Twenty years have passed since eosinophilic esophagitis was first recognized as a new and distinct entity. Current treatment modalities for eosinophilic esophagitis include the “3 Ds”: drugs, allergen avoidance with diet, and esophageal dilation. Drugs entail the limitation that only corticosteroids have a proven efficacy; most other compounds evoke only a minimal effect. Diets must be maintained continuously and they interfere markedly with the quality of life, possibly even involving some risk of malnutrition. A greater understanding of the immunopathogenesis, natural history, and disease spectrum will inevitably lead to improved therapeutic outcomes for this emerging entity.
Key points
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Twenty years have passed since eosinophilic esophagitis was first recognized as a new and distinct entity; this time span has been long enough for research to ascertain several fundamental principles, and also long enough to pose certain critical questions regarding the diagnosis, therapy, and long-term management of this disease.
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In eosinophilic esophagitis, several therapeutic modalities are available but all have important limitations; there is thus an urgent need for alternative treatment options.
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With respect to medications, second-generation CRTH2 antagonists and biologicals targeting IL-13 and/or IL-4 are promising candidates.
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As for dietary treatment, there is hope that a simplified induction regimen, more accurate allergy tests to identify causative food antigens, as well as an individualized maintenance diet will increase the utilization of the dietary approach.
Introduction
Somewhat more than 20 years have passed since eosinophilic esophagitis (EoE) was first recognized as a new and distinct entity. In the early days, the discussion was often dictated by the question, “Do you believe in eosinophilic esophagitis?” This question illustrates the broadly held skepticism that occurs when a disturbing factor invades an established concept which, at that time, was that EoE indicates gastroesophageal reflux. Twenty years later, this question and the initial skepticism have clearly disappeared and gastroenterologists are informed about, and are familiar with, this immune-mediated esophageal disease. Huge educational efforts, including establishing well-defined diagnostic criteria and therapeutic algorithms, combined with personal clinical experience coming from their own EoE patients, have led to this change among practitioners. Nevertheless, EoE is still a relatively new disease and one may ask the question, quo vadit? In this article, the focus is on promising therapeutic developments and subsequently on more general perspectives.
Introduction
Somewhat more than 20 years have passed since eosinophilic esophagitis (EoE) was first recognized as a new and distinct entity. In the early days, the discussion was often dictated by the question, “Do you believe in eosinophilic esophagitis?” This question illustrates the broadly held skepticism that occurs when a disturbing factor invades an established concept which, at that time, was that EoE indicates gastroesophageal reflux. Twenty years later, this question and the initial skepticism have clearly disappeared and gastroenterologists are informed about, and are familiar with, this immune-mediated esophageal disease. Huge educational efforts, including establishing well-defined diagnostic criteria and therapeutic algorithms, combined with personal clinical experience coming from their own EoE patients, have led to this change among practitioners. Nevertheless, EoE is still a relatively new disease and one may ask the question, quo vadit? In this article, the focus is on promising therapeutic developments and subsequently on more general perspectives.
Emerging treatment modalities for EoE
EoE is defined as a chronic, mainly Th2-type inflammatory disorder of the esophagus, characterized clinically by symptoms reflecting esophageal dysfunction and, histologically, by an eosinophil-predominant infiltration of the esophageal mucosa. Adults and adolescents with EoE usually cope for years with their swallowing disturbances until a food impaction forces them to seek medical attention. This behavior by those affected raised the question of whether EoE patients should continue with their coping strategy or be actively encouraged to seek treatment. Today, the results of several natural history studies suggest that there are at least 3 reasons to treat patients suffering from active EoE: First, dysphagia has a markedly negative impact on the quality of life and this handicap can be precluded by proper treatment. Second, untreated EoE patients are at risk for experiencing long-lasting food impactions with the danger of suffering severe esophageal injury. Third, treatment should be sought to prevent esophageal damage caused by tissue remodeling due to uncontrolled eosinophilic inflammation. All of the above-mentioned reasons for treatment are valid for both children and adults. Physicians caring for EoE patients are therefore encouraged to inform their patients comprehensively and to offer effective treatment options.
