Pathogenesis and Emerging Concepts in Eosinophilic Esophagitis

Educational Objectives

The goal of this program is to improve the management of eosinophilic esophagitis (EoE). After hearing and assimilating this program, the clinician will be better able to:

1. Compare esophageal compliance in patients with EoE with other populations.
2. Differentiate Index of Severity for Eosinophilic Esophagitis scores in patients with EoE who have low body mass index with other patients.
3. Explain pathogenesis of EoE.

Summary

Eosinophilic esophagitis (EoE): chronic EoE can lead to complications; a multidisciplinary team manages patients with EoE; endoscopy is indicated if clinical features of dysphagia or vomiting (usually diagnosed as reflux) persist in children beyond 12 mo of age; an important diagnostic criterion for EoE is the presence of eosinophils in the esophagus, exceeding 15 eosinophils/high-powered field; the symptoms must be consistent with esophageal dysfunction; Aceves et al (2018) used multicenter data to demonstrate that symptoms reported by parents correlate with those reported by children; this is particularly important for children who may not accurately self-report; in adults, the Straumann index (EosAI), a multicomponent index that includes symptoms and histology, along with a grading system and scoring, is used; Hiremath et al (2022) demonstrated the potential to predict the presence of lamina propria (LP) fibrosis by analyzing epithelial features; some biopsies may not contain sufficient LP to assess epithelial features, especially in cases of remission

Etiology: EoE is primarily driven by food allergens and less frequently by aeroallergens; this allergic reaction triggers inflammation and damages the esophageal barrier; immune cells, eg, T cells and mast cells, infiltrate the esophagus; esophageal remodeling results in fibrosis, smooth muscle hypertrophy, altered contractility, and angiogenesis

Natural history and complications: EoE is characterized by persistent eosinophilia and dysphagia; the longer the disease remains untreated, the higher the risk of developing strictures; Collins et al (2019) evaluated 146 children with EoE over a period of 5 to 11 yr; 15% of children showed minimal improvement despite various treatments; 45% experienced waxing and waning symptoms; 40% achieved sustained remission after initial treatment; evidence on adults with EoE from Straumann’s group showed similar findings, with 85% having a histologic response; complications occurred in patients who did not respond to therapy, eg, food impaction, strictures; women had more favorable outcomes than men; Bon et al (2022) showed that patients with gaps in their follow-up were at higher risk for esophageal strictures; consensus statements from Europe and the United States suggest that follow-up should include symptom, endoscopic, and histologic assessments; the importance of follow-up should be emphasized

Esophageal rigidity: study using an endoscopic functional lumen imaging probe (EndoFLIP), Moosavi et al [2023]) demonstrated that in patients with EoE or esophageal rings and furrows, esophagus was less readily stretched out (ie, had lower cross-sectional area) because of rigidity (ie, reduced esophageal compliance) compared with controls; Hassan et al (2019) showed lower esophageal compliance and cross-sectional area in children with EoE compared with controls; Muir et al (2022) found a correlation between esophageal diameter and disease severity in children with EoE; smaller esophageal diameters were associated with active EoE, histologic fibrosis, and a history of strictures; clinicians must consider longitudinal management of children with EoE; Hoffmann et al (2023) examined the relationship between esophageal distensibility and feeding behaviors using endoscopic functional lumen imaging probe; results of the study showed a strong correlation between the time taken to finish a meal and esophageal distensibility; children with less distensible esophagi took longer to complete their meals; the clinician should inquire about feeding behavior

Index of Severity for Eosinophilic Esophagitis (I-SEE) metric: a numerical scoring system designed to assess the severity of EoE; it is an application-based system that considers factors, eg, symptoms, complications, inflammatory features, histologic findings; a score >15 indicates severe EoE; this tool helps track disease progression and treatment response over time; the score evaluates histologic features of LP fibrosis and basal cell hyperplasia; available evidence suggests that basal cell hyperplasia predicts LP fibrosis; the score is easily accessible to clinicians; Dickerson et al (2024) demonstrated that the I-SEE score decreased from baseline to follow-up; patients with a low body mass index and feeding problems tended to have higher I-SEE scores at baseline and required more time to improve; patients must be monitored for signs of malnutrition

