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Examining the Role of Type 2 Inflammation in Eosinophilic Esophagitis

Open AccessPublished:May 20, 2022DOI:https://doi.org/10.1016/j.gastha.2022.05.004
      Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease characterized by an eosinophilic inflammatory infiltrate in the esophagus, leading to remodeling, stricture formation, and fibrosis. Triggered by food and aeroallergens, type 2 cytokines interleukin (IL)-4, IL-13, IL-5 produced by CD4+ T helper 2 cells (Th2), eosinophils, mast cells, basophils, and type 2 innate lymphoid cells alter the esophageal epithelial barrier and increase inflammatory cell tissue infiltration. Clustering analysis based on the expression of type 2 inflammatory genes demonstrated the diversity of EoE endotypes. Despite the availability of treatment options for patients with EoE, which include dietary restriction, proton pump inhibitors, swallowed topical steroids, and esophageal dilation, there are still no Food and Drug Administration–approved medications for this disease; as such, there are clear unmet medical needs for these patients. A number of novel biologic therapies currently in clinical trials represent a promising avenue for targeted therapeutic approaches in EoE. This review summarizes our current knowledge on the role of type 2 inflammatory cells and mediators in EoE disease pathogenesis, as well as the future treatment landscape targeting underlying inflammation in EoE.

      Keywords

      Abbreviations used in this paper:

      CAPN14 (calpain 14), CCL (C-C motif ligand), EMT (epithelial mesenchymal transition), EoE (eosinophilic esophagitis), IL (interleukin), ILC2 (type 2 innate lymphoid cells), Ig (immunoglobulin), mRNA (messenger RNA), Siglec8 (sialic acid–binding Ig-like lectin 8), STAT (signal transducer and activator of transcription), TGF-β (transforming growth factor beta), Th (T helper cell), TSLP (thymic stromal lymphopoietin)

      Introduction

      Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease characterized by eosinophilic inflammation of the esophagus, epithelial barrier dysfunction, and esophageal subepithelial fibrosis.
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      Although eosinophils are the histologic diagnostic feature of EoE, multiple immune cell types likely contribute to the complex mechanisms underlying EoE pathophysiology. EoE is characterized by epithelial barrier dysfunction in response to food antigens, leading to immune dysfunction and inflammation involving the type 2 inflammatory cytokines interleukin (IL)-4, IL-5, and IL-13.
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      Given its predominance in EoE pathogenesis, this review will focus on the underlying mechanisms associated with type 2 inflammation in EoE.
      With new targeted therapies in development for the treatment of EoE, better understanding of the underlying disease pathophysiology and the phenotypes and endotypes associated with type 2 inflammation offers the potential for precision medicine approaches in EoE. In this review, we summarize our current understanding of the roles of various type 2 inflammatory cells and cytokines in the pathophysiology of EoE and review the prospective treatment landscape targeting type 2 inflammation in EoE.

