Advances and Ongoing Challenges in Eosinophilic Gastrointestinal Disorders presented at the CEGIR/TIGERS Symposium at the 2024 American Academy of Allergy, Asthma, & Immunology Meeting

Abstract

The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERS) organized a day-long symposium at the 2024 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research and debates on the mechanisms and management of eosinophilic gastrointestinal diseases (EGIDs). Updates on recent clinical trials and consensus guidelines were also presented. Herein, we summarize the updates on EGIDs presented at the symposium.

Introduction

Eosinophilic gastrointestinal diseases (EGIDs) are a group of clinicopathologic diagnoses defined by symptoms of esophageal, gastric, or intestinal dysfunction and tissue eosinophilia. Symptoms vary according to age and the segment(s) of gastrointestinal tract affected. Diagnostic thresholds for tissue eosinophil counts have been established for EoE¹ and proposed for non-esophageal EGIDs, including eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC)². Epidemiologic studies suggest that the most common EGID, eosinophilic esophagitis (EoE), is no longer a rare disease, affecting 0.5 to 1 in 1000 individuals³. In contrast, the non-esophageal EGIDs are much less common. New genetic studies, animal models, and clinical trials have significantly advanced our understanding of EGID pathogenesis since the last CEGIR/TIGERS Symposium in 2022⁴. Despite their histologic prominence eosinophils are no longer regarded as the primary drivers of disease pathology and efforts to identify other biomarkers of disease activity and food triggers are underway^{5, 6}. In the same interval, the first two agents (i.e., dupilumab and viscous budesonide) received regulatory approval for the treatment of EoE in the United States^{7, 8}. We organized the 2024 CEGIR/TIGERS Symposium to inform the EGID community of these scientific and therapeutic advances and equip them with the knowledge to apply them in research and clinical practice.

Mechanisms of EGIDs

Innate immunity

Allergen insult to a dysregulated esophageal barrier releases epithelial-derived cytokine alarmins that expand tissue-resident group 2 innate lymphoid cells (ILC2s). ILC2s, in turn, condition dendritic cells and promote eosinophil and mast cell accumulation, collectively orchestrating a type 2 immune response. Eosinophil and mast cell derived mediators exacerbate EoE pathology, including barrier dysfunction, immune propagation, and tissue remodeling. Recent findings have revealed new complexities in this innate immune circuitry underlying EoE pathophysiology, particularly related to cellular heterogeneity and spatial organization. Esophageal epithelium conditioned with IL-13 released soluble factors that prolonged survival and dysregulated the active transcriptome of human eosinophils⁹, suggesting esophageal eosinophils are a heterogenous population dynamically shaped by the local tissue microenvironment in EoE. Single cell RNA sequencing (scRNA-Seq) analyses of esophageal biopsies revealed both transcriptional heterogeneity and spatial redistribution of mast cells between EoE disease states. Active EoE was associated with emergence of epithelial-localized mast cell populations exhibiting pro-inflammatory phenotypes, with at least one subset persisting in remission¹⁰; these data may provide at least a partial mechanistic explanation for persistence of symptoms and histologic and endoscopic abnormalities in some patients despite resolution of eosinophilia¹¹. Spatial compartmentalization of mast cells and eosinophils have been incorporated into machine learning approaches¹², adding an additional data layer for artificial intelligence-based modeling of histopathologic features in EGIDs. Beyond the reach of standard tissue biopsies, mast cells and eosinophils also infiltrate esophageal smooth muscle. Recent data reveal that signaling through IL-4Rα increased secretion of the eosinophil chemoattractant eotaxin-3 in parallel with increased tension in human esophageal smooth muscle cells¹³, adding new insights into the interplay between type 2 cytokines, innate immune cells, and esophageal distensibility in EoE.

Adaptive immunity

EoE is associated with adaptive immunity, including distinct antigen-specific T cell subsets that secrete cytokines and interact with B cells to drive selective antibody production. B cells are increased in the tissue of EoE patients¹⁴. Tissue B cells in EoE are activated and undergo class-switching, which leads to the production of antibody subtypes including IgA, IgG4, and IgE¹⁵. However, animal models of EoE in B cell knockout mice suggest B cells are not critical to the eosinophilic inflammation seen in EoE¹⁶.

