Exploring the Link Between Atopic Dermatitis and Eosinophilic Esophagitis

J Clin Aesthet Dermatol. 2025;18(3):15–20.

by Joanna Jaros, MD; Kripa Ahuja, MS; and Peter Lio, MD

Dr. Jaros is with the Department of Dermatology at Cook County Hospital and Health System in Chicago, Illinois. Ms. Ahuja is with Eastern Virginia Medical School in Norfolk, Virginia. Dr. Lio is with the Department of Dermatology at Northwestern University in Chicago, Illinois.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Lio reports being on the speaker’s bureau for AbbVie, Arcutis, Eli Lilly, Galderma, Hyphens Pharma, Incyte, La Roche-Posay/L’Oreal, Pfizer, Pierre-Fabre Dermatologie, Regeneron/Sanofi Genzyme, Verrica; reports consulting/advisory boards for Alphyn Biologics (stock options), AbbVie, Almirall, Amyris, Arcutis, ASLAN, Bristol-Myers Squibb, Burt’s Bees, Castle Biosciences, Codex Labs (stock options), Concerto Biosci (stock options), Dermavant, Eli Lilly, Galderma, Janssen, LEO Pharma, Lipidor, L’Oreal, Merck, Micreos, MyOR Diagnostics, Regeneron/Sanofi Genzyme, Sibel Health, Skinfix, Suneco Technologies (stock options), Theraplex, UCB, Unilever, Verdant Scientific (stock options), Verrica, Yobee Care (stock options). Dr. Lio also has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member emeritus of the National Eczema Association.

ABSTRACT: Eosinophilic esophagitis (EoE) and atopic dermatitis (AD) are two known and sometimes comorbid type 2 helper cell-mediated diseases. EoE shares clinical features, immunologic pathways, susceptibility loci, and risk with atopic conditions including food allergies (food allergies), asthma, allergic rhinitis (AR), and AD. These conditions share an impaired immunological response against a range of antigens or allergens, leading to CD4+ Th2 differentiation and overproduction of immunoglobulin E (IgE). The emerging coexistence of EoE and AD presents a compelling area of study. Both diseases manifest on stratified squamous epithelium along the skin-gut continuum and have overlapping treatment algorithms that include avoidance of triggers, topical steroids, and dupilumab. This narrative review highlights the clinical and immunologic nuances underlying these two conditions and sheds light on potential new research and therapeutic avenues.

Keywords: Eosinophilic esophagitis, atopic dermatitis, dermatitis, eczema, atopic eczema, atopy

Introduction

Eosinophilic esophagitis (EoE) and atopic dermatitis (AD) are two known and sometimes comorbid type 2 helper cell-mediated diseases. EoE shares clinical features, immunologic pathways, susceptibility loci, and risk with atopic conditions including food allergies (FA), asthma, allergic rhinitis (AR), and AD. These conditions share an impaired immunological response against a range of antigens or allergens, leading to CD4+ Th2 differentiation and overproduction of immunoglobulin E (IgE). The emerging coexistence of EoE and AD presents a compelling area of study. Both diseases manifest on stratified squamous epithelium along the skin-gut continuum and have overlapping treatment algorithms that include avoidance of triggers, topical steroids, and dupilumab.¹ This narrative review highlights the clinical and immunologic nuances underlying these two conditions and sheds light on potential new research and therapeutic avenues. 

Background

EoE is a newly described disease. Reports of eosinophils infiltrating the esophageal mucosa on endoscopy were first reported in the early 1970s, and case reports and series coining the term “eosinophilic esophagitis” appeared in the 1990s.² EoE was likely published at this time due to advances in diagnostic technologies (ie, modern endoscopies) that have permitted its identification and classification rather than emergence of a new entity.

EoE is postulated to be a chronic, antigen-mediated, allergic disease that presents in the esophagus with dysphagia and food impactions. Common risk factors include higher income, country of origin, family history, male sex, Cesarean delivery, and others.³ Studies on its prevalence in urban versus suburban locations are mixed.³ Based on limited population studies, EoE may be more prevalent in North America and Europe, with lesser prevalence in Australia and Asia.⁴ Less than one percent of the population is currently known to be affected, but both incidence and prevalence are increasing globally.³