      Type 2 Inflammation in EoE

      The immune system is comprised of 2 parts (innate and adaptive) in which the innate immune system acts as a rapid, nonspecific first line of defense against pathogens and environmental insults, followed temporally by the adaptive system, which acts with specificity to provide a more robust and targeted response. The type 1 vs type 2 immunity paradigm was first described in the context of cytokine production from the adaptive T helper 1 (Th1) and T helper 2 (Th2) cell subsets.
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      Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.
      It is now appreciated that the type 1/type 2 paradigm is larger than T cell subsets: type 1 immunity involves interferon-γ production from both innate and adaptive immune cells; type 2 inflammation is driven by the activity of key type 2 cytokines IL-4, IL-5, and IL-13, which are produced by the adaptive and innate arms of the immune system, including Th2 cells, type 2 innate lymphoid cells (ILC2s), mast cells, basophils, and eosinophils, through shared cellular and gene transcriptional activation domains such as GATA-3 transcription factor.
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      IgE, mast cells, basophils, and eosinophils.
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      Allergic mechanisms in eosinophilic esophagitis.
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      • Yoon B.R.
      • et al.
      IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells.
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      Signals from the various immune cells in promoting food allergy-induced eosinophilic esophagitis like disease.
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      The 3 major types of innate and adaptive cell-mediated effector immunity.
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      Recent advances in understanding the Th1/Th2 effector choice.
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      • et al.
      Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.
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      Type 2 immunity in tissue repair and fibrosis.
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      Type 2 inflammation in patients with EoE is characterized by elevated levels of type 2 cytokines IL-4, IL-5, and IL-13
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      • Rodriguez-Jimenez B.
      • et al.
      A striking local esophageal cytokine expression profile in eosinophilic esophagitis.
      ,
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      • Guzek R.
      • et al.
      Elevated expression of activated TH2 cells and milk-specific TH2 cells in milk-induced eosinophilic esophagitis.
      and chemokines such as eotaxin-3 (Table 1).
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      • Rodriguez-Jimenez B.
      • et al.
      A striking local esophageal cytokine expression profile in eosinophilic esophagitis.
      ,
      • Straumann A.
      • Bauer M.
      • Fischer B.
      • et al.
      Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.
      In addition to the presence of eosinophils, elevated levels of Th2, ILC2s, basophils, and mast cells have also been detected in esophageal biopsies from patients with EoE.
      • Doherty T.A.
      • Baum R.
      • Newbury R.O.
      • et al.
      Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.
      ,
      • Cianferoni A.
      • Ruffner M.A.
      • Guzek R.
      • et al.
      Elevated expression of activated TH2 cells and milk-specific TH2 cells in milk-induced eosinophilic esophagitis.
      ,
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      ,
      • Straumann A.
      • Bauer M.
      • Fischer B.
      • et al.
      Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.
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      • et al.
      Involvement of mast cells in eosinophilic esophagitis.
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      • Degen L.
      • et al.
      Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis.
      Furthermore, locally elevated levels of immunoglobulin (Ig) E and IgG4 to shared antigens have also been found in EoE patients.
      • Vicario M.
      • Blanchard C.
      • Stringer K.F.
      • et al.
      Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis.
      ,
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      • Fang J.C.
      • Gleich G.J.
      • et al.
      Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.
      Despite the antigen-driven process associated with EoE that includes IgE-mediated allergic comorbidities, non-IgE-mediated type 2 inflammatory pathways are now recognized as playing pivotal roles in EoE pathogenesis.
      • Greuter T.
      • Hirano I.
      • Dellon E.S.
      Emerging therapies for eosinophilic esophagitis.
      ,
      • Gonsalves N.P.
      • Aceves S.S.
      Diagnosis and treatment of eosinophilic esophagitis.
      ,
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      The genetic etiology of eosinophilic esophagitis.
      Table 1Key Type 2 Cytokines and Chemokines and Their Role in EoE
      Inflammatory mediatorProposed role in EoECitation
      IL-4Differentiation of Th2 cells; secretion of eotaxin-3; B cell class switching to IgE; proliferation and activation of mast cellsDunn 2020
      • Dunn J.L.M.
      • Shoda T.
      • Caldwell J.M.
      • et al.
      Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
      ; Swain 1990
      • Swain S.L.
      • Weinberg A.D.
      • English M.
      • et al.
      IL-4 directs the development of Th2-like helper effectors.
      ; Cheng 2013
      • Cheng E.
      • Zhang X.
      • Huo X.
      • et al.
      Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.
      ; Moore 2002
      • Moore P.E.
      • Church T.L.
      • Chism D.D.
      • et al.
      IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK.
      ; McLeod 2015
      • McLeod J.J.
      • Baker B.
      • Ryan J.J.
      Mast cell production and response to IL-4 and IL-13.
      ; Noti 2013
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      IL-5Involved in eosinophil development, activation, survival, and recruitment; promotes tissue remodelingKouro 2009
      • Kouro T.
      • Takatsu K.
      IL-5- and eosinophil-mediated inflammation: from discovery to therapy.
      ; Mishra 2008
      • Mishra A.
      • Wang M.
      • Pemmaraju V.R.
      • et al.
      Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.
      IL-13Promotes Th2 effector responses; involved in B cell class switching to IgE; eosinophil recruitment; mediates impaired epithelial architecture and barrier dysfunctionCheng 2013
      • Cheng E.
      • Zhang X.
      • Huo X.
      • et al.
      Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.
      ; Muir 2019
      • Muir A.B.
      • Wang J.X.
      • Nakagawa H.
      Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis.
      ; Aceves 2010
      • Aceves S.S.
      • Chen D.
      • Newbury R.O.
      • et al.
      Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction.
      ; Blanchard 2007
      • Blanchard C.
      • Mingler M.K.
      • Vicario M.
      • et al.
      IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids.
      ; Ryu 2020
      • Ryu S.
      • Lee K.H.
      • Tizaoui K.
      • et al.
      Pathogenesis of eosinophilic esophagitis: a comprehensive review of the genetic and molecular aspects.
      IL-25Produced by epithelial cells in response to environmental trigger; activates ILC2sCamelo 2017
      • Camelo A.
      • Rosignoli G.
      • Ohne Y.
      • et al.
      IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells.
      IL-33Produced by epithelial cells in response to environmental trigger; activates ILC2sCamelo 2017
      • Camelo A.
      • Rosignoli G.
      • Ohne Y.
      • et al.
      IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells.
      PeriostinPromotion of eosinophil chemotaxisBlanchard 2008
      • Blanchard C.
      • Mingler M.K.
      • McBride M.
      • et al.
      Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses.
      Eotaxin-3/CCL26Eosinophil chemoattractantBlanchard 2011
      • Blanchard C.
      • Stucke E.M.
      • Rodriguez-Jimenez B.
      • et al.
      A striking local esophageal cytokine expression profile in eosinophilic esophagitis.
      TSLPProduced by epithelial cells in response to environmental trigger; activates ILC2s; mediates basophil responseCamelo 2017
      • Camelo A.
      • Rosignoli G.
      • Ohne Y.
      • et al.
      IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells.
      EosinophilsPresent in esophageal mucosa in EoE; release of eosinophil-associated proteins, including IL-4, IL-13, IL-5, TGF-β, T NFα, and IL-1β amphiregulin and osteopontin; potentially contribute to fibrosisStraumann 2005
      • Straumann A.
      • Kristl J.
      • Conus S.
      • et al.
      Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract.
      ; Doyle 2020
      • Doyle A.D.
      • Masuda M.Y.
      • Kita H.
      • et al.
      Eosinophils in eosinophilic esophagitis: the road to fibrostenosis is paved with good intentions.
      Mast cellsRelease inflammatory mediators, including type 2 cytokines, TGF-β, histamines, and proteases; contribute to smooth muscle dysfunctionAceves 2010
      • Aceves S.S.
      • Chen D.
      • Newbury R.O.
      • et al.
      Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction.
      ; McLeod 2015
      • McLeod J.J.
      • Baker B.
      • Ryan J.J.
      Mast cell production and response to IL-4 and IL-13.
      ; Ryu 2020
      • Ryu S.
      • Lee K.H.
      • Tizaoui K.
      • et al.
      Pathogenesis of eosinophilic esophagitis: a comprehensive review of the genetic and molecular aspects.
      Th2 cellsProduce of type 2 inflammatory cytokines IL-4, IL-5, IL-13Wen 2019
      • Wen T.
      • Aronow B.J.
      • Rochman Y.
      • et al.
      Single cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis.
      ; Cianferoni 2018
      • Cianferoni A.
      • Ruffner M.A.
      • Guzek R.
      • et al.
      Elevated expression of activated TH2 cells and milk-specific TH2 cells in milk-induced eosinophilic esophagitis.
      Type 2 innate lymphoid cells (ILC2s)Produce high levels of L-5 and IL-13; potential role in steroid resistanceDoherty 2015
      • Doherty T.A.
      • Baum R.
      • Newbury R.O.
      • et al.
      Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.
      CCL26, C-C motif chemokine ligand 26; EoE, eosinophilic esophagitis; Ig, immunoglobulin; IL, interleukin; TGF-β, transforming growth factor beta; Th2, T helper cell type 2; TSLP, thymic stromal lymphopoietin.