Limitations of established treatment modalities
Currently, the treatment modalities for EoE include the 3 Ds: drugs, allergen avoidance by elimination or elemental diets and, finally, esophageal dilation. Furthermore, each of these 3 modalities encompasses several particular options: for instance, at least 10 different drugs are recommended for medical treatment; 3 different dietary regimens are available for allergen avoidance strategy; and 2 types of dilation are currently used. With respect to the long list of available therapeutic modalities, one could ask the question of whether there is actually a need for developing further therapies.
Drugs have the limitation that only corticosteroids have a proven efficacy; indeed, most other compounds have shown only limited or even no effect. Swallowed topical corticosteroids (TCS) have undergone the most investigation; they achieve successful remission in up to 80% of patients with active EoE symptoms and inflammation. Some 10% of EoE patients require higher doses of TCS to achieve this goal and, with the higher dose, there is an increased risk of systemic side effects. In another 10% of patients, symptoms and inflammation are refractory to TCS treatment. Moreover, swallowed TCS have only a limited efficacy in sustaining EoE in clinical and histologic remission over a longer period of time. Systemically administered corticosteroids or immunosuppressants are alternatives, but according to the literature, not superior to TCS and, in addition, their efficacy has not yet been adequately evaluated. In several controlled, randomized clinical trials, specific eosinophil-targeted drugs, such as the 2 anti-IL-5 antibodies, mepolizumab and reslizumab, have demonstrated rather disappointing results with persistence of symptoms and endoscopic abnormalities, despite a significant reduction in eosinophils in esophageal tissue and peripheral blood. A new approach using the prostaglandin pathway to treat Th2-type inflammations was recently evaluated in EoE: an 8-week blockade of the so-called CRTH2 receptor with the orally available small molecule, OC000459, led to a significant reduction in the eosinophilic inflammation in esophageal tissue, and to a moderate resolution of symptoms and endoscopic abnormalities. Although the drug was well tolerated, this first-generation CRTH2 antagonist was less effective than swallowed TCS.
Allergen avoidance by dietary measures, the second D, was one of the first modalities attempted to treat EoE. Since the initial endeavors, 3 different dietary approaches that reduce the exposure of the esophagus to allergens have been established. All 3 approaches have demonstrated efficacy in bringing active EoE into remission, with complete elimination of food proteins by amino acid formulae proving to be the most successful. Of note, these dietary restrictions likely need to be maintained indefinitely because symptoms and inflammation reappear rapidly after the reintroduction of the causative food. Unfortunately, each of these dietary restrictions interferes markedly with the patient’s quality of life, either through restricting daily eating habits with amino acid formulae or by elimination of several staple foods, such as milk, wheat, and eggs. In addition, severe dietary restrictions entail a risk of malnutrition.
The third D, dilation, has been used to treat EoE since the disease was first recognized and provides a rapid and unexpected long-lasting relief of symptoms. Nevertheless, because it does not modulate the underlying inflammation, dilation cannot be considered a first-line treatment of EoE.
In summary, the list of potential therapeutic modalities is, in theory, long, but in reality, rather short. Furthermore, each of the available treatments has severe limitations and none is currently approved. Indeed, even today, in a substantial number of EoE patients, the disease cannot be controlled, and the search continues for successful alternative therapeutic options.
The search for new targets
The first step in the discovery and development of any new and novel anti-inflammatory drug consists of the identification of targets that are critically involved in the pathway of the particular inflammation. Identification of relevant pro-inflammatory mediators and their corresponding receptors requires a profound understanding of the disease-specific inflammatory properties. Of note, one difficulty in this procedure is the redundancy of almost all relevant signaling mechanisms. This harbors the risk that blockade of an assumed key signaling pathway does not necessarily lead to the expected effect. Before addressing several candidate drugs, some key properties of the eosinophilic inflammation characterizing EoE are discussed.