Peak incidence of EoE occurs after the onset of AD, FA and asthma, and concurrently with AR. Presence of AD, FA, and/or asthma was shown to increase risk of development of EoE in the future, while development of EoE increased risk of subsequent AR.⁵ Given this shared pathogenesis and co-existence, EoE has been suggested to be a “fifth member of the march” in some papers.⁵ While this may be true for some phenotypes of EoE, appearance of EoE is not always conditional on prior atopic disease.⁶ 

The diagnosis of EoE requires both clinical symptoms of esophageal dysfunction, such as dysphagia or food impaction, and histologic findings (15 or more eosinophils/high-powered microscope field).⁷ EoE is a histological diagnosis, and the rise and ease of endoscopy may have aided in bringing this clinical entity into the light.⁷ Additional endoscopic features include rings, strictures, furrows, edema, exudates-features commonly reported using the Eosinophilic Esophagitis Endoscopic Reference Score.⁷ 

Current treatments include elimination diet, esophageal dilations for strictures, swallowed topical corticosteroids, dupilumab, and proton pump inhibitors. The most common elimination diet excludes dairy and is often referred to as the “1-food elimination diet” (1-FED) in the literature.⁸ Patients that fail 1-FED can consider trialing 6-FED (ie, elimination of milk, wheat, eggs, fish/shellfish, nuts and soy). Improvements in clinical symptomatology, resolution of esophageal eosinophilia and endoscopic abnormalities, improved quality of life, and return to baseline esophageal function are considered standard treatment metrics.^4,9,10 

A striking number of EoE patients—an estimated 50 to 75 percent—have comorbid atopic dermatitis.¹¹ Concomitant AD was not found to confer a higher degree of severity of EoE.¹² A recent systematic review and meta-analysis found that AD was associated with significantly higher prevalence of EoE in 2 of 11 studies, numerically higher EoE prevalence in another 7 of 11 studies, and significantly higher odds of EoE (O:E 2.85, 95% CI:1.87-4.34) compared with controls.^13,14 One small study published found that up to 21 percent of pediatric patients with AD had comorbid EoE.¹² Preliminary data suggests that many patients with EoE have AD, and a smaller amount of AD patients develop EoE.

While EoE is relatively new to our literature, AD is an ancient affliction that can be traced back to at least 400 BC.¹⁵ AD is thought to be a chronic, relapsing, inflammatory disease with known disruptions in barrier genes and proteins, cutaneous microbiome, neurocutaneous control of pruritus, and Th2-driven inflammation. Unlike EoE, AD may have more systemic components.¹⁶ The global prevalence of AD is about 20 percent in children and approximately five percent in adults, and like EoE, it is increasing.¹⁷ AD does not appear to have a distinct geographical distribution.¹⁸ Risk factors for AD include family history, female gender, and others.¹⁷ Common comorbid conditions include asthma, allergic rhinitis, and food allergies. 

AD is a clinical diagnosis, and diagnostic criteria from the American Academy of Dermatology (AAD) include essential features that must be present for diagnosis including a chronic or relapsing history of eczema, pruritus, and typical morphology and age-specific patterns; important features that support the diagnosis including a personal or family history of atopy, early age at onset, IgE activity, and xerosis.¹⁹

Topical therapies include prescription topical corticosteroids (TCS), calcineurin inhibitors (TCIs), Janus kinase (JAK) inhibitors, phosphodiesterase-4 inhibitors (PDE-4), antimicrobials, and antihistamines.²⁰ Current biologic therapeutics include monoclonal antibodies dupilumab and tralokinumab and Janus kinase inhibitors such as abrocitinib and upadacitinib, with multiple new therapies under study.²¹

Disease Endotypes

A disease endotype is defined as the molecular mechanisms underlying the visible features/phenotype.²² The characterization of three distinct EoE endotypes has been an essential tool in helping understand the EoE pathogenesis.²³ The endotypes are classified using histologic, endoscopic, and molecular disease features (Table 1).²³

EoE endotype 1 (EoEe1) is associated with a normal-appearing esophagus, relatively mild histologic and molecular changes, and steroid responsiveness.²³ EoE endotype 2 (EoEe2) is associated with pediatric-onset, the highest degree of endoscopic and histologic severity for inflammation, the highest expression of inflammatory cytokines, and steroid-resistant disease.²³ EoE endotype 3 (EoEe3) is associated with adult-onset, the highest degree of endoscopic and histologic severity for fibrostenotic components, and the lowest expression of epithelial differentiation genes.²³ Interestingly, absolute tissue eosinophil levels did not serve to differentiate any of the endotypes, indicating that the underlying distinctions in pathophysiology go beyond eosinophil-centered immunopathogenesis.^23–25 Studies describing specific localization of each endotype to a particular region of the esophagus are lacking. 