      Characterization of Endotypes in EoE

      Three distinct endotypes of EoE, with differing levels of type 2 inflammation, have been described in a multisite cross-sectional study of differential gene expression patterns in esophageal biopsies using the esophagitis diagnostic panel.
      • Shoda T.
      • Wen T.
      • Aceves S.S.
      • et al.
      Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study.
      Endotype 1 is characterized by a normal endoscopic appearance, usually steroid sensitive, and has normal levels of type 2 inflammation hallmarks, classified as Th2 low; endotype 2 is seen primarily in pediatric patients and is associated with atopy, lack of a steroid response, and upregulation of pro-inflammatory cytokines (eg, IL-4 and thymic stromal lymphopoietin [TSLP]), classified as Th2 high; endotype 3 is seen primarily in adults, is non-atopic, is associated with fibrostenosis and narrow-caliber esophagus, and is associated with low expression of genes controlling epithelial differentiation, classified as Th2 intermediate (Figure). In a separate study, 5 subgroups of patients with active EoE were identified by unsupervised clustering based on the expression of the type 2 inflammatory genes IL4, IL5, IL13, C-C motif ligand (CCL)26, TSLP, Charcot-Leyden crystal, C-C motif chemokine receptor 3, and carboxypeptidase A3.
      • Dunn J.L.M.
      • Shoda T.
      • Caldwell J.M.
      • et al.
      Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
      Group V patients had the highest expression of IL5, TSLP, CCL26, and genes associated with tissue remodeling; IL5 and IL13 were highly expressed in group IV; groups II and III had intermediate expression of IL5 and carboxypeptidase A3, with high TSLP and IL13 in group III.
      • Dunn J.L.M.
      • Shoda T.
      • Caldwell J.M.
      • et al.
      Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
      The 5 groups varied not only by the expression of type 2 inflammatory genes but also in terms of membership in EoE endotypes 1–3 (Figure). Interestingly, the 3 endotypes had similar levels of esophageal eosinophils, indicating an apparent disconnect between the level of type 2 inflammation and number of eosinophils infiltrating the esophagus
      • Dunn J.L.M.
      • Shoda T.
      • Caldwell J.M.
      • et al.
      Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
      ; this represents a challenge to the clinician in terms of personalizing and optimizing treatment. As these endotypes suggest, heterogenous type 2 gene expression is observed in patients with EoE as a whole; however, the degree of type 2 gene overexpression is not directly correlated with the severity of disease features as defined by peak esophageal eosinophil count (Figure).
      • Dunn J.L.M.
      • Shoda T.
      • Caldwell J.M.
      • et al.
      Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
      These findings may drive the variable responses to currently available therapies and to targeted biologic therapy, emphasizing the clinical importance of understanding the endotypes associated with the type 2 inflammatory pathophysiology of EoE.
      Figure thumbnail gr1
      FigureEndotypes of eosinophilic esophagitis and their characteristic features. (A) Model depicting patient progression from Th2-low phenotype (endotype 1) to a Th2-high phenotype (endotype 2) following allergic or inflammatory insult. On steroid treatment, food elimination, or biologic therapy the Th2-gene expression decreases and patients either resolve inflammation by reverting to a Th2-low phenotype or develop a fibrostenotic (endotype 3) signature. (B) Five subgroups of patients with active EoE were identified based on a variety of criteria, including expression of IL5, IL13, CCL26, TSLP, and CPA3. Relative levels of each criterion are reported in red (high), yellow (intermediate), or green (low). The 5 groups differed in the EoE endotypes spanned, but not in eosinophil levels, which were universally high. Group V patients had the highest expression of IL5, TSLP, CCL26, and genes associated with tissue remodeling. Groups II and III (which exhibited intermediate expression of IL5 and CPA3) were differentiated by high TSLP and IL13 in group III. CCL26, C-C motif chemokine ligand 26; EDP, eosinophilic esophagitis diagnostic panel; EREFS, endoscopic reference score; Th2, T helper cell type 2; TSLP, thymic stromal lymphopoietin (Adapted from J Allergy Clin Immunol: 2020;145:1629–1640.e4.).
      • Dunn J.L.M.
      • Shoda T.
      • Caldwell J.M.
      • et al.
      Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
      There are several lines of evidence to support the paradigm that these endotypes and their associated clinical phenotypes may reflect the natural history of EoE, although further understanding is required to determine how these may be positioned within EoE classification. Distinct differences in clinical presentation and endoscopic findings are seen in pediatric vs adult EoE patients.
      • Gonsalves N.
      Distinct features in the clinical presentations of eosinophilic esophagitis in children and adults: is this the same disease?.
      ,
      • Straumann A.
      • Aceves S.S.
      • Blanchard C.
      • et al.
      Pediatric and adult eosinophilic esophagitis: similarities and differences.
      One study revealed that endoscopically defined inflammatory, fibrostenotic, and mixed EoE phenotypes were associated with distinct clinical characteristics and symptomatology and that for every 10-year increase in age, the odds of having a fibrostenotic phenotype more than doubles.
      • Dellon E.S.
      • Kim H.P.
      • Sperry S.L.
      • et al.
      A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease.
      It is noted, however, that interpretation of this study is limited, given its retrospective nature, which by design only included patients who followed up. The association of fibrostenosis with age suggests that the natural history of EoE may be a progression from an inflammatory to a fibrostenotic disease. However, not all patients may progress at the same rate, and this progression may be related more to the duration of untreated disease than age,
      • Schoepfer A.M.
      • Safroneeva E.
      • Bussmann C.
      • et al.
      Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.
      underscoring the potential importance of rapidly and efficaciously bringing inflammation under control. This concept remains to be further investigated with prospective longitudinal studies.

