Eosinophilic esophagitis (referred to as EoE) involves an atypical allergic response to food in the esophagus. In some patients, the response can be triggered by simply the smell of the problematic food. The cells involved are not part of the adaptive immune system and do not react to self antigens. Thus, it is not an autoimmune disease. It is an immune disease that is diagnosed by the presence of >15 eosinophils per high power field (∼60 eosinophils/mm2) in biopsy samples of the esophagus.
The major symptoms are gastroesophageal reflux (GERD), difficulty swallowing, food impaction in the esophagus, or recurrent vomiting. Weight loss (or failure to gain weight in children) and “finicky” eating are also common.
The diagnosis of EoE has increased in the past few decades. Some of the increase relates to the increased use of endoscopy with biopsies to diagnose upper GI conditions. Some of the increase relates to changes in the classification of the disease. Unfortunately, the treatment options for this condition are limited.
One therapeutic strategy is to identify the foods that cause the reaction and remove them from the diet. Unlike food allergies that cause the throat to swell immediately, the food allergies that cause EoE cannot typically be identified through skin tests. Instead, elimination diets tend to be required. However, this can be challenging, especially in a very active person or an athlete. The full elimination diet, which can be required to clear the system before introducing foods in a controlled way, can result in a reduction in calories that causes rapid weight loss. Foods have to be slowly re-introduced, and the definitive method to know if a food does not cause symptoms is to have the esophagus checked through endoscopy and a biopsy. With each new food requiring several weeks to confirm no reaction or to recover if there is a reaction, it can be many months before the patient’s dietary requirements to minimize EoE are determined.
The only available medications for treating EoE are proton pump inhibitors (PPIs) and synthetic glucocorticoids. PPIs reduce acid production in the stomach and thus reduce GERD, which can alleviate some symptoms. Indeed, a subset of patients, referred to as patients with proton pump inhibitor-responsive eosinophilic esophagitis (PPI-REE), have complete resolution of their symptoms and normalization of the number of eosinophils in their esophagus in response to PPI treatment. However, they may need to take these medications intermittently or regularly for the rest of their lives to maintain this healthy state.
PPIs
- Nexium (esomeprazole)
- Prevacid (lansoprazole)
- Prilosec and Zegerid (omeprazole)
- Protonix (pantoprazole)
- Aciphex (rabeprazole)
- Dexilant and Kapidex (dexlansoprazole)
PPIs are metabolized by enzymes in the liver, and different people metabolize the drugs at different rates. Those people that are classified as extensive metabolizers may require increased dosing or concentrations of PPIs for effectiveness. Those that are classified as poor metabolizers may require less. Whether there is a correlation between the metabolism of these drugs and PPI-REE is unknown. Whether genetic variations in the genes for the liver enzymes contribute to the responsiveness of EoE patients to PPIs is an area for research.
Synthetic glucocorticoids can be administered orally to suppress the entire immune response, or they can be administered to the esophagus. None of the currently used medicines are prepared in a formulation for targeted administration to the esophagus. Instead, these medicines (fluticasone or budesonide) are prescribed as preparations for treating asthma. One improvement to treating this condition would be to provide an EoE formulation for patients, rather than requiring them to prepare their own by either “swallowing” medicine from the inhaler sprayed into the mouth (fluticasone) or removing the medicine (budesonide) from asthma inhalers, mixing it with a thick liquid (such as honey, sucralose, or agave syrup), and swallowing the mixture. Clinical trials are underway to develop such properly formulated glucorticoids that can be swallowed and act on the esophagus.
Glucocorticoids do not cure the condition, but they do limit the inflammation associated with it and can permit the patient to eat foods that trigger the allergic response. Unfortunately, the swallowed glucocorticoids are associated with the development of thrush in the mouth and throat, resulting from overgrowth of the naturally occurring yeast that are present. When this occurs, treatment must stop to allow the immune system to fight the yeast overgrowth, which can let the inflammation from the eosinophil response recur or become worse, especially if the symptoms are not adequately controlled through dietary restriction.