Several subtypes of T cells are increased in EoE including CD4, CD8, and invariant NK T cells¹⁷. A critical subtype of CD4 T cell increased in the tissue is the pathogenic effector Th2 cell (peTh2 cell), which secretes cytokines such as IL-4, IL-5, and IL-13. scRNA-Seq analysis of peTh2 cells demonstrated T cell receptor (TCR) clonality, suggesting increased numbers of clonally expanded peTh2 cells in the tissue compared to peripheral Th2 cells in the blood¹⁸. Bulk TCR sequencing confirms clonality among children with EoE, but not adults¹⁹. In children with active EoE, the relative abundance of common TCRs inversely correlates with intra-epithelial CD4 T cell counts by immunohistochemistry, suggesting that increases in CD4 T cells in the mucosa are due to clonal expansion. Moreover, specific TCRs were identified among patients with diet-responsive EoE only when they were consuming the allergenic food(s). Data thus far have identified overlapping and highly similar TCRs in patients who react to similar allergenic food(s). Together these data suggest a food allergen-restricted TCR repertoire in the mucosal tissue of patients with food-driven EoE.

Mouse models of EoE

Numerous mouse models of EoE are reported in the literature. These models rely on various techniques, including antigen (e.g., ovalbumin or hapten) sensitization followed by challenge, exogenous cytokine administration, or genetic modification. The models show a range of pathologies from limited or no intraepithelial eosinophils or basal zone hyperplasia (BZH) to models that recapitulate features of clinical EoE, like mucosal eosinophilia, BZH, and fibrosis. Histopathology tends to be more representative in hapten-based and genetic models^20–23. For example, the recently described EoE33 model is based on constitutive overexpression of IL-33 from the esophageal epithelium²³. EoE33 mice show marked esophageal inflammation and remodeling including intraepithelial eosinophilia and increased mast cells, Th2 cells, and type 2 cytokines. Additionally, there are BZH, dilated intercellular spaces, and fibrosis. Notably, EoE33 develops an adaptive immune response against wheat, a primary component of the rodent chow. EoE33 pathology does not require eosinophils but is dependent on IL-13 and steroid-responsive. In addition, an inducible version of this model, iEoE33, was created to address disease initiation, progression, and resolution. The model is comprised of two transgenic mice. The first, iSophagus, expresses reverse tetracycline transactivator from the esophageal epithelium. The second, TRE33, uses a tetracycline responsive element to drive IL-33 expression. When crossed, these mice generate iEoE33 which, when induced with doxycycline, develops pathology similar to EoE33²⁴. Finally, a recent mouse model was developed to investigate environmental exposure to the household detergent sodium dodecyl sulfate (SDS) as a potential causative factor in EoE. Mice exposed to 0.5% oral SDS (toothpastes contain up to 3%) develop EoE-like pathology after 2 weeks²⁵. Together, these robust models will shed new light on disease mechanisms of EoE.

In vitro models and omics studies

Experiments in humans have enabled the discovery of molecular mechanisms driving the etiology and pathology of EGIDs. The fact that biopsies of the affected tissues are clinically important has enabled scientists to learn about the immunological, cellular, and molecular mechanisms of EGIDs. Cell lines have facilitated studies with and without expression of specific genes to identify whether they are necessary and sufficient for cytokine production and other disease-associated cell biology^{22, 25}. When grown in an air-liquid interface and in organoid cultures, cell lines and primary cells from biopsies have been used to study epithelial barrier phenotypes²⁶.

Studies of genetic risk have focused on EoE, in part due to the lack of patient cohorts large enough to provide statistical power for genome-wide assessment of other EGIDs. These studies have revealed over 30 independent polymorphic loci in the human genome that increase risk of EoE^{26, 27}. While most genetic studies have focused on patients of European ancestry, a study in 2022 used the genetic admixture of patients of African American ancestry to identify novel risk loci²⁸. In 2024, a comprehensive assessment of genotype-dependent regulatory activity at EoE genetic risk loci was published²⁹. Epigenetic studies focused on histone marks, chromatin accessibility, and methylation have established regulatory genomic mechanisms of EoE²⁶. These mechanisms have been linked to the EoE transcriptome which has been studied through multiple experimental platforms²⁶. Single cell and single nuclei studies have enabled the direct assessment of the transcriptome of individual cell types such as eosinophils, mast cells, T cells, and epithelial cells present in EoE patient biopsy tissue³⁰. More recently, genomic features have been used to endotype different presentations of EoE³¹. For non-esophageal EGIDs, recent gene expression studies of patient biopsies have established unique and shared transcriptional signals³².

