From Genetics to Treatment of Eosinophilic Esophagitis
From Genetics to Treatment of Eosinophilic Esophagitis
The current understanding of the pathobiology of EoE is incomplete, but evolving it seems to point to three factors leading to the development of EoE: atopy, genetic predisposition, and a local Th2 inflammation driven by a dysfunctional esophageal epithelium.
Current EoE management is based on current knowledge of the disease and is mainly based on two main clinically accepted clinical treatment strategies like any other atopic disease: allergen avoidance and corticosteroid treatment (Table 3).
The new genetic studies that are pointing to the esophageal dysfunction are shaping the treatment for tomorrow that will be based on antigen tolerance induction and specific biological treatments.
Steroids are a very effective treatment of EoE. Oral steroids are very effective, but not recommended as a long-term therapy for the well known side-effects (Table 3). Swallowed inhaled corticosteroids are effective in 50–80% of patients and can be considered as first-line therapies for initial and maintenance management of EoE, as they have low bioavailability and fewer systemic side-effects. Fluticasone is administered by spraying in the mouth with a metered dose inhaler without a spacer, and swallowed twice daily. Budesonide is used as an oral viscous slurry once or twice daily. Swallowed inhaled corticosteroids appear to be well tolerated when used in the short term, but they can lead to increased risk of localized yeast infections and have potential long-term side-effects, including growth suppression and osteopenia (low-bone density). Although steroids are effective for treatment, clinical, and histologic features of EoE return upon discontinuation. Steroids may reverse the esophageal fibrosis in children but not in adults with EoE.
The majority of patients with EoE are allergic to food allergens and aeroallergens (Table 3). Dietary elimination therapy should be considered in all children and motivated adults diagnosed with EoE. Dietary elimination approaches include a strictly elemental diet, specific antigen avoidance based on allergy testing, and empiric food elimination based on the most common food antigens. All three methods have been proven to be effective with improved clinical symptoms and pathology and the regimen chosen should be based on the individual patient. Treatment with food avoidance is highly successful, with rates close to 100% with elemental diets (amino acid formulas) and up to 80% for elimination diet. However, amino acid formulas are unpalatable and lead to low quality of life. Elimination diet on the basis of allergy testing or empirical elimination may be sustainable in the long-term albeit with some difficulties, and many patients refuse to continue them. For additional details of dietary management, please see recent review.
Esophageal fibrosis and esophageal strictures are known complications of EoE. Endoscopic stricture dilation is sometimes necessary for short-term symptomatic relief but should be considered as a treatment option only if patients have failed dietary and medical therapy.
Other treatments that have been investigated include anti-IL-5 and chemoattractant homologous receptor expressed on Th2 cells (CRTH2) antagonist (Table 3). Both strategies have shown limited or no efficacy in controlling the disease, suggesting that a broader inhibition of Th2 inflammation may be needed due to the redundancy of its mediators.
IL-5 is the major survival factor for eosinophils and is indispensable for the differentiation, recruitment, and activation of the eosinophils. Therefore, humanized monoclonal antibodies against IL-5 Mepolizumab (SB240563) and Reslizumab (Sch55700) have been used in clinical trials for EoE treatment. Both antibodies in pediatrics and adult trials have failed to show symptomatic improvement beyond the placebo effect. However, both Reslizumab and Mepolizumab had a good safety profile and significantly decreased eosinophils numbers in the esophageal biopsies in adults and children with EoE, even if only few patients achieved normal biopsies. These data confirm that eosinophils are likely only one of the players in EoE inflammation and the importance of other cells and mediators in the pathogenesis of EoE that can be a target for immunological therapy.
Other biological treatment such as anti-TNFα (Infliximab), anti-IgE (omalizumab) have been tried in small groups of patients without showing any efficacy.
A recent study has been published on the efficacy of anti-CRTH in treatment of EoE and showed promising albeit small results. OC000459 is a potent, selective, and orally bioavailable CRTH2 antagonist, which blocks prostaglandin 2-mediated chemotaxis and activation of CRTH2-expressing cells. In a small group of patients with severe EoE dependent or resistant to corticosteroids anti-CRTH2 had a modest, but significant, antibeneficial clinical effect.