The global prevalence of each endotype is unknown; however, in a single study, EoEe1 represented 35 percent of subjects, EoEe2 represented 29 percent of subjects, and EoEe3 represented 36 percent of subjects.²⁴ Children who have EoE have a greater history of asthma and a greater proportion of a positive reaction to foods on patch testing.²⁶ There was no statistically significant difference between adults and children on history of allergic rhinitis, AD, IgE-mediated food allergy, and family history of atopy.²⁶ 

Attempts to classify AD endotypes have been suggested and have been largely unsuccessful to date.²⁷ One method attempted to differentiate AD into IgE-high, extrinsic subtype and the IgE-normal, intrinsic subtype.²⁸ More recent attempts have tried to classify AD based on racial and ethnic profiles and serum markers. These endotypes remain speculative, and none are in common clinical use, despite high perceived clinical need.²⁹ Further study is needed to better understand disease endotypes in AD. 

Pathogenesis

The pathogenesis of both EoE and AD is incompletely understood. What is known is that they involve genetic, host immune, and environmental constituents. The skin–gut axis may also be involved. 

Skin–gut axis. Any alteration in the gut microbiome can lead to increased host vulnerability and disrupt mucosal immunological tolerance.³⁰ Further evidence supports a bidirectional interaction between the gut and the skin with gut microorganisms influencing skin health through their metabolic activities and immunological effects.³⁰ For instance, commensal gut microbes promote skin balance by regulating T-cell differentiation.³⁰ Particularly, for AD, changes in the gut microbiome lead to the production of inflammatory mediators.³¹ Other environmental factors including stress, diet, and pollutants can affect the microbiome and contribute to disease phenotypes.³¹ There is evidence to suggest that the gut microbiome in early life is associated with the age of onset, severity, remission, and flares of AD.³⁰ Supportive evidence for this relationship includes the proportion of greater amounts of bacteria including Clostridium difficile, Escherichia coli, and Staphylococcus aureus (S. aureus) in patients with AD, while certain gram-negative (Neisseria, Corynebacterium, and Haemophilus) are increased in EoE than in healthy controls.^31,32 These bacteria may induce eosinophilic inflammation. The short-chain fatty acid (SCFA) pathway may also be greater in patients with AD.³¹

Tight junction proteins. The loss of tight junction proteins is implicated in the pathogenesis of both EoE and AD.^33–36 Importantly, in EoE, treatment with steroids increases levels of filaggrin and claudin, and may also be affected by IL-13 levels.^33,34 Levels of claudin and filaggrin are also decreased in patients with AD and are also affected by various interleukins including IL-4, IL-5, IL-13, and IL-31.^35,36 

Genetic. Defects within the skin and esophageal “building blocks” or barrier proteins have areas of overlap between AD and EoE. In AD, intrinsic defects in the barrier (e.g. filaggrin mutations) may promote increased transcutaneous entry of allergens, leading to allergic sensitization and subsequent development of disease.^13,37 Defects common to both EoE and AD include decreased filaggrin (FLG), involucrin (IVLL), and small proline-rich proteins (SPRP).³⁷ 

Host immune. AD and EoE share Th2-driven pathogenesis (Figure 1), although defects may occur in different parts of a common pathway. In EoE, experimental modeling suggests that barrier dysfunction and allergic sensitization to food drives activation of eosinophils, mast cells, eventuating in the production of IL-5 and IL-13 and esophageal damage.²² 

Interleukin (IL)-13 plays a specifically crucial role in the pathophysiology of EoE.²³ The most highly expressed gene, compared to controls, is the IL-13-induced gene CCL26 which encodes eotaxin-3.³⁸ This protein attracts eosinophils to the esophageal mucosa.³⁸ IL-13 is produced by Th2 lymphocytes, eosinophils, and mast cells, and it drives the eosinophilic inflammatory response, including eosinophil chemotaxis and tissue recruitment.²³ IL-13 is also associated with a compromised barrier function and diminished epithelial cell differentiation, which may be responsible for the endoscopic findings in EoE.²³ Importantly, mice models have demonstrated that in mice lacking IL-13, EoE fails to develop, highlighting the significance of IL-13.²³

