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. keywords: gluten, zonulin, inflammation, malabsorption 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, celiac disease presents with a set of diverse clinical features which typically includes fatigue, weight loss, diarrhea, anemia, osteoporosis and depression. Intestinal damage is the main component of celiac disease and is characterized by intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy. 1 these pathologic changes develop in the intestinal mucosa of sensitive individuals in response to gluten or the other related peptides 2 and improvement is usually observed by gluten withdrawal from the diet.

3 currently, the prevalence of celiac disease is estimated to be approximately 1% in western countries and increasing incidence of both diagnosed and undiagnosed cases has been reported. 4 x02013 6 celiac disease is also commonly seen in association with extraintestinal manifestations, such as the typical skin lesions known as dermatitis herpetiformis, and the neurologic disorders that primarily present with ataxia or neuropathy. 7 ,8 in addition, patients with longstanding untreated celiac disease may develop serious complications such as osteoporosis, refractory sprue and malignant lymphoma that are potentially preventable with early diagnosis and treatment. 9 however, due to the broad spectrum of presenting symptoms, the diagnosis may not be so obvious or easy.

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10 thus, it is important to have a greater awareness and lower threshold for testing for this disorder. When celiac disease is suspected, serologic testing and subsequently duodenal biopsies are required to confirm the diagnosis. 11 antibodies to tissue transglutaminase and endomysial of the iga isotype iga anti ttg and anti ema testing have been repeatedly shown to be highly sensitive and specific for identification of celiac disease, 12 ,13 however as assay performance is mainly dependent on pretest probability of the disease, 14 histologic 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 celiac disease, which has been proven to relieve the symptoms in most cases and effectively prevent potential complications. 15 x02013 22 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. 23 ,24 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. 25 ,26 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. 27 ,28 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 underlay celiac 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 celiac disease. 29 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.

30 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 celiac disease. 31 ,32 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 29 and presentations of the disease. However, the innate response to gluten, which may not be specific to celiac disease, is nonetheless required.

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33 hence, approaches that target either arm of the immune system may be helpful in the containment of their response to gluten. Though 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 celiac 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 preformed 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. Cited articles were selected based on the novelty and the relevancy to the purpose of this review. The association of celiac disease with wheat consumption and similar cereals was first reported by dicke, and since then gluten withdrawal has been considered as the cornerstone for the treatment of this condition. 33 however, the gluten free diet, despite being safe and mostly effective, is not ideal. United states fda and european union allow x0201c gluten free x0201d labeling only on the food products that contain less than 20 part per million ppm of gluten. In addition daily amount of tolerable gluten is variable among people but intake of less than 10 mg of gluten per day has been reported to be safe for patients with celiac disease.

34 strict adherence to gluten free diet is frequently affected by patients x02019 compliance and gluten contamination is a matter of concern which leads to increased burden of the disease. Furthermore, the gluten free diet is expensive and not widely available in many countries, which makes it even more difficult for the patients to comply with such a treatment. 35 x02013 37 additionally, despite high risk of morbidity and mortality in a significant number of patients with celiac disease, dietary treatment is not completely effective, as many of these patients could be either unresponsive or require combination therapies.

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38 histologic improvement is not always achievable even in the adult patients with typical celiac disease who are desirably responsive to a gluten free diet in terms of symptoms and serologic markers. 27 ,39 ,40 ,41 this lack of complete healing common in adults, is not benign and may be associated with negative long term consequences. A recent study from england documented dissatisfaction with a gluten free diet by the great majority of patients with celiac disease.

Patients were also asked to describe their preference for three different potential therapeutic approaches, of which patients preferred a vaccine approach over an anti zonulin and peptidase approach by a moderate amount. In addition, patients with celiac disease also use complementary and alternative medicine approximately one fifth of the time. 41 therefore, investigation for developing novel therapeutic approaches seems to be justified as alternative treatment options are desired. Generation of new therapies is needed for the patients who have difficulty being gluten free as well as those compliant patients afraid of inadvertent gluten contamination. Alternative therapies could free diagnosed individuals from the restrictive diet and provide a passport to eat gluten with impunity. It is possible that some regimens even prevent celiac disease in individuals with genetic susceptibility, such as those with a history of the disease in their family. It is, of course, difficult to predict what regulatory agencies will require of treatments for a disease which has not had drug therapy before.