      Role of Key Type 2 Effector Cells and Inflammatory Mediators in the Pathophysiological Features of EoE

      Eosinophils and Mast Cells

      Eosinophils and mast cells are type 2 effector cells that are similar yet distinct classes of granulocytes, serving critical roles in allergic inflammation.
      • Stone K.D.
      • Prussin C.
      • Metcalfe D.D.
      IgE, mast cells, basophils, and eosinophils.
      Eosinophils and mast cells are both found in the esophageal epithelium of patients with EoE (Table 1) and can persist in some patients despite clinical remission.
      • Straumann A.
      • Kristl J.
      • Conus S.
      • et al.
      Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract.
      ,
      • Strasser D.S.
      • Seger S.
      • Bussmann C.
      • et al.
      Eosinophilic oesophagitis: relevance of mast cell infiltration.
      ,
      • Bolton S.M.
      • Kagalwalla A.F.
      • Arva N.C.
      • et al.
      Mast cell infiltration is associated with persistent symptoms and endoscopic abnormalities despite resolution of eosinophilia in pediatric eosinophilic esophagitis.
      When activated, both eosinophils and mast cells degranulate to release pro-inflammatory mediators (particularly type 2 cytokines) that can contribute to inflammation, remodeling, and fibrosis when dysregulated (Table 1).
      • Ryu S.
      • Lee K.H.
      • Tizaoui K.
      • et al.
      Pathogenesis of eosinophilic esophagitis: a comprehensive review of the genetic and molecular aspects.
      ,
      • Doyle A.D.
      • Masuda M.Y.
      • Kita H.
      • et al.
      Eosinophils in eosinophilic esophagitis: the road to fibrostenosis is paved with good intentions.
      ,
      • Hill D.A.
      • Spergel J.M.
      The immunologic mechanisms of eosinophilic esophagitis.
      The critical role of eosinophils as a mediator of EoE pathophysiology has been demonstrated by several transgenic murine models. Notably, greater basal layer thickening and increased collagen deposition were observed in the epithelial mucosa and lamina propria of mice with experimental EoE compared with experimental controls. Conversely, eosinophil-deficient mice have significantly reduced the thickening of the basal layer and lamina propria collagen and do not develop esophageal strictures.
      • Mishra A.
      • Wang M.
      • Pemmaraju V.R.
      • et al.
      Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.
      ,
      • Mavi P.
      • Rajavelu P.
      • Rayapudi M.
      • et al.
      Esophageal functional impairments in experimental eosinophilic esophagitis.
      Further support for the role played by eosinophils comes from models of egg-induced EoE. These have demonstrated that inhibition of AMCase, an innate immune modulator, or sialic acid–binding immunoglobulin-like lectin (Siglec), a receptor highly expressed by eosinophils, reduces eosinophilic inflammation and esophagus remodeling.
      • Cho J.Y.
      • Rosenthal P.
      • Miller M.
      • et al.
      Targeting AMCase reduces esophageal eosinophilic inflammation and remodeling in a mouse model of egg induced eosinophilic esophagitis.
      ,
      • Rubinstein E.
      • Cho J.Y.
      • Rosenthal P.
      • et al.
      Siglec-F inhibition reduces esophageal eosinophilia and angiogenesis in a mouse model of eosinophilic esophagitis.
      In addition, evidence from an allergen-induced mouse model of EoE demonstrated that mast cells increase under inflammatory conditions, but esophageal eosinophil recruitment was not dependent on the presence of mast cells.
      • Niranjan R.
      • Mavi P.
      • Rayapudi M.
      • et al.
      Pathogenic role of mast cells in experimental eosinophilic esophagitis.
      In addition, mice genetically deficient in mast cells were protected from smooth muscle cell hyperplasia in this model, suggesting that mast cells may impact peristaltic function in EoE.
      • Niranjan R.
      • Mavi P.
      • Rayapudi M.
      • et al.
      Pathogenic role of mast cells in experimental eosinophilic esophagitis.
      Although eosinophils are a defining feature of EoE histopathology,
      • Dellon E.S.
      • Liacouras C.A.
      • Molina-Infante J.
      • et al.
      Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.
      ,
      • Gonsalves N.P.
      • Aceves S.S.
      Diagnosis and treatment of eosinophilic esophagitis.
      peripheral blood eosinophils do not correlate with esophageal eosinophil counts or disease activity. Furthermore, there is a well-described discrepancy between peak esophageal eosinophil counts and symptom severity in adults,
      • Safroneeva E.
      • Straumann A.
      • Coslovsky M.
      • et al.
      Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis.
      ,
      • Pentiuk S.
      • Putnam P.E.
      • Collins M.H.
      • et al.
      Dissociation between symptoms and histological severity in pediatric eosinophilic esophagitis.
      although this may not be the case in children.
      • Aceves S.S.
      • King E.
      • Collins M.H.
      • et al.
      Alignment of parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple CEGIR sites.
      Other measures of disease severity, such as the level of esophageal fibrosis, have been correlated with the extent of esophageal eosinophilic degranulation rather than eosinophil count.
      • Chehade M.
      • Sampson H.A.
      • Morotti R.A.
      • et al.
      Esophageal subepithelial fibrosis in children with eosinophilic esophagitis.
      These observations are important for the clinician who is looking for objective measures to guide clinical decision-making. In addition, given the lack of association between eosinophils and symptomatology, other factors clearly contribute to this observation.