Immunologic pathogenesis: EoE is an immunologically complex disease; epithelial activation may be triggered by food antigens, aeroallergens, or acid, or may relate to a genetic primary barrier disruption disease; the activated epithelium releases eotaxin 3, a key chemokine that attracts eosinophils; eosinophils, mast cells, and T cells (CD4+ and CD8+) are drawn to the site of inflammation; these cells release cytokines, eg, interleukin (IL)-5, IL-13, and transforming growth factor β (TGF-β); the combined effect of these cytokines leads to tissue fibrosis and initiates a positive feedback loop for epithelial barrier disruptions; dysregulation of cytokines IL-13 and TGF-β downregulates important proteins like E-cadherin and desmoglein (DSG), disrupts the epithelial barrier, and stimulates excessive fibrosis, vascular activation, and smooth muscle hypertrophy; the clinician aims to break these feedback loops

Evidence: Ben-Baruch Morgenstern et al (2024) utilized single-cell sequencing to examine various cell types, including eosinophils, mast cells, monocytes, macrophages, dendritic cells (DCs), and plasma cells (PCs); the study highlighted the involvement of multiple immune cell types beyond eosinophils, eg, lymphocytes, type 2 inflammatory cells, T regulatory cells, T helper 17 cells, and various T-cell subsets; article in Journal of Allergy and Clinical Immunology (Jacobse et al [2024]) analyzed publicly available bulk RNA sequencing data to compare gene expression patterns of men vs women and adults vs children; the results of the study indicate that children with EoE have a mast cell-dominant phenotype, while adults have macrophage-dominant phenotype; thus, underlying disease mechanisms may change over time, and treatment strategies should be tailored to the specific stage of the disease and the dominant immune cell type involved; gene expression profiles of the epithelium in children with endoscopically defined fibrotic eosinophilic EoE revealed differences in the expression of genes related to collagen and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) proteins between fibrotic and nonfibrotic patients; the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) network study by Shoda et al (2018) used transcriptomic data to identify different endotypes of EoE, ie, atopic steroid-refractory and fibrotic; using single-cell sequencing, Ding et al (2024) revealed complex intracellular networks involving multiple cell types, including fibroblasts; evidence suggests TGF-β signaling and changes in pluripotent cells in EoE, corroborating previous laboratory findings

Role of lymphocytes: cluster of differentiation 4 (CD4+) T cells play a crucial role in driving EoE by producing cytokines, eg, IL-5, IL-13, IL-17; the T cells interact with G protein-coupled receptor 15 ligand and produce tumor necrosis factor superfamily member 14 (TNFSF14 or LIGHT), which belongs to the tumor necrosis factor α superfamily; LIGHT can drive fibroblasts to become proinflammatory and produce molecules such as IL-33, intercellular adhesion molecule (ICAM), and complement 3, leading to fibroblast tethering; Manresa et al (2020) showed that fibroblasts in EoE tether to each other through a process involving ICAM-1 and LIGHT receptors; this tethering is observed in vitro and in vivo; Schuyler et al (2018) demonstrated that local deposition of immunoglobulin G4 (suggesting the involvement of B cells) may play a role in activating mast cells

Role of structural cells: in EoE, the epithelial cells are dysfunctional and remain in a “transitional” state, unable to differentiate properly; this impaired barrier function, particularly in individuals with SPINK 7 defects, may lead to the recruitment of eosinophils through urokinase-type plasminogen activator receptors (uPAR); Laky et al (2023) created a mouse model with a TGF-β receptor mutation and found that the mice spontaneously developed EoE-like symptoms, including esophageal inflammation, basophil hyperplasia, and increased numbers of T cells, group 2 innate lymphoid cells (ILC2), mast cells, and eosinophils

Fibroblasts: evidence suggests that the extracellular matrix (ECM) from patients with EoE may induce normal fibroblasts to behave like diseased fibroblasts, producing more collagen and smooth muscle actin; the ECM drives the creation of profibrotic myofibroblasts; further investigation revealed that a protein called thrombospondin 1 (TSP 1) is increased in biopsies from patients with EoE; TSP 1 may induce collagen production in fibroblasts; evidence suggests that a stiff esophageal environment can cause changes in smooth muscle cells, making them larger and less functional; this mechanism involves a protein called phospholamban (PLN), which stabilizes the actin cytoskeleton and traps a protein called YES-associated protein-1 (YAP) in the nucleus, a known mechanotransduction 5 molecule; YAP then activates genes that promote cell growth and differentiation

