The following is a summary of currently accepted therapies in eosinophilic esophagitis, which as noted above has been the best studied of these diseases. These treatments have been reviewed in the process of developing two consensus statements on the diagnosis and management of EoE. In the case of EG and EC, the relative rarity of these diseases has prevented the development of treatment guidelines at this time. One of the driving forces for the creation of CEGIR is to increase the number of patients studied to allow for the development of evidence-based treatment protocols.

Treatment Options-Eosinophilic Esophagitis
EoE is a chronic esophageal inflammatory disease that is resistant to acid suppressive therapy and associated with a variety of upper GI dysfunctional symptoms. Dietary antigen exposure appears to be an important driving factor for disease pathogenesis as the disease is reversible following the appropriate elimination of triggering food groups. The high response rate to food elimination diets, especially amino acid–based elemental diets, and the frequent recurrence of disease with food reintroduction imply that the disease is mediated by allergic sensitization to foods. Indeed, experimental EoE in mice can be induced by exposure to oral antigens, aeroallergens, or both through a variety of entry points, including the skin and the respiratory and GI tracts. Consistent with an allergic etiology rather than an acid-induced esophagitis, SGCs have also been shown to be effective for the treatment of EoE but not GERD. However, there are no FDA-approved drugs for the specific treatment of EoE, and there are substantial questions remaining about the best therapies, their most appropriate usage (e.g. duration of treatment), phenotypic characteristics and/or biomarkers that predict responsiveness to therapy, and how to select which foods to remove from the diet (e.g. utility of skin testing). One school of thought focuses on the value of skin testing, in the form of skin prick tests (SPTs; measuring IgE-mediated responses) and atopy patch tests (APTs; measuring T cell–dependent delayed type hypersensitivity responses); whereas, another line of thinking focuses on empirically avoiding the top six most common food allergens in the USA, those being milk, egg,

wheat, soy, peanut/tree nuts, and fish/shellfish. Both the skin testing and six-food elimination diet (6FED) approaches have shown response rates of ~70%, with the empiric elimination diet approach being attractive due to the fact that no allergy testing is required, yet more foods may have to be removed than is necessary to achieve disease remission. Removal of these six major food groups is very challenging, difficult to tolerate (i.e. substandard compliance), and associated with substantial impairment in QOL, highlighting the need to develop better therapy, including a less restrictive diet. In all of the currently prescribed dietary therapies, the goal is to reintroduce foods systematically and identify specific causative food antigens via subsequent endoscopy, necessitating repeated esophagogastroduodenoscopies (EGDs), which are typically recommended after the addition of 1-3 new foods. As an alternative to dietary elimination therapy, SGCs in formulations originally designed for inhalation in asthmatics have been shown to be efficacious in 50-85% of patients with EoE. Due to the unknown risks of chronic SGCs, patients and/or their families frequently choose to initially implement dietary therapy, especially because this may be closer to treating the underlying driving factors. While all of these treatments can be effective, they require continuous use or disease reoccurs; they are also limited by the presence of substantial fractions of patients who remain refractory to these two treatments.

Evidence for Treatment Options
Consensus recommendations indicate that EoE is typically distinguished from GERD by the failure to respond to PPI therapy and the higher level of esophageal eosinophilia (≥15 peak eosinophils/HPF). The high response rate to food elimination diets, especially amino acid–based elemental diets, and the frequent recurrence of disease with food reintroduction imply that EoE is mediated by immune sensitization to foods. Indeed, experimental EGIDs including EoE in mice can be induced by exposure to dietary or inhaled allergens or to IL-13 via a variety of entry points including the skin, respiratory, and GI tracts. Consistent with an allergic etiology rather than an acid-induced esophagitis, SGCs are effective for the treatment of EoE and elicit local changes in esophageal gene expression, but there are substantial rates of glucocorticoid resistance and/or relapse while on therapy, necessitating a better understanding of drug resistance, relapse, and chronicity. It is critically important to develop therapy for EoE as it is now appreciated that the length of time that EoE goes untreated is associated with risk of stricture formation, as recently reported by the CEGIR Investigator Dr. Straumann. Clinical practice for the evaluation of allergies in patients with EoE mainly relies on SPTs. However, the specificity of SPTs is approximately 50%, making positive results especially difficult to interpret. As EoE is thought to be primarily non–IgE mediated, skin testing based on delayed hypersensitivity to foods, namely APTs, has been advocated. Unfortunately, the interpretation of APT results is subjective, prone to significant inter-observer variation, and hindered by the lack of standardized extracts; furthermore, APTs have not been validated in an EoE population with the use of a control group. Additionally, APT methods vary considerably between institutions and may not be widely applicable. Only one group has found that APT is predictive of EoE diet outcomes; as this group is part of CEGIR, we aim to reconcile these apparently discrepant results by standardizing the skin testing across centers. Thus, SPTs, serum IgE tests, and APTs may be adjunctive in identifying causative foods in EoE. However, food triggers can only currently be identified by confirming disease remission after a specific food elimination followed by EoE relapse on reintroduction of that food.