      Type 2 Innate Lymphoid Cells and T Helper 2 Cells

      The type 2 inflammatory cascade in EoE is thought to begin with environmental triggers such as food and/or aero antigens, resulting in epithelial release of the inflammatory alarmin molecules TSLP, IL-25, and IL-33; these in turn activate ILC2s and promote Th2 cell differentiation via effects on APCs, resulting in IL-4, IL-13, and IL-5 production (Table 1).
      • Doherty T.A.
      • Baum R.
      • Newbury R.O.
      • et al.
      Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.
      ,
      • Blanchard C.
      • Mingler M.K.
      • Vicario M.
      • et al.
      IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids.
      ,
      • Mjösberg J.M.
      • Trifari S.
      • Crellin N.K.
      • et al.
      Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.
      ,
      • Sherrill J.D.
      • Gao P.S.
      • Stucke E.M.
      • et al.
      Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis.
      Th2 cells are the dominant population of T cells in EoE pathology, expressing high levels of IL-13, IL-4, and IL-5 (Table 1).
      • Wen T.
      • Aronow B.J.
      • Rochman Y.
      • et al.
      Single cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis.
      ILC2s express high levels of IL-13 and IL-5 (Table 1), are highly enriched in biopsies of patients with active EoE, and are positively correlated with esophageal eosinophil counts.
      • Doherty T.A.
      • Baum R.
      • Newbury R.O.
      • et al.
      Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.
      Interestingly, the production of IL-5 and IL-13 from ILC2s is not sensitive to steroid inhibition and may provide mechanistic insight into steroid resistance in some EoE patients.
      • Lianto P.
      • Zhang Y.
      • Che H.
      Signals from the various immune cells in promoting food allergy-induced eosinophilic esophagitis like disease.
      These Th2- and ILC2-derived type 2 inflammatory cytokines drive a positive feedback loop to promote further inflammation and epithelial barrier dysfunction (Table 1).
      • Sherrill J.D.
      • Kc K.
      • Wu D.
      • et al.
      Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis.
      ,
      • Hill D.A.
      • Spergel J.M.
      The immunologic mechanisms of eosinophilic esophagitis.