Although the cells that define this condition clinically are eosinophils, other cells in the immune system contribute. In particular, a type of T cell called T helper type 2 (Th2) cells release signals that promote maturation of eosinophils in the bone marrow and also stimulate their release from the bone marrow and recruitment to the esophagus. Th2 cells are components of the adaptive immune system and are the cells that specifically respond to the molecules called antigens that trigger the allergy. Indeed, it may be abnormal activity of Th2 cells is the underlying problem in EoE. Consistent with this idea, increased amounts of Th2 cytokines (IL-4, IL-5, and IL-13) have been found in esophageal biopsies from EoE patients.
Several experimental strategies target the Th2 cytokines or the receptor for these cytokines (Table 1). The available data from clinical trials suggest that the antibodies targeting IL-5 reduce eosinophils in the esophagus but do not provide clinical improvement in symptoms or in the esophageal tissue. All of these drugs except for the antibody that targets IL-13 are approved for the treatment of eosinophilic asthma, and some are approved for other eosinophilic diseases. However, the apparent difference in the responsiveness of patients with eosinophilic diseases in different tissues suggests that the underlying biological basis for the diseases may be different.
Table 1. Antibody-Based Therapies Investigated for EoE. None are approved for EoE yet.
| Name | Brand | Target | Approved Uses |
|---|---|---|---|
| Reslizumab | Cinqair (Teva Pharmaceutical Industries Ltd) | IL-5 | Severe or eosinophilic asthma |
| Mepolizumab | Nucala (GSK) | IL-5 | Eosinophilic asthma, eosinophilic granulomatosis with polyangitis (Churg-Strauss syndrome) |
| Benralizumab | Fasenra (AstraZeneca) | IL-5 | Eosinophilic asthma |
| RCP4046 | n/a (Celgene) | IL-13 | None yet, experimental only, in clinical trials |
| Dupilumab | Dupixent (Sanofi Genzyme and Regeneron) | IL-4Ra (IL-4 and IL-13 receptor protein) | Allergic dermatitis, eosinophilic asthma, chronic rhinosinusitis with nasal polyposis |
Like typical allergies, EoE can involve antibodies of the IgE class, which cause immediate allergic symptoms in some patients. However, the chronic symptoms associated with EoE, such as the damage to the esophagus and the formation of scar tissue (fibrosis), result from chronic inflammation that is independent of IgE. Because of the complexity of the response to the allergic triggers, skin tests and blood tests for specific antibodies that react to food allergens do not typically identify the relevant triggers. Additionally, trials of therapies targeting IgE, such as the antibody drug omalizumab, have not been proven successful.
Additional therapeutic opportunities relate to esophageal-targeted interference with the signaling pathways of Th2 cells or eosinophils, such as those mediated by kinases of the JAK family. Eventually, studies may support the use of immune modulatory therapies currently used to treat other conditions. Thus, the path to clinical translation for those types of medicines may be relatively short.
Other options involve inhibiting the proteins that the epithelial cells produce that promote the damaging tissue remodeling or that help recruit the eosinophils into the esophagus. A preclinical study into how EoE changes the proteins produced by the epithelial cells was published in 2018. Studies, by a team of scientists and clinicians at the Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, found that the expression of the gene SPINK7, encoding a protease inhibitor, was barely detectable in the esophagus of patients with EoE. In contrast, this gene is highly expressed in normal healthy esophagus. Primarily from experiments with cells in culture and correlative analysis of patient tissues, the researchers concluded that the loss of SPINK7 led to impairment of epithelial barrier of the esophagus, activation of eosinophils in the esophagus, and stimulation of epithelial cells to release allergy-promoting cytokines. Of potential clinical relevance, application of the protease inhibitor A1AT to an esophageal epithelial cell line (EPC2) in which SPINK7 was deficient improved the ability of these cells to form a functional barrier. Thus, targeted administration of protease inhibitors to the esophagus, which would exert their effects without having to enter the cells, could be a therapeutic strategy.
For most types of therapy, the ideal strategy would be to deliver the treatment to the esophagus rather than having to administer the drugs systemically. Such targeted delivery would limit the possibility of systemic immune suppression or other adverse effects.
Additional areas of active research are the development of less invasive ways than endoscopy and biopsy to test for EoE or active disease and response to treatment. Some researchers are investigating possible connections between EoE and the esophageal and salivary microbiome, the community of microorganisms that are present in the esophagus and saliva, respectively. This research could lead to noninvasive “spit” tests to help monitor EoE patients.
Although it is not good news that the frequency of EoE and other GI eosinophilic diseases is increasing, it should spark research and encourage development of treatments for these conditions.