The role of IgG4 in EGID pathogenesis

Immunoglobulin G4 (IgG4) is present in the esophageal tissue in patients with active EoE³³, and these levels correlate with eosinophil counts and IL-10 expression in active disease³⁴. Recent studies have found that IgG4 binds food and non-food allergens in the esophageal mucosa of patients with active EoE, and that these allergen-IgG4 deposits are near eosinophils³⁵. These data suggest that IgG4 may play an integral role in the pathophysiology of EoE through the coordination of the innate and adaptive immune response, though the exact mechanisms remain unclear (Table 1).

Table 1.

Pro/con debate: IgG4 plays a role in the pathogenesis of eosinophilic esophagitis (EoE)

Pro: IgG4 plays a role in EGID pathogenesis IgG4 is present in the esophageal tissue in EoE, and levels correlate with EoE disease severity33, 34.	Con: IgG4 plays no role in EGID pathogenesis EoE develops in individuals with IgG4 deficiency and common variable deficiency36, 37.
IgG4 binds food and non-food allergens in the esophageal tissue in active EoE, and these deposits are located near eosinophils35.	Diets based on IgG4 levels or results do not result in significant improvement in histology or symptoms80, 81.
The IgG4 response occurs in the tissue. While peripheral IgG4 levels are markedly higher in EoE patients compared to allergic controls, blood levels do not always capture the tissue response82, 83.	IgG4 levels increase due to type 2 cytokines. IgG4 increases with dietary consumption of the food.
Mice do not make IgG4, so our ability to use mouse models to define the role of IgG4 in EGIDs is limited.	Mice develop EoE without any immunoglobulin including IgG and the mouse equivalent to human IgG4 (mouse IgG1)16, 38.

Conversely, IgG4 is produced in response to type 2 cytokines and chronic antigen exposure, which is emblematic of the inflammatory response seen in EoE. Therefore, IgG4 production could be an epiphenomenon of this underlying immune response. In addition, individuals with IgG4 deficiency^{36, 37} and mice lacking immunoglobulins^{16, 38} can still develop EoE, suggesting that IgG4 is not necessary in the pathogenesis of this disease (Table 1).

Emerging research in EGIDs

The symposium featured oral abstracts investigating lipid composition of the esophageal epithelium in EoE, the relationship between EGIDs and elevated basal serum tryptase, and CD73 activity in EoE fibroblasts. Braskett et al.³⁹ performed lipidomic analysis on esophageal brushing samples by mass spectrometry and identified alterations in lipid composition that correlated with IL-5 and IL-13 levels measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) (Figure 1). These lipid alterations may contribute to barrier dysfunction of the esophageal epithelium.

Figure 1. Lipidomic analysis of esophageal epithelium reveals unique sphingolipid profile in EoE.

Quantitative lipidomics were performed via mass spectroscopy on esophageal brushing samples from 14 controls with normal histology and 7 individuals with EoE (≥ 15 eos/hpf) from a medication-naïve pediatric cohort. The expression of inflammatory mediators and lipid biosynthesis enzymes was examined by RT-qPCR in esophageal biopsy samples. Non-hydroxy fatty acid sphingosine (NS) ceramides and their precursors, non-hydroxy fatty acid dihydrosphingosine (NDS) ceramides were significantly increased in EoE, with a concomitant decrease in non-hydroxy fatty acid phytoceramides (NP), resulting in selectively increased NS/NP ceramide ratios as compared to controls. Individuals with EoE had notably decreased expression of DEGS1 and DEGS2, the enzymes involved in the biosynthesis of NS and NP ceramides. The NS/NP ceramide ratio correlated strongly with IL-5 and IL-13 mRNA expression. These unique alterations in sphingolipid composition and biosynthesis likely contribute to esophageal epithelial barrier dysfunction in EoE. Created with Biorender.com

Abbreviations: RT-qPCR - reverse transcription-quantitative polymerase chain reaction; NS ceramide - non-hydroxy fatty acid sphingosine ceramide; NDS ceramide - non-hydroxy fatty acid dihydrosphingosine ceramide; NP ceramide - non-hydroxy fatty acid sphingosine phytoceramide; DEGS1 - Delta 4-desaturase, sphingolipid 1; DEGS2 - Delta 4-desaturase, sphingolipid 2

Constantine et al.⁴⁰ analyzed 85 patients with EGIDs and found that 17.6% had basal tryptase levels ≥11.4 ng/mL (Figure 2). Among those with elevated tryptase levels, two were diagnosed with an underlying myeloid neoplasm. To determine the underlying cause of elevated tryptase among the remaining thirteen individuals, digital droplet PCR and next generation genetic sequencing were performed. Five patients had increased TPSAB1 copy number, four had JAK2 V617F variants, and one had a KIT D816V variant. Several others had variants associated with myeloid disorders. In summary, hereditary alpha-tryptasemia and myeloid disorders may be more common in EGIDs than previously appreciated.