      IL-4 and IL-13

      IL-4 and IL-13 are key and central mediators of type 2 inflammation affecting a range of inflammatory cells and downstream mediators (Table 1).
      • Davis B.P.
      • Rothenberg M.E.
      Mechanisms of disease of eosinophilic esophagitis.
      ,
      • Aceves S.S.
      • Chen D.
      • Newbury R.O.
      • et al.
      Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction.
      ,
      • Muir A.B.
      • Wang J.X.
      • Nakagawa H.
      Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis.
      ,
      • Stone K.D.
      • Prussin C.
      • Metcalfe D.D.
      IgE, mast cells, basophils, and eosinophils.
      ,
      • Wechsler J.B.
      • Bryce P.J.
      Allergic mechanisms in eosinophilic esophagitis.
      ,
      • Doherty T.A.
      • Baum R.
      • Newbury R.O.
      • et al.
      Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis.
      ,
      • McLeod J.J.
      • Baker B.
      • Ryan J.J.
      Mast cell production and response to IL-4 and IL-13.
      ,
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      ,
      • Camelo A.
      • Rosignoli G.
      • Ohne Y.
      • et al.
      IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells.
      ,
      • Abonia J.P.
      • Blanchard C.
      • Butz B.B.
      • et al.
      Involvement of mast cells in eosinophilic esophagitis.
      ,
      • Gause W.C.
      • Wynn T.A.
      • Allen J.E.
      Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths.
      • Miller D.E.
      • Forney C.
      • Rochman M.
      • et al.
      Genetic, inflammatory, and epithelial cell differentiation factors control expression of human calpain-14.
      • Ozdemir C.
      • Akdis M.
      • Akdis C.A.
      T-cell response to allergens.
      • Cocks B.G.
      • de Waal Malefyt R.
      • Galizzi J.P.
      • et al.
      IL-13 induces proliferation and differentiation of human B cells activated by the CD40 ligand.
      • Nilsson G.
      • Nilsson K.
      Effects of interleukin (IL)-13 on immediate-early response gene expression, phenotype and differentiation of human mast cells. Comparison with IL-4.
      • Roufousse F.
      Targeting the interleukin-5 pathway for treatment of eosinophilic conditions other than asthma.
      IL-4 and IL-13 share some overlapping features because of shared receptor signaling. The type I heterodimeric IL-4 receptor is comprised of the IL-4Rα subunit paired with the common γ chain, expressed largely on hematopoietic cells. However, IL-4, as well as IL-13, can signal through the type II heterodimeric receptor, the IL-4Rα subunit paired with IL-13Rα1, expressed on nonhematopoietic cells.
      • LaPorte S.L.
      • Juo Z.S.
      • Vaclavikova J.
      • et al.
      Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system.
      A second receptor for IL-13 is IL-13Rα2, previously thought to be a decoy receptor.
      • Arima K.
      • Sato K.
      • Tanaka G.
      • et al.
      Characterization of the interaction between interleukin-13 and interleukin-13 receptors.
      Multiple cell types express IL-4Rα, including mast cells, eosinophils, macrophages, lymphocytes, and epithelial cells. IL-4 and 13 signaling through IL-4Rα activates signal transducer and activator of transcription 6 (STAT6), contributing to Th2 effector function and the production of type 2 cytokines IL-4, IL-5, and IL-13 through GATA3.
      • Gandhi N.A.
      • Pirozzi G.
      • Graham N.M.H.
      Commonality of the IL-4/IL-13 pathway in atopic diseases.
      ,
      • Swain S.L.
      • Weinberg A.D.
      • English M.
      • et al.
      IL-4 directs the development of Th2-like helper effectors.
      ,
      • Zhu J.
      • Guo L.
      • Watson C.J.
      • et al.
      Stat6 is necessary and sufficient for IL-4’s role in Th2 differentiation and cell expansion.
      Both IL-4 and IL-13 upregulate the expression of chemokines, such as eotaxin-3 and periostin, which promote migration and trafficking of inflammatory cells, including eosinophils, to the site of inflammation, contributing to additional inflammatory infiltrate, cytokine production, and tissue remodeling and fibrosis in the context of EoE (Table 1).
      • Davis B.P.
      • Rothenberg M.E.
      Mechanisms of disease of eosinophilic esophagitis.
      ,
      • Stone K.D.
      • Prussin C.
      • Metcalfe D.D.
      IgE, mast cells, basophils, and eosinophils.
      ,
      • Lianto P.
      • Zhang Y.
      • Che H.
      Signals from the various immune cells in promoting food allergy-induced eosinophilic esophagitis like disease.
      ,
      • Miyake K.
      • Karasuyama H.
      Emerging roles of basophils in allergic inflammation.
      IL-4 and IL-13 also contribute to B cell class switching to IgE,
      • Vicario M.
      • Blanchard C.
      • Stringer K.F.
      • et al.
      Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis.
      leading to mast cell and basophil degranulation and the resulting release of pro-inflammatory mediators.
      • Davis B.P.
      • Rothenberg M.E.
      Mechanisms of disease of eosinophilic esophagitis.
      ,
      • Stone K.D.
      • Prussin C.
      • Metcalfe D.D.
      IgE, mast cells, basophils, and eosinophils.
      ,
      • McLeod J.J.
      • Baker B.
      • Ryan J.J.
      Mast cell production and response to IL-4 and IL-13.
      ,
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      ,
      • Abonia J.P.
      • Blanchard C.
      • Butz B.B.
      • et al.
      Involvement of mast cells in eosinophilic esophagitis.
      ,
      • Ozdemir C.
      • Akdis M.
      • Akdis C.A.
      T-cell response to allergens.
      • Cocks B.G.
      • de Waal Malefyt R.
      • Galizzi J.P.
      • et al.
      IL-13 induces proliferation and differentiation of human B cells activated by the CD40 ligand.
      • Nilsson G.
      • Nilsson K.
      Effects of interleukin (IL)-13 on immediate-early response gene expression, phenotype and differentiation of human mast cells. Comparison with IL-4.
      In addition, IL-4 directly activates mast cells leading to their enhanced proliferation and survival, increased type 2 cytokine production, and enhanced mast cell degranulation (Table 1).
      • McLeod J.J.
      • Baker B.
      • Ryan J.J.
      Mast cell production and response to IL-4 and IL-13.
      ,
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      There may also be a role for basophil-derived IL-4 in eosinophil infiltration into tissue.
      • Miyake K.
      • Karasuyama H.
      Emerging roles of basophils in allergic inflammation.
      Elevated IL-4 is observed in blood, in esophageal biopsies, and in esophageal T cells from patients with EoE,
      • Dunn J.L.M.
      • Shoda T.
      • Caldwell J.M.
      • et al.
      Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
      ,
      • Blanchard C.
      • Mingler M.K.
      • Vicario M.
      • et al.
      IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids.
      ,
      • Wen T.
      • Aronow B.J.
      • Rochman Y.
      • et al.
      Single cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis.
      ,
      • Hill D.A.
      • Spergel J.M.
      The immunologic mechanisms of eosinophilic esophagitis.
      highlighting the potential role of this cytokine in EoE pathogenesis, and suggesting IL-4-targeted therapies may be promising for treatment of EoE.
      IL-13 plays a critical role in tissue remodeling, fibrosis, and smooth muscle contractility in EoE, mediated largely through effects on epithelial cells, including the induced expression of proteases and matrix proteins (Table 1).
      • Davis B.P.
      • Rothenberg M.E.
      Mechanisms of disease of eosinophilic esophagitis.
      ,
      • Aceves S.S.
      • Chen D.
      • Newbury R.O.
      • et al.
      Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction.
      ,
      • Muir A.B.
      • Wang J.X.
      • Nakagawa H.
      Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis.
      ,
      • Cheng E.
      • Zhang X.
      • Huo X.
      • et al.
      Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.
      IL-13 contributes to impaired epithelial architecture and barrier dysfunction by inducing calpain 14 (CAPN14), an intracellular calcium-activated protease, more than 100-fold in esophageal epithelial cells.
      • Davis B.P.
      • Rothenberg M.E.
      Mechanisms of disease of eosinophilic esophagitis.
      CAPN14 overexpression is associated with impaired epithelial architecture and barrier dysfunction,
      • Davis B.P.
      • Stucke E.M.
      • Khorki M.E.
      • et al.
      Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment.
      and CAPN14 genetic variants are implicated in very early onset EoE.
      • Lyles J.L.
      • Martin L.J.
      • Shoda T.
      • et al.
      Very early onset eosinophilic esophagitis is common, responds to standard therapy, and demonstrates enrichment for CAPN14 genetic variants.
      In fibroblasts, IL-13 induces the expression of matrix proteins, including collagen, matrix metalloproteases, and periostin.
      • Cheng E.
      • Zhang X.
      • Huo X.
      • et al.
      Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.
      IL-13 may also mediate barrier function by downregulating DSG-1, filaggrin, and involucrin genes important for epithelial integrity.
      • Ryu S.
      • Lee K.H.
      • Tizaoui K.
      • et al.
      Pathogenesis of eosinophilic esophagitis: a comprehensive review of the genetic and molecular aspects.
      Finally, IL-13 promotes epithelial mesenchymal transition (EMT), a process in which polarized epithelial cells transition to a mesenchymal cell phenotype, via transforming growth factor beta (TGF-β), contributing to tissue fibrosis in the context of chronic inflammation.
      • Muir A.B.
      • Wang J.X.
      • Nakagawa H.
      Epithelial-stromal crosstalk and fibrosis in eosinophilic esophagitis.
      ,
      • Cheng E.
      • Zhang X.
      • Huo X.
      • et al.
      Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.
      The process of EMT contributes to the subepithelial fibrosis characteristic of EoE, and in esophageal biopsies from EoE patients, EMT is correlated with the presence of eosinophils and eosinophil peroxidase, TGF-β, and fibrosis.
      • Kagalwalla A.F.
      • Akhtar N.
      • Woodruff S.A.
      • et al.
      Eosinophilic esophagitis: epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment.
      In vivo data support IL-13 as a promising therapeutic target in EoE. IL-13 antibody blockade reduces esophageal eosinophilia in these models.
      • Akei H.S.
      • Mishra A.
      • Blanchard C.
      • et al.
      Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice.
      • Akei H.S.
      • Brandt E.B.
      • Mishra A.
      • et al.
      Epicutaneous aeroallergen exposure induces systemic TH2 immunity that predisposes to allergic nasal responses.
      • Blanchard C.
      • Mishra A.
      • Saito-Akei H.
      • et al.
      Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody (CAT-354).
      • Mishra A.
      • Rothenberg M.E.
      Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.
      Intratracheal delivery of recombinant IL-13 induces epithelial hyperplasia in the esophagus in a manner dependent on both STAT6 and IL-5.
      • Mishra A.
      • Rothenberg M.E.
      Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.
      In mouse models of allergen-induced EoE, mice genetically deficient in IL-13, IL-5, or STAT6 were at least partially protected from disease.
      • Akei H.S.
      • Mishra A.
      • Blanchard C.
      • et al.
      Epicutaneous antigen exposure primes for experimental eosinophilic esophagitis in mice.
      Real-world evidence also supports a role for IL-13 in EoE pathogenesis. IL-13 messenger RNA (mRNA) levels are increased in esophageal biopsies from EoE patients compared with healthy controls,
      • Blanchard C.
      • Mingler M.K.
      • Vicario M.
      • et al.
      IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids.
      and IL-13 expression is significantly elevated in activated eosinophils in the esophagus and intestine of patients with EoE.
      • Straumann A.
      • Kristl J.
      • Conus S.
      • et al.
      Cytokine expression in healthy and inflamed mucosa: probing the role of eosinophils in the digestive tract.
      Experimentally, IL-13 stimulation of esophageal epithelial cells in vitro induces an EoE-specific esophageal transcriptome very similar to that observed in biopsies from EoE patients, suggesting that IL-13 is a fundamental regulator of EoE.
      • Blanchard C.
      • Mingler M.K.
      • Vicario M.
      • et al.
      IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids.
      Both increased IL-13 levels and the EoE transcriptome are largely reversible after steroid treatment in vivo, which acts as a global, nonspecific suppressor of inflammation.
      • Blanchard C.
      • Mingler M.K.
      • Vicario M.
      • et al.
      IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids.
      Taken together, the evidence presented here implicates IL-13 as an important driver of epithelial barrier dysfunction and fibrosis, driving esophageal dysfunction and food impaction, respectively.