EoE presents many features of a Th2-type inflammation. Eosinophils, mast cells, and T cells are involved in this type of inflammatory response, but eosinophils are visually predominant and likely the key effectors. After maturation in the bone marrow, eosinophils relocate to the peripheral circulation and, finally, traffic to specific tissues, primarily the gastrointestinal tract, where they reside for at least 1 week. Although a multitude of cytokines and growth factors are vital in enhancing eosinophil development, it is important to point out that the proliferation and terminal differentiation of eosinophils from precursor myeloblasts depend critically on the presence of interleukin-5 (IL-5). IL-5 is a major eosinophil-specific regulator that is not only responsible for the proliferation and maturation of eosinophils in the bone marrow and release into the circulation, but also for promoting eosinophil survival and activation. In addition, IL-5 primes the response to chemoattractants, such as eotaxin-1, also known as CC-chemokine ligand 11 (CCL11). Expressed by gastrointestinal epithelial and other cells, eotaxin-1 is important for trafficking and accumulation of eosinophils in the gastrointestinal tract in both the steady state and inflammatory conditions. In addition to eotaxin-1, 2 other members of eosinophil-specific chemokines, eotaxin-2 (CCL24) and eotaxin-3 (CCL26), have been identified in humans. Eotaxin-1, eotaxin-2, and eotaxin-3 act through CC-chemokine receptor 3 (CCR3), which is expressed in high levels on eosinophils. Among these eosinophil-specific chemokines, eotaxin-3 appears to play a key role in the pathogenesis of EoE, as it has been demonstrated that the level of expression of the eotaxin-3 gene is increased by 53-fold in EoE patients when compared with control subjects. This RNA response has been confirmed at the protein level by immunohistochemistry showing that, in biopsies of EoE patients, the levels of eotaxin-3 correlated with the density of the eosinophils in the esophageal tissue. Allergen exposure in patients with EoE results in an influx of activated Th2 lymphocytes to the site of inflammation and an increase in the tissue levels of Th2 cytokines, thereby leading to eosinophil recruitment and activation at the site of exposure.
The process of eosinophil activation is regulated by a multitude of cytokines, such as IL-5, IL-13, IL-4, and tumor necrosis factor α, which are produced by activated Th2 and mast cells. On activation, eosinophils produce IgE, up-regulate production of numerous cytokines and chemokines, and then degranulate, thereby releasing preformed granules containing at least 4 major cationic and cytotoxic proteins: eosinophil peroxidase, eosinophil cationic protein, eosinophil-derived neurotoxin, and major basic protein. In the presence of an antigen, the complex interplay between the esophageal epithelium and many of the immune cells, including antigen-presenting cells, Th2, mast cells, and eosinophils, eventually leads to chronic esophageal inflammation. The effect of IL-5 blockade with mepolizumab and reslizumab on EoE has been evaluated in 3 controlled trials. This highly selective IL-5 blockade was well tolerated but, unfortunately, neither in children nor in adults, did it fulfill expectations. The significant but isolated eosinophil reduction in esophageal tissue and blood did not lead to a substantial resolution of EoE symptoms, thereby indicating that this approach might be too selective. Based on these results, IL-4, IL-13, and the eotaxin-receptor, CCR3, might prove more promising targets.
In addition to this eosinophil-centered pathway, it has been demonstrated that several cells centrally involved in Th2-type inflammation express a common receptor on their surface. This so-called CRTH2 (chemoattractant receptor expressed on Th2 cells) is a G protein-coupled receptor expressed, in particular, by Th2 lymphocytes, eosinophils, and basophils. It mediates chemotaxis of these cells in response to prostaglandin D 2 , a key prostanoid in allergic responses produced by mast cells. It can therefore be expected that a blockade of the CRTH2 receptor abolishes the ability of prostaglandin D 2 to cause chemotaxis and activation of Th2 lymphocytes and eosinophils, resulting finally in a suppression of the eosinophilic tissue inflammation associated with EoE.
In summary, based on the above-outlined understanding of EoE’s immunopathogenic mechanisms, as well as on the results of in vitro studies, animal models, and clinical trials, the Th2 cytokines, IL-13 and IL-4, the CRTH2 receptor, and the eosinophil-specific chemokine, eotaxin-3, are currently the most promising targets for discovering new antieosinophil drugs.