Figure 2. Evaluation of elevated serum tryptase among individuals with eosinophilic gastrointestinal diseases (EGIDs).

Participants (n=85) with EGID and a measured serum tryptase were examined, genomic DNA was isolated and digital droplet PCR (ddPCR) performed to determine tryptase genotypes (TPSAB1 and TPSB2) and to screen for JAK2 p.V617F and KIT p.D816V variants associated with clonal myeloid disorders. Elevated BST (≥11.4 ng/mL) was observed in 17.6% of individuals with EGID (n=15/85). Of the 15 EGID individuals with elevated BST, two were diagnosed with an underlying myeloid neoplasm responsive to tyrosine kinase inhibition. Of the remaining thirteen individuals, five had increased TPSAB1 copy number, ddPCR detected JAK2 V617F in four individuals and KIT D816V in another. Somatic and mosaic variant calling analysis identified multiple variants of interest that are under further investigation. Additional studies are ongoing to determine the underlying cause for elevated BST in the remaining individuals with EGID. Created with Biorender.com.

Abbreviations: EGID – eosinophilic gastrointestinal disease; ddPCR - digital droplet PCR; BST - basal serum tryptase

Abud et al.⁴¹ assessed the role of the 5’ nucleotidase-Ecto (CD73) in fibroblast homeostatic function of migration. Active EoE fibroblasts displayed increased wound healing and migration compared to healthy esophageal fibroblasts. EoE fibroblasts had significantly lower CD73 expression and activity compared to healthy fibroblasts. Inhibition of CD73 activity in healthy fibroblasts increased their migration and wound healing while the CD73 enzymatic end-product, adenosine, normalized EoE fibroblast migration. These data demonstrate that CD73 activity alters fibroblast homeostatic properties and suggest pathogenic fibroblast function occurs in part via CD73 axis. Future studies will examine how CD73 expression and activity is governed in EoE.

EGIDs and the environment

Environmental exposures and pathoetiology

The incidence of EoE has increased dramatically over the previous two decades and while numerous susceptibility SNPs have been associated with EoE⁴², the proportion of phenotypic variability observed in the population explained by genotype (heritability) remains relatively low. Further, given the rapid increase in incidence, environmental factors likely contribute to disease pathoetiology. To date, the most convincing body of evidence for environmental factors centers on exposures incurred during early life. Perinatal factors that have been implicated include gestational age, with earlier gestational ages at greater risk of developing EoE, reduced weight for gestational age, admission to the neonatal intensive care unit, and maternal complications⁴³. Infant antibiotic use and acid suppressant use have also been implicated. In a very recent study conducted in Denmark, both maternal and infant use of antibiotics were associated with increased risk, and this risk increased with more prescriptions or days of prescription provided, suggesting a potential dose response in the associations observed⁴⁴. Experimental evidence supports the observed association between antibiotic use and development of EoE. In a mouse model of neonatal exposure to broad spectrum antibiotics, antibiotic exposure led to a higher relative abundance of inflammation-associated bacteria and type 2 inflammation in esophageal and colonic tissue⁴⁵. Future work will explore the potential role of gene-environment interaction in the development of EoE.

The esophageal microbiome in EoE

Early studies using 16S rRNA sequencing identified enrichment of select organisms, such as Haemophilus and Streptococcus, in the esophagus^{46, 47}. In 2019, investigators expanded their view to examine the fecal microbiome in pediatric patients with EoE using the same sequencing technology⁴⁸. They found that patients with EoE (n=12) had decreased abundance of spore-forming communities, Clostridia and Clostridiales, compared to 12 non-EoE controls (n=12). These smaller studies were then followed with a larger adult and pediatric multi-center study conducted through CEGIR. This study used mucosal biopsies and stool samples from EoE and EoG patients and performed 16S rRNA sequencing. Investigators confirmed that Streptococcus is a dominant esophageal species in EoE esophagi, and Prevotella is a dominant species in gastric mucosa of EoG patients. Fecal microbial examinations were limited by variability among individuals and did not correlate with mucosal biopsies. Lastly, a mouse model of EoE demonstrated several findings, one of which included discrete microenvironment niches for varied bacterial species⁴⁵. Specifically, Bifidobacteriales species tend to occupy the proximal esophagus, whereas Lactobacillales dominate in the distal esophagus. These region-specific communities have varied functional properties such as pH tolerance and microbial metabolite differences, and the microbes were found to interact with the respective epithelia impacting their development. While these findings were in mice, if site-specific esophageal niches are similar in humans, this could contribute to the variability in microbial communities identified in studies to date.