Readings

Aceves SS, King E, Collins MH, et al. Alignment of parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple CEGIR sites. J Allergy Clin Immunol. 2018;142(1):130-138.e1. doi:10.1016/j.jaci.2018.05.014; Ben-Baruch Morgenstern N, Rochman M, Kotliar M, et al. Single-cell RNA-sequencing of human eosinophils in allergic inflammation in the esophagus. J Allergy Clin Immunol. 2024;154(4):974-987. doi:10.1016/j.jaci.2024.05.029; Bon L, Safroneeva E, Bussmann C, et al. Close follow-up is associated with fewer stricture formation and results in earlier detection of histological relapse in the long-term management of eosinophilic esophagitis. United European Gastroenterol J. 2022;10(3):308-318. doi:10.1002/ueg2.12216; Collins CA, Palmquist J, Proudfoot JA, et al. Evaluation of long-term course in children with eosinophilic esophagitis reveals distinct histologic patterns and clinical characteristics. J Allergy Clin Immunol. 2019;144(4):1050-1057. doi:10.1016/j.jaci.2019.06.015; Dickerson A, Kolemen A, Kime K, et al. The Index of Severity for Eosinophilic Esophagitis (I-SEE) reflects longitudinal clinicopathologic changes in children. Clin Gastroenterol Hepatol. 2024;22(4):732-740. doi:10.1016/j.cgh.2023.09.015; Ding J, Garber JJ, Uchida A, et al. An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission. Nat Commun. 2024;15(1):3344. doi:10.1038/s41467-024-47647-0; Hassan M, Aceves S, Dohil R, et al. Esophageal compliance quantifies epithelial remodeling in pediatric patients with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2019;68(4):559-565. doi:10.1097/MPG.0000000000002202; Hiremath G, Sun L, Correa H, et al. Development and validation of web-based tool to predict lamina propria fibrosis in eosinophilic esophagitis. Am J Gastroenterol. 2022;117(2):272-279. doi:10.14309/ajg.0000000000001587; Hoffmann NV, Keeley K, Wechsler JB. Esophageal distensibility defines fibrostenotic severity in pediatric eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2023;21(5):1188-1197. doi:10.1016/j.cgh.2022.08.044; Jacobse J, Brown R, Revetta F, et al. A synthesis and subgroup analysis of the eosinophilic esophagitis tissue transcriptome. J Allergy Clin Immunol. 2024;153(3):759-771. doi:10.1016/j.jaci.2023.10.002; Laky K, Kinard JL, Li JM, et al. Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis. Sci Immunol. 2023;8(79):eabp9940. doi:10.1126/sciimmunol.abp9940; Manresa MC, Chiang AWT, Kurten RC, et al. Increased production of LIGHT by T cells in eosinophilic esophagitis promotes differentiation of esophageal fibroblasts toward an inflammatory phenotype. Gastroenterology. 2020;159(5):1778-1792. doi:10.1053/j.gastro.2020.07.035; Moosavi S, Shehata C, Kou W, et al. Measuring esophageal compliance using functional lumen imaging probe to assess remodeling in eosinophilic esophagitis. Neurogastroenterol Motil. 2023;35(4):e14525. doi:10.1111/nmo.14525; Muir AB, Ackerman SJ, Pan Z, et al. Esophageal remodeling in eosinophilic esophagitis: Relationships to luminal captured biomarkers of inflammation and periostin. J Allergy Clin Immunol. 2022;150(3):649-656. doi:10.1016/j.jaci.2022.03.022; Schuyler AJ, Wilson JM, Tripathi A, et al. Specific IgG₄ antibodies to cow’s milk proteins in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2018;142(1):139-148. doi:10.1016/j.jaci.2018.02.049; Shoda T, Wen T, Aceves SS, et al. Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study. Lancet Gastroenterol Hepatol. 2018;3(7):477-488. doi:10.1016/S2468-1253(18)30096-7; Straumann A. Clinical evaluation of the adult who has eosinophilic esophagitis. Immunol Allergy Clin North Am. 2009;29(1):11-vii. doi:10.1016/j.iac.2008.09.007.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Aceves is a consultant for Ferring, Inc. and Regeneron-Sanofi; has a financial relationship with Takeda Pharmaceutical Company Ltd.; receives grant/research support from Bristol Myers Squibb; and is on the Speaker's Bureau for Ferring, Inc. and Regeneron-Sanofi. Members of the planning committe reported nothing to relevant disclose.

Acknowledgements

Dr. Aceves was recorded at the Eosinophilic Esophagitis and Eosinophilic Gastrointestinal Disease Conference, held on August 24, 2024, in San Diego, CA, and presented by Scripps Health. For information on upcoming CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and Scripps Health for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

GE390201

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

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Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.