Related Resources
Eosinophilic Esophagitis. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/eosinophilic-esophagitis/symptoms-causes/syc-20372197 (accessed 13 September 2019)
Cincinnati Center for Eosinophilic Disorders. Cincinnati Children’s Hospital Medical Center. https://www.cincinnatichildrens.org/service/c/eosinophilic-disorders/about (accessed 13 September 2019)
Eosinophilic Gastrointestinal Disorders Q & A with Marc Rothenberg, MD, PhD. https://www.youtube.com/watch?v=aiVuzeyCTEw (viewed on 13 September 2019)
Eosinophilic Esophagitis (EOE). American Academy of Allergy Asthma & Immunology. https://www.aaaai.org/conditions-and-treatments/related-conditions/eosinophilic-esophagitis (accessed 13 September 2019)
Related Reading
Arias, et al., Toll-like receptors-mediated pathways activate inflammatory responses in the esophageal mucosa of adults eosinophilic esophagitis. Clin. Transl. Gastroenterol. 9, 147 (2018). DOI: 10.1038/s41424-018-0017-4 PubMed
Azouz, et al., The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses. Sci. Transl. Med. 10, eaap9736 (2018).
Carr, et al., Correction to: Eosinophilic esophagitis. Allergy Asthma Clin. Immunol. 15, 2 (2019). DOI: 10.1186/s13223-019-0336-3 PubMed
Dellon et al., Updated international consensus diagnostic criteria for eosinophilic esophagitis: Proceedings of the AGREE Conference. Gastroenterology 155, 1022-1033 (2018). DOI: 10.1053/j.gastro.2018.07.009 PubMed
Hirano, et al., RPC4046, a monoclonal antibody against IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis. Gastroenterology 146, 592-603 (2019). DOI: 10.1053/j.gastro.2018.10.051 PubMed
Hiremath, et al., The salivary microbiome is altered in children with eosinophilic esophagitis and correlated with disease activity. Clin. Transl. Gastroenterol. 10, e00039 (2019). DOI: 10.14309/ctg.0000000000000039 PubMed
Loizou, et al., A pilot study of omalizumab in eosinophilic esophagitis. PLoS ONE 10, e0113483. https://doi.org/10.1371/journal.pone.0113483 https://www.ncbi.nlm.nih.gov/pubmed/25789989
Molina-Infante, et al. from the PPI-REE Task Force of the European Society of Eosinophilic Oesophagitis (EUREOS), Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut 65, 524 – 531 (2016). DOI: 10.1136/gutjnl-2015-310991 PubMed
Clinical Trials
Continuation Study With Budesonide Oral Suspension (BOS) for Adolescent and Adult Subjects With Eosinophilic Esophagitis (EoE). https://clinicaltrials.gov/ct2/show/NCT03245840
Maintenance of Remission With Budesonide Orodispersible Tablets vs. Placebo in Eosinophilic Esophagitis (EOS-2). https://clinicaltrials.gov/ct2/show/NCT02493335
An Extension Study to Evaluate Maintenance of Efficacy and Long-term Treatment Effect of Oral Budesonide Suspension (OBS) in Adults and Adolescents With Eosinophilic Esophagitis (EoE) (ORBIT2). https://clinicaltrials.gov/ct2/show/NCT02736409
Efficacy, Safety, and Pharmacokinetics of APT-1011 in Subjects With Eosinophilic Esophagitis (EoE) (FLUTE). https://clinicaltrials.gov/ct2/show/NCT03191864
Eosinophilic Esophagitis Clinical Therapy Comparison Trial. https://clinicaltrials.gov/ct2/show/NCT01821898
Dose Ranging Study of RPC4046 in Eosinophilic Esophagitis. https://clinicaltrials.gov/ct2/show/NCT02098473
Study to Determine the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients With Eosinophilic Esophagitis (EoE). https://clinicaltrials.gov/ct2/show/NCT03633617
Also of Interest
N. R. Gough, Attack of the Eosinophil. BioSerendipity (3 September 2019). https://www.bioserendipity.com/attack-of-the-eosinophil
Cite as: N. R. Gough, Eosinophilic Esophagitis: When Food Is the Enemy. BioSerendipity (14 September 2019) https://www.bioserendipity.com/eosinophilic-esophagitis-when-food-is-the-enemy