Minimally-invasive diagnostics

Since the early 1990’s, EoE has been managed by physicians as a clinical food allergy using empiric food elimination diets followed by endoscopy and esophageal biopsy to monitor the condition’s sine qua non of eosinophilic inflammation⁴⁹. This practice was subsequently bolstered by immunologic investigations that revealed that EoE has a strong predominance of type 2 inflammation¹⁷. Despite this, immunologic evidence of antigen presentation and recognition by the immune system in EoE was initially elusive. As a result, the development of accurate and minimally invasive diagnostics to identify EoE-causal foods has also eluded us.

Translational studies from the past few years have begun to shed light on this important knowledge gap. We now know that there is a central role for the esophageal epithelium in modulating the mucosal immune response. For example, IFNγ and IFNγ-related pathways have been shown to be upregulated in the context of EoE⁵⁰. This is relevant as one study described a human esophageal epithelium cell line that expressed HLA-DR after treatment with IFNγ⁵¹. This work has been complemented by studies of T cells from EoE patients. We now know that food-allergen activated T cells are present in the circulation of patients with EoE^52–54. Further, scRNA-seq of patient biopsies has elucidated the effector phenotype¹⁷ and identified clonal expansion¹⁸ of esophageal T cells in EoE. Despite these advances, the specific molecules that mediate food antigen presentation and subsequent recognition by T cells in EoE remain both unknown and an important area for future research. Addressing this need will facilitate the development of new lab tests that identify EoE-causal foods in patients.

Ongoing challenges

Diversity, equity, inclusion, and accessibility in EGIDs

A recent systematic review of population based EGID studies revealed that fewer than 50% of studies reported demographic information related to sex, race and ethnicity, and a minority of those that did followed established guidelines⁵⁵. This gap in knowledge can lead to misconceptions about disease demographics resulting in underdiagnosis and treatment delays in underrepresented groups⁵⁶. Compounding factors include the impact of social determinants of health (e.g., economic status and stability, education, language, and cultural factors) on access to care⁵⁷. For example, a recent study examining the prevalence of EoE (EoE) using the 2012 Medicaid database (>18 million children) showed that differences previously noted between the urban and rural prevalence of EoE could be largely explained by distance from a pediatric gastroenterologist⁵⁸. In contrast, the strong inverse correlation between poverty and the probability of an EoE diagnosis was preserved.

Diversity, equity, inclusion, and accessibility are not only important in the context of clinical care but play an important role in access to research studies, as well as patient recruitment and retention. This, in turn, has implications for the generalizability of research results. Fortunately, as exemplified by the recent Passive Immunity Trial for Our Nation (PassITON) trial⁵⁹, these issues are addressable through improved community engagement (to increase awareness and reduce mistrust) and flexibility in trial design (to accommodate logistical burdens such as inflexible work schedules, childcare responsibilities, and language barriers). The PassITON trial was a multicenter randomized controlled trial of convalescent plasma in adults hospitalized with COVID-19 which achieved greater than 40% participation among underrepresented minoritized commumities using a multicultural and multilingual awareness-raising strategy.

Dietary management of EoE

As medical therapies for EoE expand, dietary management also evolves. Biologics may allow for a broader diet, but nutritional intake may still be repressed by food aversion and feeding delays resultant from years of refractory disease or delayed diagnosis⁶⁰. Newer options for dietary therapies may also allow for a broader diet in comparison to the elemental and six food elimination (milk, wheat, egg, soy, seafood, nuts) diets. The 4FED (milk, wheat, egg, soy/legumes), 2FED (milk and wheat) and 1FED (milk) for children and adults all demonstrated similar efficacy⁶¹. These more liberal diets allow increased dietary variety, which may mitigate nutritional risk and financial burden while improving quality of life⁶⁰. Elimination diet research has not been consistent across the categories of foods eliminated. Inconsistencies include soy versus broader all legume elimination and gluten versus wheat elimination⁶². Legumes are more frequently appearing in replacement products for milk and wheat, making the broader elimination difficult or even unfeasible. Dual or alternate medical and diet therapy have also been shown to induce remission and increase patient EoE management choices⁶². Shared decision making may help patients choose the ideal therapy with consideration of comorbid atopic disease, baseline nutritional status, access to food, food preferences and barriers to implementation and adherence⁶³. Feeding difficulties as well as poor growth may be a contraindication to starting diet therapy and should be evaluated when considering treatment⁶⁰. Partnership with a registered dietitian (RD) to provide baseline and ongoing nutrition assessment, avoidance education and individualized resources may enhance provider and patient outcomes⁶⁴.