Similar to EoE, recent data has suggested that IL-13 has a larger role in AD than previously thought.³⁹ Studies suggest that IL-4 may be more relevant for central aspects of the Th2 response while IL-13 may play a more prominent role in the periphery, acting at the tissue level.³⁹ These IL-4-driven central mechanisms localized in the lymph node and include the regulation of humoral immunity, including the generation of Immunoglobulin (Ig) E.³⁹ 

A recent molecular analysis of disease-specific transcripts from tissue specimens (biopsies or nasal brushes) revealed that EoE and AD share a close molecular relationship, particularly centered around IL-13-driven pathways. The two diseases were found to have 181 shared mRNA transcripts which amounted to a 10-percent overlap. The overlap between the IL-13-stimulated epithelial cell transcriptome and the respective disease transcriptome was 22 percent and 9 percent in EoE and AD, respectively. This suggests a higher involvement of the IL-13 pathway in EoE than AD (p=0.02).⁴⁰ Perhaps surprisingly then, although tissue IL-13 levels correlate with disease severity in AD, they do not appear to do so in EoE.^41–43 The type 1 IL-4 receptor is found in lymphocytes and myeloid cells, and the type II IL-4 receptor is found in myeloid cells and all non-hematopoietic cells, while the IL-13 receptor is found on B cells, monocytes/macrophages, basophils, mast cells, endothelial cells, but not T cells.^44,45 In patients with AD, epidermal DCs carry FcεRI on their surfaces, which is the high-affinity receptor for IgE.⁴⁶ In patients with EoE, basal layer cells contribute to pathogenesis by overexpressing IL-33, inducing a Th2 response.⁴⁷ 

Th17 and Th22 cells may be involved in the pathogenesis of both EoE and AD, however specifically in AD, early-onset pediatric AD is characterized by a Th17/Th22 inflammation response.⁴⁸ These T cells may also be involved in race-specific AD, as European American AD cohorts feature higher activity of the Th22 axis, and the Asian and African American AD cohorts exhibit greater Th17 activity.⁴⁹ Such specific relationships are not observed in EoE. 

Environmental effects. Climate change, air pollution, microplastics, tobacco smoke, changes and loss of biodiversity, alterations in dietary habits, and the microbiome due to modernization, urbanization, and globalization make up our surrounding environment or exposome.⁵⁰ An intact skin and mucosal barrier is crucial to maintaining physiological homeostasis.⁵¹ This principle underlies the “epithelial barrier hypothesis,” which suggests that industrialization and urbanization have led to increased damage to the epithelial barrier, which then subsequently leads to the development of allergic, autoimmune, and chronic conditions.⁵¹ Leaky epithelial barriers can lead to translocation of bacteria and the development of inflammation.⁵¹ 

While multifaceted and highly complex, supporting evidence for this hypothesis stems from the correlated increases in AD with household products that contained surfactants and enzymes in the 1960s.⁵⁰ EoE increase is thought to be correlated with the use of food emulsifiers and dishwasher detergents after the 1990s.⁵⁰ 

Microbiome. The role of the microbiome in AD is emerging.⁵² While the role of S. aureus is the overwhelmingly most notable, S. epidermidis, S. haemolyticus, S. hominis, and S. lugdunensis have also been shown to play a role in AD pathogenesis and symptoms.⁵² On the other hand, decreases in Cutibacterium, Streptococcus, Acinetobacter, Corynebacterium, and Prevotella generas have been observed in AD.⁵² Notably, an overall lack of microbial diversity is a characteristic of atopic skin and is even noted on non-affected areas in patients with AD.⁵² Importantly, the percentage of healthy carriers of S. aureus increased nearly nine-fold, from four percent to 35 percent in the past 40 years, while at present day, up to 90 percent of patients with AD have S. aureus colonization.^50,51 

In EoE, the data is much more limited.⁵³ A small study of 70 patients does suggest microbiome disruption and an increase in Haemophilus species in untreated EoE.⁵³ These findings are not seen in GERD or treated EoE patients.⁵³ Further studies are needed to elucidate the microbiome changes in EoE.⁵³ For example, the strongest and most consistent evidence of an association (4/5 studies) has been observed between EoE and antibiotic use in infancy.⁵⁴ On the other hand, the data surrounding antibiotic use in infancy and AD is mixed, some studies have found that antibiotic exposure during the second week of life is associated with a lower risk of subsequent AD.⁵⁵ However, other studies have found that antibiotic use in the first year of life disrupts the infant gut microbiome, leading to an increased risk of AD.⁵⁶ Thus, the exact relationship between antibiotic use in infancy and the development of AD remains complex and incompletely understood. 