Anti-IL-13 antibodies have also been tried in asthma and more recently in the treatment of EoE. Given the importance of Th2 inflammation and IL-13 in particular in EoE pathogenesis Rothenberg et al. tried anti-IL-13 (QAX576) in a double-blind placebo-controlled clinical trial for EoE treatment. The treated group had a significant reduction of esophageal eosinophilia and other markers of Th2 inflammation and epithelial dysfunction compared with those treated with placebo. However, even if there was a trend for improved symptoms, particularly dysphagia, this did not reach statistical significance. QAX576 was well tolerated. Therefore, the authors concluded that QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease-related transcripts in adults with EoE but the clinical significance of such treatment remains to be established.
The recent identification of TSLP and its receptor as key components in the EoE pathogenesis suggests that blockage of the TSLP–TSLPR activation could provide an attractive approach to treating the cause of EoE. This has been confirmed in animal studies wherein blockage of Noti et al. recently described a novel mouse model of EoE in which the development of EoE-like features was dependent upon TSLP. In such a model TSLP-blocking antibodies ameliorated the EoE-like disease including the development of food impaction, when administered after the onset of disease. This is not surprising as anti-TSLP antibodies have been shown to be beneficial in various murine models of atopy.
A humanized anti-TSLP monoclonal antibody (AMG 157) that specifically binds human TSLP and prevents its interaction with TSLPR has been tested in adult asthmatic patients in a double-blind, placebo-controlled study. In the group receiving the antibody there were: attenuated allergen-induced bronchoconstriction in both early and late asthmatic responses; reduced markers of systemic and airway inflammation. Although this was only a proof-of-concept study, which did not determine whether anti-TSLP therapeutics will have clinical impact, these findings confirm that TSLP has a key role in allergic asthma. TSLP antibodies have not been tested in EoE yet.
We and others have reported that in both adults and children, milk is the most common trigger of EoE, initiating inflammation in a genetically susceptible individual via a disrupted epithelial barrier. Epicutaneous immunotherapy (EPIT) has recently been proposed as a way to bypass the dysfunctional and TSLP-producing esophageal epithelium, and induce lasting food tolerance in EoE. In murine models of EoE, EPIT induces a persistent resolution of esophageal eosinophilia. In humans, EPIT has been shown to be a well tolerated method to desensitize IgE food allergic patients. EPIT, therefore, could be a promising strategy to cure food allergy and the consequent development of EoE in children with EoE due to food allergy.
Potential Pathways for Treatment
The current understanding of the pathobiology of EoE is incomplete, but evolving it seems to point to three factors leading to the development of EoE: atopy, genetic predisposition, and a local Th2 inflammation driven by a dysfunctional esophageal epithelium.
Current EoE management is based on current knowledge of the disease and is mainly based on two main clinically accepted clinical treatment strategies like any other atopic disease: allergen avoidance and corticosteroid treatment (Table 3).
The new genetic studies that are pointing to the esophageal dysfunction are shaping the treatment for tomorrow that will be based on antigen tolerance induction and specific biological treatments.
Steroid Treatment
Steroids are a very effective treatment of EoE. Oral steroids are very effective, but not recommended as a long-term therapy for the well known side-effects (Table 3). Swallowed inhaled corticosteroids are effective in 50–80% of patients and can be considered as first-line therapies for initial and maintenance management of EoE, as they have low bioavailability and fewer systemic side-effects. Fluticasone is administered by spraying in the mouth with a metered dose inhaler without a spacer, and swallowed twice daily. Budesonide is used as an oral viscous slurry once or twice daily. Swallowed inhaled corticosteroids appear to be well tolerated when used in the short term, but they can lead to increased risk of localized yeast infections and have potential long-term side-effects, including growth suppression and osteopenia (low-bone density). Although steroids are effective for treatment, clinical, and histologic features of EoE return upon discontinuation. Steroids may reverse the esophageal fibrosis in children but not in adults with EoE.
Dietary Intervention
The majority of patients with EoE are allergic to food allergens and aeroallergens (Table 3). Dietary elimination therapy should be considered in all children and motivated adults diagnosed with EoE. Dietary elimination approaches include a strictly elemental diet, specific antigen avoidance based on allergy testing, and empiric food elimination based on the most common food antigens. All three methods have been proven to be effective with improved clinical symptoms and pathology and the regimen chosen should be based on the individual patient. Treatment with food avoidance is highly successful, with rates close to 100% with elemental diets (amino acid formulas) and up to 80% for elimination diet. However, amino acid formulas are unpalatable and lead to low quality of life. Elimination diet on the basis of allergy testing or empirical elimination may be sustainable in the long-term albeit with some difficulties, and many patients refuse to continue them. For additional details of dietary management, please see recent review.