Shared decision making in EoE

As the landscape of effective pharmacologic and dietary treatments continues to evolve rapidly, recognizing and addressing patient priorities, as well as engaging in shared decision making, are crucial components of successfully managing EoE.⁶³ Shared decision making is most appropriate when there is clinical equipoise between treatment options, and requires presentation of clear, unbiased, evidence-based knowledge about options (e.g., risks vs benefits, potential burdens), sharing patients’ experiences, values, and goals, and fostering open patient-clinician communication.

Clinicians must acknowledge that patients’ views, preferences, and lifestyles are individualistic, subject to change over time, and may differ from those of healthcare providers. Shared decision making may not be a “one time only” event but can be an ongoing discussion that evolves over time, informed by new data and patients’ experiences or circumstances. As joint experts in their disease, patients, and families with EoE both want to and need to know that they can be part of the decision-making process. It is important for patients to understand that they have the agency to change their minds about treatments, as forecasting which treatments they may prefer or are effective can be challenging. Optimizing EoE treatment requires a multidisciplinary team approach, and both allergists and gastroenterologists can partner with patients to assess responses to treatment and advance disease management.

First line therapy for severe fibrostenotic EoE

Untreated inflammation in EoE can lead to tissue remodeling and fibrostenosis. Patients with fibrostenotic disease often suffer from dysphagia and may demonstrate esophageal rings and/or stricture on endoscopy, reduced esophageal distensibility, and lamina propria fibrosis on histopathology⁶⁵. Determining the optimal first-line therapy for fibrostenotic EoE remains challenging due to the lack of comparative clinical trials. Table 2 highlights the advantages and disadvantages of dupilumab and swallowed topical corticosteroids (STCs) in the treatment of fibrostenotic EoE, while acknowledging that both treatments have demonstrated efficacy in reversing features of remodeling and fibrostenosis.

Table 2.

Dupilumab vs. swallowed topical steroids for treatment of fibrostenotic EoE

Dupilumab		Swallowed Topical Corticosteroids
Pros	Cons	Pros	Cons
First FDA approved treatment for EoE7.	Associated with higher cost; limited availability in some regions.	Only therapy to be strongly recommended by the 2020 AGA-JTF guidelines for the treatment of EoE84.	Maintenance therapy remains an off-label indication; more widely available.
Acts on IL-4Rα to block IL-4 and IL-13 signaling, directly inhibiting IL-13 mediated fibrosis85, 86.	Given the specificity for IL-4/IL-13 signaling, it may not address other relevant EoE pathways.	Broad immunosuppressive spectrum may impact pathways beyond IL-4/IL-13; decreases IL-13 mRNA expression87.	Broad mechanism of action may have unintended side effects.
RCT populations received PPI therapy prior to dupilumab treatment suggesting more treatment refractory cases7.	Limited data for first-line use.	Early RCTs did not require prior PPI therapy for treatment (used as first line therapy)88–90.	Lack of clear consensus on the most effective strategies for maintenance therapy.
Improves dysphagia symptoms (DSQ and SDI)7, 85.		Improves dysphagia symptoms (DSQ and EEsAI)91, 92.
Can improve fibrostenotic endoscopic features, including rings and strictures93, 94.	Limited data available, systematic studies focused on fibrostenotic disease are needed.	Can improve fibrostenotic endoscopic features, including rings and strictures66, 75, 91.	Limited data available, systematic studies focused on fibrostenotic disease are needed.
Can improve esophageal distensibility85.	Limited data available, additional studies are needed.	Can improve esophageal distensibility66.	Limited data available, additional studies are needed.
FDA-approved for induction and maintenance therapy, ages 1 year and older.	Data for long-term maintenance limited to 52 weeks7.	BOS FDA-approved for induction therapy (12 weeks), 11 years and older.	Concerns remain about the maintenance of histologic remission (possibly related to adherence and sub-standard dosing)95, 96.
Well-tolerated in RCTs with rare discontinuation due to adverse effects7, 85.	Local injection-site reaction is common, long-term safety data is lacking7, 85.	Generally, well tolerated with limited side effects97, 98.	Risk of oral and/or esophageal candidiasis, concern for adrenal suppression, reduced bone density, growth impairment97.

