Jacob Gunter

Background: Eosinophilic Esophagitis (EoE) is a chronic, immune-mediated disease caused by an increased accumulation of eosinophils infiltrating the esophageal mucosa resulting in upper gastrointestinal symptoms.¹ The disease exhibits a prominent 3:1 male-to-female predominance, with a rising annual incidence reaching 40.1 cases per 100,000 individuals.⁵ If left untreated, chronic tissue inflammation drives tissue remodeling, subepithelial fibrosis, and esophageal stenosis, rendering the esophagus narrowed, stiff, and dysfunctional.⁵ Current standard interventions present distinct compliance barriers.² Elimination diets achieve clinical remission but are socially restrictive and difficult to sustain.² Proton pump inhibitors demonstrate variable efficacy with reduced clearance in patients with high eosinophilic burden.² Biologics are highly effective but are costly and require long-term intramuscular injections.^{2, 3, 4} Swallowed topical corticosteroids (STCs) offer a vital alternative for both untreated and treatment-resistant EOE patients by providing local anti-inflammatory effects with limited systemic exposure.²

Objective: In this narrative review, we explored the cellular mechanisms and clinical efficacy of STCs, in comparison to alternative therapies, in reducing remission in EOE.

Search Methods: Online searches in the PubMed and MDPI databases were conducted from 2021 to 2026 using the following keywords: “eosinophilic esophagitis”, “glucocorticoids”, “swallowed topical corticosteroids”, “steroid”, “interleukin”.

Results: Pathophysiologically, interleukin-13 (IL-13) acts on the esophageal epithelial cells to trigger the hypersecretion of Eotaxin-3, which acts as a chemical chemoattractant that pulls eosinophils out of the bloodstream and into the esophageal wall.⁶ Simultaneously, IL-13 weakens tight junction proteins making the esophagus leaky, allowing more dietary allergens to penetrate the tissue, which in turn stimulates more Th2 cells to produce more IL-13.⁶ Chronic IL-13 signaling also activates fibroblasts to become myofibroblasts, producing the excessive, stiff collagen that physically narrows the esophagus into strictures.⁹ Transforming growth factor-beta 1 (TGF-B1) and chemokine ligand 18 (CCL-18) serve as the primary inflammatory mediators directly linked to fibrosis.⁹   STCs successfully normalize approximately 98% of the abnormal gene activity in the esophagus; the delivery method is key as orally dispersible tablets maximize mucosal contact time compared to swallowed inhalers.² However, 15% of patients exhibit glucocorticoid resistance driven by an intracellular IL-5 shield.⁸ High levels of IL-5 protect eosinophils from steroid-induced apoptotic signaling, requiring targeted biologics like mepolizumab to neutralize.⁸ To optimize safety, a new generation of selective glucocorticoid receptor modulators (SGRMs) target a specific side pocket or solvent channel on the receptor, inducing allosteric tuning.⁷ This preserves the transrepression of pro-inflammatory cytokines (IL-4 and IL-13) with the same potency as traditional steroids without damaging the T cells necessary for a healthy immune response.⁷ While steroids are excellent at lowering cell counts, targeted biologics are superior at repairing the physical epithelial barrier and correcting the underlying genetic fingerprint of the disease.¹⁰ Thus, targeting the early alarm signals rather than the later inflammation is more effective for long-term esophageal health.¹⁰

Conclusion: IL-13 is the primary trigger for EoE inflammation, whereas IL-5 mediates cellular steroid resistance. STCs remain vital, normalizing nearly the entire disease transcriptome and slowing esophageal remodeling. Future treatments (SGRMs and targeted biologics) aim to fix the genetic blueprint while minimizing side effects like immune suppression.

Works Cited:

1. O’Shea KM, Aceves SS, Dellon ES, et al. Pathophysiology of eosinophilic esophagitis. Gastroenterology. 2018;154(2):333-345. doi:10.1053/j.gastro.2017.06.065
2. Barchi A, Girelli M, Ventimiglia A, et al. Orally dispersible swallowed topical corticosteroids in eosinophilic esophagitis: a paradigm shift in the management of esophageal inflammation. Pharmaceutics. 2025;17(10):1325. doi:10.3390/pharmaceutics17101325
3. Alkhowaiter S. Eosinophilic esophagitis: an update. J Clin Med. 2023;12(14):4759. doi:10.3390/jcm12144759
4. Rothenberg ME, Dellon ES, Katzka DA, et al. Efficacy and safety of dupilumab in children 1 to 11 years of age with eosinophilic esophagitis: results from a phase 3 randomized trial. Gastroenterology. 2024;167(4):713-726. doi:10.1053/j.gastro.2024.05.005
5. Muir AB, Mukkada V, Spergel JM, Dellon ES. Elements of eosinophilic esophagitis: the etiology, epidemiology, and pathogenesis. Dig Dis Sci. 2020;65(3):828-844. doi:10.1007/s10620-020-06105-z
6. Blanchard C, Stucke EM, Rodriguez-Jimenez B, et al. A unique gene expression signature that identifies a dominant role for IL-13 in eosinophilic esophagitis. J Clin Invest. 2010;120(5):1612-1623. doi:10.1172/JCI40653
7. Kobylski RR, Min CK, Nwachukwu JC, et al. Selective glucocorticoid receptor modulators of immune checkpoint function. bioRxiv. Published online February 4, 2026. doi:10.64898/2026.02.02.703046.
8. Stokes K, Akuthota P, Wang HB, et al. Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes. Clin Exp Allergy. 2019;49(12):1598-1604. doi:10.1111/cea.13509
9. Massironi S, Mulinacci G, Gallo C, et al. Mechanistic insights into eosinophilic esophagitis: therapies targeting pathophysiological mechanisms. Cells. 2023;12(20):2473. doi:10.3390/cells12202473.
10. Pasta A, Bertin L, Mari A, et al. The therapeutic pipeline for eosinophilic esophagitis: current outlook and future directions. Pharmaceutics. 2024;18(12):1882. doi:10.3390/ph18121882.