      Interleukin-5

      Early in vitro studies indicated a role for IL-5 as an eosinophil-specific differentiation factor.
      • Yamaguchi Y.
      • Suda T.
      • Suda J.
      • et al.
      Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors.
      IL-5 is now appreciated as a critical factor in the maturation, differentiation, and survival of eosinophils.
      • Kouro T.
      • Takatsu K.
      IL-5- and eosinophil-mediated inflammation: from discovery to therapy.
      IL-5 signals through a heterodimeric receptor, consisting of the IL-5Rα chain and the common β chain, to activate Janus kinase-STAT as well as phosphoinositide 3-kinase (extracellular signal-regulated kinase signaling pathways).
      • Dougan M.
      • Dranoff G.
      • Dougan S.K.
      GM-CSF, IL-3, and IL-5 family of cytokines: regulators of inflammation.
      In humans, the IL-5Rα chain is expressed by eosinophils and basophils (Table 1).
      • Kouro T.
      • Takatsu K.
      IL-5- and eosinophil-mediated inflammation: from discovery to therapy.
      Mouse models support a role for IL-5 in EoE (Table 1).
      • Mishra A.
      • Wang M.
      • Pemmaraju V.R.
      • et al.
      Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.
      ,
      • Masterson J.C.
      • McNamee E.N.
      • Hosford L.
      • et al.
      Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis.
      • Mishra A.
      • Hogan S.P.
      • Brandt E.B.
      • et al.
      IL-5 promotes eosinophil trafficking to the esophagus.
      • Mishra A.
      Significance of mouse models in dissecting the mechanism of human eosinophilic gastrointestinal diseases (EGID).
      Experimentally, overexpression of IL-5 in the esophagus leads to elevated local levels of IL-13 and eotaxin-1.
      • Masterson J.C.
      • McNamee E.N.
      • Hosford L.
      • et al.
      Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis.
      Transgenic mice overexpressing IL-5 in T cells have an eosinophilic infiltrate in the esophagus that recapitulates features of human disease such as strictures, supporting a role for IL-5 in fibrostenosis.
      • Mishra A.
      • Hogan S.P.
      • Brandt E.B.
      • et al.
      IL-5 promotes eosinophil trafficking to the esophagus.
      ,
      • Mishra A.
      Significance of mouse models in dissecting the mechanism of human eosinophilic gastrointestinal diseases (EGID).
      In an allergen-induced mouse model of EoE, IL-5-mediated eosinophilia promoted tissue remodeling of the esophagus, including collagen deposition in the mucosa and lamina propria, and thickening of the basal layer.
      • Mishra A.
      • Wang M.
      • Pemmaraju V.R.
      • et al.
      Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia.
      Therefore, IL-5 presents another attractive therapeutic target. Data on the role of IL-5 in EoE in humans come largely from clinical trials, in which monoclonal antibodies were used to target IL-5 and its receptor. These monoclonal antibodies reduced total esophageal eosinophil counts, but clinical improvement was not consistently noted. However, these were studies undertaken before the development of validated patient report outcome measures.
      • Straumann A.
      • Conus S.
      • Grzonka P.
      • et al.
      Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial.
      • Assa’ad A.H.
      • Gupta S.K.
      • Collins M.H.
      • et al.
      An antibody against IL-5 reduces numbers of oesophageal intraepithelial eosinophils in children with eosinophilic esophagitis.
      • Spergel J.M.
      • Rothenberg M.E.
      • Collins M.H.
      • et al.
      Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial.
      • Otani I.M.
      • Anilkumar A.A.
      • Newbury R.O.
      • et al.
      Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis.
      The role of IL-5 as a therapeutic target is currently being investigated (NCT03656380).

