Emerging therapies for eosinophilic esophagitis

Abstract

Despite advances in the pathologic understanding of eosinophilic esophagitis (EoE), as of yet, no single agent has been approved by the US Food and Drug Administration to treat EoE. Off-label, EoE is currently treated by using the 3 Ds: drugs (particularly swallowed topical corticosteroids), dietary restriction, and endoscopic dilation. In the recent past, considerable progress in terms of EoE treatment has been made: (1) new EoE-specific steroid formulations optimizing mucosal deposition have been developed, which has culminated in recent approval of a budesonide effervescent tablet in Europe; (2) biologics used for other T_H2-mediated diseases, such as allergic asthma and atopic eczema, as well as purpose-developed biologics, have been studied in phase II trials in patients with EoE; and (3) novel dietary restriction strategies have evolved. Finally, further insights into the pathogenesis of EoE have revealed several novel disease mediators that might be targeted in the future. In the following article we will discuss recent advances in EoE treatment with regard to swallowed topical steroids, biological agents, dietary approaches, and novel molecular targets.

Keywords: Eosinophilic esophagitis; biologics; diet; steroids; treatment.

FIGURE 1:

Development pipeline of EoE-specific programs over the last two decades with progression from phase I/II to phase III stage. EG, eosinophilic gastritis.

FIGURE 2:

Potential therapeutic targets in EoE. In a simplified model, esophageal epithelial cell-released TSLP and IL-33 can trigger Th2 response through involvement of basophils and IL-4. Th2 cells secrete IL-5 which – together with calcium channel-mediated eotaxin release from epithelial cells – results in eosinophil recruitment. Integrin α4β7 is expressed on lymphocytes and eosinophils. By binding to its vascular counterpart MAdCAM1, it mediates cell trafficking to the esophageal mucosa. Secretion of IL-9 (from eosinophils and Th9 cells) further drives epithelial barrier disruption (together with IL-13 from Th2 cells) and mast cell recruitment. Release of TGFβ (secreted by eosinophils and mast cells) perpetuates eosinophilic infiltration and drives tissue remodeling through activation of fibroblasts. Siglec-8 is selectively expressed on eosinophils and mast cells with a key role in apoptosis.