IL-4R, IL-4 receptor; RCT, randomized controlled trials; DSQ, Dysphagia Symptom Questionnaire; SDI, Straumann Dysphagia Index; EEsAI, Eosinophilic Esophagitis Activity Index; BOS, budesonide oral suspension; FDA, Food and Drug Administration

Current evidence suggests that other therapies, including proton pump inhibitors (PPIs) and empiric FEDs, can also reverse features of fibrostenosis^{66, 67}. Therefore, it is crucial for patients or their families as well as healthcare providers to engage in shared decision-making to collaboratively determine the most suitable treatment approach⁶⁷.

Clinical updates on EGIDs

Updates on non-esophageal EGIDs

Non-EoE EGIDs include EoG, EoN [including eosinophilic duodenitis (EoD), eosinophilic jejunitis, eosinophilic ileitis], and EoC. They are considered rare, with a reported prevalence of 2–8 per 100,000 individuals depending on the specific organ with pathologic tissue eosinophilia⁶⁸. However, it is likely that non-EoE EGIDs are under-diagnosed. Results from a longitudinal retrospective cohort study of patients with EoG/EoD, conducted using data from a U.S. administrative claims database, revealed a mean diagnostic delay of 3.6 years⁶⁹. Alternative diagnoses included other gastroenteritides, functional dyspepsia, peptic ulcer, and irritable bowel syndrome⁶⁹. Patients with non-EoE EGIDs present with multiple gastrointestinal symptoms, which vary depending on the depth of disease through the gut layers, but all are non-specific⁶⁹. Guidelines for diagnosis were only recently published for the pediatric population² and are still in development for adults with non-EoE EGIDs. Presence of atopic comorbidities⁶⁹, peripheral blood eosinophilia, anemia, and/or hypoproteinemia/hypoalbuminemia⁶⁹, though present in only a subset of patients, should increase the suspicion for EoG/EoD. Diagnosis of non-EoE EGIDs relies on an upper endoscopy or colonoscopy with biopsies, demonstrating pathologic tissue eosinophilic infiltration. An endoscopic scoring system for patients with EoG, detailing and grading seven potential endoscopic findings, was recently published⁷⁰, and another scoring system for patients with EoD is being developed. Procuring multiple biopsies is essential for the diagnosis (8 gastric biopsies for EoG and 4 duodenal biopsies for EoD)⁷¹, given the patchy nature of these diseases. In addition, ongoing communication with pathologists about EGIDs is essential for timely diagnosis⁷². Treatment approaches for non-EoE EGIDs have included food elimination diets⁷³, systemic corticosteroids and STCs, immunomodulators, or combinations of the above⁷⁴, and more recently biologics, with variable success rate.

Updates on EGID guidelines and clinical trials

There has been an explosion in the number of clinical trials conducted for EGIDs. With the development and validation of clinical outcome metrics, as well as increased knowledge of EGID pathogenesis, multiple agents are in the drug development pipeline and making their way through registration trials (Table 3). There have been notable successes with the clinical trials, including milestone drug approvals, as well as some occasional failures that can serve as learning opportunities. The budesonide oral dispersible tablet was initially approved by the European Medicines Agency (EMA) in 2018⁷⁵, and the U.S. Food and Drug Administration (FDA) approved budesonide oral solution in 2024 after the initial submission in 2021⁸. Dupilumab was FDA-approved for EoE in 2022 for patients 12 years and older⁷, and approved in 2024 for patients 1–11 years old⁷⁶. In contrast, trials of eosinophil-depleting biologics [e.g. lirentelimab (an antibody targeting siglec-8) and benralizumab (an antibody targeting the IL-5rα) led to near complete tissue eosinophil depletion in both EoE and EoG without symptom improvement and with persistent signs of disease activity^{77, 78}. These results suggest that eosinophil depletion alone is not an appropriate endpoint, and that other endpoints should be considered⁶. Finally consensus guidelines have been published to update EGID nomenclature⁷⁹ and for non-EoE EGIDs in children². Additional non-EoE consensus guidelines are being developed for patients of all ages, with a focus on disease chronicity, gastrointestinal eosinophilia, disease complications and associations, and exclusion of alternate causes of tissue eosinophilia.