Esophageal Dilation
Esophageal fibrosis and esophageal strictures are known complications of EoE. Endoscopic stricture dilation is sometimes necessary for short-term symptomatic relief but should be considered as a treatment option only if patients have failed dietary and medical therapy.
Other Biological Treatment
Other treatments that have been investigated include anti-IL-5 and chemoattractant homologous receptor expressed on Th2 cells (CRTH2) antagonist (Table 3). Both strategies have shown limited or no efficacy in controlling the disease, suggesting that a broader inhibition of Th2 inflammation may be needed due to the redundancy of its mediators.
Antiinterleukin-5
IL-5 is the major survival factor for eosinophils and is indispensable for the differentiation, recruitment, and activation of the eosinophils. Therefore, humanized monoclonal antibodies against IL-5 Mepolizumab (SB240563) and Reslizumab (Sch55700) have been used in clinical trials for EoE treatment. Both antibodies in pediatrics and adult trials have failed to show symptomatic improvement beyond the placebo effect. However, both Reslizumab and Mepolizumab had a good safety profile and significantly decreased eosinophils numbers in the esophageal biopsies in adults and children with EoE, even if only few patients achieved normal biopsies. These data confirm that eosinophils are likely only one of the players in EoE inflammation and the importance of other cells and mediators in the pathogenesis of EoE that can be a target for immunological therapy.
Other biological treatment such as anti-TNFα (Infliximab), anti-IgE (omalizumab) have been tried in small groups of patients without showing any efficacy.
A recent study has been published on the efficacy of anti-CRTH in treatment of EoE and showed promising albeit small results. OC000459 is a potent, selective, and orally bioavailable CRTH2 antagonist, which blocks prostaglandin 2-mediated chemotaxis and activation of CRTH2-expressing cells. In a small group of patients with severe EoE dependent or resistant to corticosteroids anti-CRTH2 had a modest, but significant, antibeneficial clinical effect.
Anti-IL-13 antibodies have also been tried in asthma and more recently in the treatment of EoE. Given the importance of Th2 inflammation and IL-13 in particular in EoE pathogenesis Rothenberg et al. tried anti-IL-13 (QAX576) in a double-blind placebo-controlled clinical trial for EoE treatment. The treated group had a significant reduction of esophageal eosinophilia and other markers of Th2 inflammation and epithelial dysfunction compared with those treated with placebo. However, even if there was a trend for improved symptoms, particularly dysphagia, this did not reach statistical significance. QAX576 was well tolerated. Therefore, the authors concluded that QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease-related transcripts in adults with EoE but the clinical significance of such treatment remains to be established.
Antithymic Stromal Lymphopoietin
The recent identification of TSLP and its receptor as key components in the EoE pathogenesis suggests that blockage of the TSLP–TSLPR activation could provide an attractive approach to treating the cause of EoE. This has been confirmed in animal studies wherein blockage of Noti et al. recently described a novel mouse model of EoE in which the development of EoE-like features was dependent upon TSLP. In such a model TSLP-blocking antibodies ameliorated the EoE-like disease including the development of food impaction, when administered after the onset of disease. This is not surprising as anti-TSLP antibodies have been shown to be beneficial in various murine models of atopy.
A humanized anti-TSLP monoclonal antibody (AMG 157) that specifically binds human TSLP and prevents its interaction with TSLPR has been tested in adult asthmatic patients in a double-blind, placebo-controlled study. In the group receiving the antibody there were: attenuated allergen-induced bronchoconstriction in both early and late asthmatic responses; reduced markers of systemic and airway inflammation. Although this was only a proof-of-concept study, which did not determine whether anti-TSLP therapeutics will have clinical impact, these findings confirm that TSLP has a key role in allergic asthma. TSLP antibodies have not been tested in EoE yet.
Food Immunotherapy
We and others have reported that in both adults and children, milk is the most common trigger of EoE, initiating inflammation in a genetically susceptible individual via a disrupted epithelial barrier. Epicutaneous immunotherapy (EPIT) has recently been proposed as a way to bypass the dysfunctional and TSLP-producing esophageal epithelium, and induce lasting food tolerance in EoE. In murine models of EoE, EPIT induces a persistent resolution of esophageal eosinophilia. In humans, EPIT has been shown to be a well tolerated method to desensitize IgE food allergic patients. EPIT, therefore, could be a promising strategy to cure food allergy and the consequent development of EoE in children with EoE due to food allergy.
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