Additionally, studies have found an inverse association between Helicobacter pylori and EoE as well as AD.^54,57 Therefore, the exact role of environmental factors in the development of EoE and AD remains to be fully elucidated, and is a potential area for future investigation. 

Treatment

The treatment of EoE and AD shares many similarities and includes avoidance of allergic triggers, topical steroids, and dupilumab.^22,58 Allergen immunotherapy and elimination diets may have some part in treating both EoE and AD, but there is a lack of evidence supporting these and response to therapy may be variable depending on many factors.^22,59 Conventional food allergy testing is not helpful in EoE, and elimination diets such as the 1-FED (cow’s milk) and 6-FED (wheat, cow’s milk, nuts, shellfish, soy, and eggs) are typically used. Elimination diets take 4 to 6 weeks and are re-assessed endoscopically. Food allergies in the atopic march overlap with EoE trigger foods although the mechanism of the response is distinct and can be confirmed via serum IgE level or skin prick testing.

Dupilumab, a fully human monoclonal antibody acting against the IL-4-alpha receptor that binds IL-4 and IL-13, has been successful in treating AD and EoE and is now FDA-approved for both conditions.⁵⁸ Tralokinumab is an IL-13-specific monoclonal antibody that is currently FDA-approved for atopic dermatitis.⁶⁰ Given this mechanism, tralokinumab is a potential therapeutic modality for EoE , which has increased IL-13 involvement in pathogenesis. Similarly, Janus kinase (JAK) inhibitors may be a promising treatment modality given the involvement of the JAK-STAT pathway. There are no current clinical trials for tralokinumab or JAK inhibitors in EoE at this time.⁶¹ 

Treatment response is variable in both EoE and AD. EoE tends to be chronic and requires life-long intervention for almost all pediatric and adult patients.⁶² EoEe1 is milder and responsive to PPIs. EoEe2 is typically refractory to PPIs but responds to elimination diets and steroids. EoEe3 is typically unresponsive to therapy and requires endoscopic intervention due to stricture formation.⁶³ In contrast, a majority of pediatric AD wanes, and only a small percentage of patients go on to have a chronic, relapsing-remitting phenotype that requires prolonged intervention.⁶⁴ A large meta-analysis (n=110,651) found that 20 percent of childhood AD was sustained after eight years of age; less than 5 percent of patients had chronic disease 20 years after diagnosis.⁶⁵

Given these emerging links between EoE and AD, it is important for clinicians caring for AD patients to be aware of EoE symptoms, such as difficulty swallowing, food impactions, and/or treatment-resistant acid reflux. These patients should be referred to gastroenterology for further evaluation to prevent delays in diagnosis. Multidisciplinary, integrated care is needed for patients with overlapping atopic conditions. Biologic therapy should be considered in these patients.

Conclusion

AD and EoE are two distinct conditions, but they can co-exist in some individuals and have increased in prevalence and require new treatment strategies.^3,17,66 The complex interplay between IL-4, IL-13, and Th2 cells is a significant mechanistic pathway common to both AD and EoE as well as other atopic conditions.^23,39 

IL-13 is a key player in EoE, and recent data suggests that IL-13 may have a larger role in AD than previously understood.³⁹ The coexistence of EoE and other eczematous conditions has yet to be described; one case series (n=4) suggests a relationship between dyshidrotic eczema and EoE.⁶⁷ The pathway of lichenification in AD versus that of fibrostenotic changes in EoE is yet to be explored. Distinct endotypes of EoE offer a method to further classify and understand EoE, and we suspect these subtypes also exist and are yet to be classified in atopic dermatitis.²³ Topical steroids and dupilumab are cornerstone therapy in both EoE and AD of therapy; and emerging biologic therapies for the two entities overlap. The efficacy of known AD treatments such as TCIs, JAKi, tralokinumab, and PDE-4 inhibitors is yet to be studied in the esophagus. Elimination diets are an integral pillar of EoE management but are not recommended for patients with AD.^22,58 Elimination diets may take up to six months to work in patients with EoE.⁶⁸ Dermatologist awareness of EoE may help facilitate expedient recognition in atopic patients. Multiple co-morbid atopic conditions may signal the need for biologic therapy and multidisciplinary, integrated treatment protocols. Future directions may include integrated treatment protocols that address both conditions simultaneously and multidisciplinary collaboration between allergists, dermatologists, and gastroenterologists. 

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