Table 3.

Selected agents in the EGID drug development pipeline

Study phase	Agent
Phase 1/proof of concept	Injectable long-acting fluticasone Janus kinase inhibitor Anti-IL-15 Losartan Alpha-1 trypsin inhibitor
Phase 2	Mometasone-impregnated membrane Immuno-regulatory protein mTB chaperone 60.1 Sphingosine-1 phosphate modulator (etrasimod) Anti-KIT (barzolvolimab) (ongoing) Anti-IL-5 (mepolizumab; reslizumab)* Anti-IgE (omalizumab)
Phase 3	Budesonide orodispersible tablet Budesonide oral suspension Fluticasone dissolvable tablet (ongoing) Anti-IL-13 (cendakimab) (ongoing) Anti-TSLP (tezepelumab) (ongoing) Anti-IL-4rα (dupilumab) (EoE; EoG – ongoing) Anti-siglec-8 (lirentelimab) (EoE; EoG/EoD)* Anti-IL-5rα (benralizumab) (EoE; EoG)*
Phase 4	Anti-IL-4rα (dupilumab) (ongoing)

^*indicates agents that are no longer being pursued.

Summary

The field of EGIDs is rapidly evolving with new insights into disease mechanisms, promising diagnostics, and novel treatments. Most of what we know about EGID pathophysiology stems from studies of EoE. Early-life exposures (e.g., antibiotics) alter the developing microbiome predisposing to dysbiosis and epithelial barrier dysfunction. The ensuing innate immune response leads to exacerbation of barrier impairment, alteration of antigen presentation, clonal T cell proliferation, and antibody production to innocuous food antigens (e.g., IgG4). Re-exposure to food antigen triggers perpetuates inflammatory pathology, eventually resulting in tissue remodeling and fibrostenosis. Animal models and clinical trials of eosinophil-depleting therapies now suggest that eosinophils may be dispensable to EoE pathogenesis. The relative contribution of other cell types, such as mast cells and T cells, is an area of active discovery. Further, validation of non-invasive biomarkers to assess disease activity and identify food triggers is a major unmet need for all EGIDs and evaluation of antigens-specific T cell responses may fill this gap. Studies of diet elimination approaches suggest a less-restrictive diet (e.g., 1FED) may have similar efficacy to a 6FED. Finally, several agents may suppress the inflammatory response in EoE preventing complications of fibrostenosis.

Some of the key questions that remain including the following: (1) How do early life exposures shape the developing microbiome and how does potential dysbiosis lead to barrier dysfunction and antigen sensitization?; (2) What histologic or blood-based markers correlate better with disease activity than eosinophils?; (3) Why do some patients fail to respond to blockade of IL-4 and IL-13 in a type 2 inflammatory disease, and are there biomarkers that can predict treatment response?; (4) What changes in the epithelial and stromal compartments of the esophagus lead to disease recurrence when anti-inflammatory agents are stopped?

In conclusion, the field of EGIDs has made considerable progress with the development of consensus nomenclature, diagnostic guidelines, and the regulatory approval of two new therapeutic options. Substantial efforts to dissect pathophysiology coupled with multiple clinical trials indicate that we can expect continued progress and better outcomes for patients with EGIDs in the future.

Abbreviations:

BZH

basal zone hyperplasia

CEGIR

Consortium of Eosinophilic Gastrointestinal Disease Researchers

EGID

eosinophilic gastrointestinal disease

EGPA

eosinophilic granulomatous polyangiitis

EMA

European Medicines Agency

EoC

eosinophilic colitis

EoD

eosinophilic duodenitis

EoE

eosinophilic esophagitis

EoG

eosinophilic gastritis

EoE33

IL33 overexpressing transgenic mice

FDA

Food and Drug Administration

FED

food elimination diet

HES

hypereosinophilic syndrome

iEoE33

inducible IL33 overexpressing transgenic mice

ILC2s

group 2 innate lymphoid cells

PassITON

Passive Immunity Trial for Our Nation

peTh2

pathogenic effector Th2 cells

RT-qPCR

reverse transcription-quantitative polymerase chain reaction

scRNA-seq

single cell RNA sequencing

SDS

sodium dodecyl sulfate

STC

swallowed topical corticosteroid

TCR

T cell receptor

TIGERS

The International Gastrointestinal Eosinophil Researchers