvement is usually observed by gluten withdrawal from the diet. Currently, the prevalence of coeliac disease is estimated to be approximately 1% in western countries and increasing incidence of both diagnosed and undiagnosed cases has been reported. Coeliac disease is also commonly seen in association with extraintestinal manifestations, such as the typical skin lesions known as Dermatitis Herpetiformis, and the neurological disorders that primarily present with ataxia or neuropathy. In addition, patients with longstanding untreated coeliac disease may develop serious complications such as osteoporosis, refractory sprue and malignant lymphoma that are potentially preventable with early diagnosis and treatment. However, due to the broad spectrum of presenting symptoms, the diagnosis may not be so obvious or easy. Thus, it is important to have a greater awareness and lower threshold for testing for this disorder. When coeliac disease is suspected, serological testing and subsequently duodenal biopsies are required to confirm the diagnosis. Antibodies to tissue transglutaminase of the IgA isotype (IgA anti tTg) and anti endomysial antibody testing have been repeatedly shown to be highly sensitive and specific for identification of coeliac disease; however, as assay performance is mainly dependent on pretest probability of the disease, histological studies are still being considered as the gold standard for establishing the diagnosis.
Currently, adherence to a gluten-free diet is considered as the first line and indeed only therapy for coeliac disease, which has been proven to relieve the symptoms in most cases and effectively prevent potential complications. The availability of a readily applicable and safe therapy in the gluten-free diet has reduced the impetus for alternative therapies. However, the costly and restrictive aspect of complying with a life-long gluten-free regimen may have a significant adverse impact upon the quality of life of the patients. Human nature in dealing with temptation, motivation to resume regular diet especially with milder disease, and the hidden gluten in the diet are the main issues. In many cases, what should be naturally considered as gluten-free foods are widely contaminated with wheat. Moreover, even with achieving and maintaining a truly gluten-free diet, especially in adults, there might be a lack of complete recovery in the intestine which may impact survival. All these concerns along with ineffectiveness in some cases have warranted the development of alternative and complementary approaches to dietary treatment. Improved understanding of pathogenic pathways that underlie coeliac disease has led to development of multiple new therapeutic approaches, some of which have reached clinical studies. It may be especially important to provide optimum aids and eventually alternatives to the gluten-free diet for those with mild or no symptoms for whom the motivation to be gluten-free may be less.
As a chronic autoimmune disorder, both adaptive and innate immune responses are involved in pathogenesis of coeliac disease. In genetically susceptible individuals who express HLA DQ2 or DQ8, gluten consumption leads to the recognition of gliadin by T lymphocytes through antigen presentation process. At the intestine level, tissue transglutaminase interacts with gliadin proteins, resulting in selective deamidation of certain glutamine residues. The deamidated gliadin peptide-TTG complexes presented by antigen presenting B cells provoke augmented activation of specific gluten-responsive T cells. Similarly, transient T-cell response has been shown with gluten challenge in the peripheral blood of patients with coeliac disease. Interaction between activated T cells and the B cell response together lead to stimulation of antibody-secreting cells and produce an inflammatory process that results in destruction of intestinal mucosa and presentations of the disease.
It is well recognised that the role of the T cell-based adaptive immunity, i.e. HLA restricted, is required for coeliac disease and also specific to the disease. However, the innate response to gluten, which may not be specific to coeliac disease, is nonetheless required. Hence, approaches that target either arm of the immune system may be helpful in the containment of their response to gluten. Although directed at the specific T cell, responses to gluten are more likely to have a degree of specificity not seen with blocking the innate response. It is also important to preserve particularly innate responses to infections within the intestine.
In this article, we aim to review the recent advances in novel therapeutic options that have been suggested as adjuvant therapy for dietary restriction as well as the potential true alternatives to gluten-free diet in coeliac disease. Therapies that focus on detoxification of gluten are briefly discussed as they have been recently reviewed elsewhere.
An extensive literature search through August 2011 for English articles and abstracts was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrials.gov. A combination of controlled vocabulary (MeSH, EMTREE) was used for MEDLINE and EMBASE. The terms 'Celiac disease', 'Coeliac disease', 'diet therapy', 'drug therapy', 'prevention and control', as well as text-words; 'new', 'novel', 'strategies', 'developments', 'advances', 'alternatives', 'compared', 'comparison', 'comparative' and 'gluten-free' were applied in the searching process. Subject headings and publication types, including 'clinical trials', 'case reports', 'case series', 'controlled trials', 'randomised controlled trials', 'cohort studies', 'retrospective/prospective studies', 'major clinical studies', 'meta-analysis', and 'systematic review', were used to identify the relevant literature. Cited articles were selected based on the novelty and the relevancy to the purpose of this review.
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