An alternative approach to food elimination has been recommended on the basis of empiric avoidance of the six most common allergenic foods in the US (milk, egg, soy, wheat peanuts/tree nuts, and fish/shellfish). Using a response cutoff of 10 or fewer esophageal eosinophils/HPF, Kagalwalla and his colleagues at NW initially reported a histologic response of 74% for this empiric 6FED. Complete elimination of eosinophilic inflammation (<1 eosinophil/HPF) was reported in 29% (10/35) of patients in the 6FED group and in 56% (14/25) of patients in the elemental diet group. These findings are consistent with the original report by Kelly et al. that 80% of patients with EoE have complete histologic resolution and 100% have at least partial resolution after an elemental diet. Several studies, including those conducted by CEGIR Investigators, published in the past year on both adult and pediatric EoE have compared skin test–directed elimination diets to the 6FED in terms of effectiveness and/or ability to identify causative foods. Hirano, Gonsalves, and colleagues conducted a prospective, non-randomized, uncontrolled study of 50 adult patients (>18 years old) with EoE that assessed the effects of the 6FED and subsequent food reintroduction on histologic response, symptoms, and QOL. Rothenberg, Henderson, Abonia, King, Collins, and colleagues conducted a retrospective study of pediatric patients (≤ 21 years old) with EoE that compared the remission rates among three dietary therapies: elemental diet, 6FED, and a skin test–directed elimination diet. Spergel, Liacouras, and colleagues conducted a retrospective analysis of pediatric patients with EoE to determine the effectiveness of allergy testing– directed diets in patients with EoE.

Collectively, these studies demonstrated that milk, egg, and wheat were responsible for triggering EoE in ~80% of patients, that 6FED had comparable efficacy (~70%) compared with skin test–directed diets and that skin tests have low predictive value for identifying the causative foods, although Spergelet al. found that the combined negative predictive value for foods (except milk) by skin tests (SPTs, APTs) was reasonable (92%). Finally, Lucendo et al. recently reported a ~70% response rate to the 6FED and that the patient population was roughly divided in thirds by whether 1, 2, or 3 foods were causative for EoE. Indeed, the top three causative foods were cow's milk (62%), wheat (29%), and egg (26%); unfortunately, prior skin tests showed no concordance with food reintroduction results. Interestingly, Kagalwalla et al. recently found that 65% of patients with EoE had partial histological remission (≤14 and ≤6 peak eosinophils/HPF) after avoidance of milk alone; however, this study was limited by a retrospective design and only included 17 patients. As an alternative to dietary therapy, the most effective medicine for the treatment of EoE is SGCs. Faubion etal. showed that swallowed fluticasone propionate (FP) was effective and safe for treating EoE in four pediatric patients. In a collaborative study between multiple CEGIR Investigators, Konikoff et al. demonstrated a 50% rate of histological normalization in patients with EoE after a three-month treatment course of 880 mcg of daily swallowed FP compared to 9% in the placebo group. Konikoff et al. and Noel et al. showed that patients documented to be “allergic” were less likely to respond to FP and that subject responsiveness to FP positively correlated with younger patient age, smaller height, and lower weight when compared to nonresponders. CEGIR Investigator Dr. Gupta and colleagues examined the effects of prednisone vs. swallowed FP in one of the largest EoE treatment studies (n = 80 children). Using a histology grading scale, they found that swallowed high-dose FP (up to 1760 mcg/day total dose) resulted in inflammatory and epithelial change improvement in 34 of 36 children treated with swallowed FP. More recently, Rothenberg, Spergel, Furuta, and Gleich received an NIH NIAID U01 grant to examine the effect of high-dose FP (1760 mcg per day) for the treatment of EoE. The investigators found that high-dose FP was highly effective, with a complete response rate of 65% in the treatment group and 0% in the placebo group, and they presented evidence for SGC resistance in a substantial subset of patients based on histological and molecular analysis of dysregulated esophageal transcripts, part of the EoE transcriptome previously described by Rothenberg and colleagues. Besides FP, CEGIR Investigator Dr. Aceves and colleagues have shown that budesonide improves dysphagia and significantly reduces esophageal eosinophils vs. placebo with complete remission rates of 35-72% and 0-11%. following drug vs. placebo, respectively. Notably, Aceves et al. have reported that polymorphisms in the TGFB gene have been preliminarily linked with steroid resistance; we will pursue related findings in a pilot study examining the TGF-β–lowering drug losartan. Further, CEGIR Investigator Dr. Dellon and colleagues conducted a randomized trial comparing administration of budesonide as either nebulized or swallowed compared to an oral viscous slurry and demonstrated that symptoms improved in all groups but that the esophageal eosinophil improvement was greater in the oral viscous slurry group, supporting the view that a topical mechanism was operational. Indeed, Rothenberg, Aceves, and colleagues showed that SGCs induce de novo gene expression in the esophagus, suggesting a local effect, particularly on the epithelium.

Collectively, these studies, conducted in large part by CEGIR Investigators, have provided the foundation for the SOFEED Trial (Clinical Trial 2) of the CEGIR grant.