      Role of Other Inflammatory Mediators on the Pathophysiologic Features of EoE

      Other mediators have been implicated in the type 2 inflammatory pathways contributing to the pathogenesis of EoE, including periostin, eotaxin-3, IgE, and the alarmin TSLP.
      Periostin is an extracellular matrix protein largely produced by fibroblasts and epithelial cells, which can be induced by TGF-β and IL-13 (Table 1).
      • Blanchard C.
      • Mingler M.K.
      • McBride M.
      • et al.
      Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses.
      As a result of its interaction with extracellular matrix proteins, it may play a role in promoting eosinophil trafficking and adhesion.
      • Hill D.A.
      • Spergel J.M.
      The immunologic mechanisms of eosinophilic esophagitis.
      In a mouse model of allergen-induced esophageal eosinophilia, mice genetically deficient in periostin had increased blood eosinophils levels and decreased eosinophils in the esophagus compared with controls, directly implicating periostin in eosinophil chemotaxis.
      • Blanchard C.
      • Mingler M.K.
      • McBride M.
      • et al.
      Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses.
      Although serum periostin levels are only slightly elevated in EoE patients compared with controls,
      • Dellon E.S.
      • Higgins L.L.
      • Beitia R.
      • et al.
      Prospective assessment of serum periostin as a biomarker for diagnosis and monitoring of eosinophilic oesophagitis.
      periostin expression is increased in the esophageal mucosa of active EoE patients.
      • Politi E.
      • Angelakopoulou A.
      • Grapsa D.
      • et al.
      Filaggrin and periostin expression is altered in eosinophilic esophagitis and normalized with treatment.
      Eotaxin-3 (CCL26) is a potent eosinophil and mast cell chemoattractant (Table 1). In vitro, IL-4 and IL-13 can induce eotaxin-3 expression via STAT6 in esophageal epithelial cells.
      • Cheng E.
      • Zhang X.
      • Huo X.
      • et al.
      Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.
      Eotaxin-3 not only attracts eosinophils but also induces eosinophil activation and degranulation via MAP kinase activation.
      • Kampen G.T.
      • Stafford S.
      • Adachi T.
      • et al.
      Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases.
      Eotaxin signaling is required for the development of EoE in an experimental mouse model.
      • Blanchard C.
      • Wang N.
      • Stringer K.F.
      • et al.
      Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.
      Eotaxin-3 is the most highly expressed gene in esophageal tissue in patients with EoE relative to controls, and mRNA and protein levels of eotaxin-3 correlate with the number of eosinophils and mast cells in tissue.
      • Blanchard C.
      • Wang N.
      • Stringer K.F.
      • et al.
      Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.
      Highlighting the importance of this protein, a single nucleotide polymorphism in the untranslated region of the eotaxin-3 gene is associated with susceptibility to EoE.
      • Blanchard C.
      • Wang N.
      • Stringer K.F.
      • et al.
      Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.
      Esophageal eotaxin-3 mRNA level alone has an 89% sensitivity in distinguishing patients with and without EoE, and circulating eotaxin-3 levels correlate with esophageal eotaxin-3 expression, suggesting its potential utility as a diagnostic biomarker.
      • Blanchard C.
      • Stucke E.M.
      • Rodriguez-Jimenez B.
      • et al.
      A striking local esophageal cytokine expression profile in eosinophilic esophagitis.
      ,
      • Shoda T.
      • Wen T.
      • Caldwell J.M.
      • et al.
      Molecular, endoscopic, histologic, and circulating biomarker-based diagnosis of eosinophilic gastritis: multi-site study.
      The high concurrence of comorbid atopic conditions in EoE suggests a role for IgE in EoE pathophysiology.
      • Simon D.
      • Marti H.
      • Heer P.
      • et al.
      Eosinophilic esophagitis is frequently associated with IgE-mediated allergic airway diseases.
      However, experimental models indicate that EoE can develop in an IgE-independent manner, dependent instead on TSLP-elicited basophils.
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      The anti-IgE antibody omalizumab had limited clinical or histologic effects in EoE patients, further supporting only a peripheral role for IgE in directly impacting disease pathogenesis.
      • Clayton F.
      • Fang J.C.
      • Gleich G.J.
      • et al.
      Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.
      TSLP is a cytokine expressed by epithelial cells and keratinocytes. TSLP can induce activated dendritic cells to express the co-stimulatory molecule OX-40 ligand, a member of the tumor necrosis factor superfamily, which is involved in interactions between dendritic cells and T cells. OX-40 ligand is thought to drive the subsequent polarization of naïve Th cells toward a type 2 phenotype.
      • Ito T.
      • Wang Y.H.
      • Duramad O.
      • et al.
      TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand.
      TSLP also activates ILC2 cells, which also serve as important sources of IL-5 and IL-13 in the type 2 immune cascade (Table 1). TSLP can also induce basophils to express IL-4, particularly in the context of non-IgE type 2 inflammation.
      • Hill D.A.
      • Spergel J.M.
      The immunologic mechanisms of eosinophilic esophagitis.
      Experimentally, TSLP mRNA expression can be induced in primary esophageal epithelial cells in response to toll-like receptor signaling, suggesting the esophageal epithelium is an important source of TSLP in EoE.
      • Sherrill J.D.
      • Gao P.S.
      • Stucke E.M.
      • et al.
      Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis.
      In a mouse model of food antigen-driven EoE, TSLP was required for the development of disease in a manner that was also dependent on basophils, suggesting a role for the TSLP-basophil axis in EoE development.
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      In this model, neutralizing antibodies to TSLP were also effective in treating established EoE.
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      TSLP levels are elevated in esophageal tissue from patients with EoE compared with controls,
      • Noti M.
      • Wojno E.D.
      • Kim B.S.
      • et al.
      Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis.
      ,
      • Rothenberg M.E.
      • Spergel J.M.
      • Sherrill J.D.
      • et al.
      Common variants at 5q22 associate with pediatric eosinophilic esophagitis.
      ,
      • Simon D.
      • Radonjic-Hösli S.
      • Straumann A.
      • et al.
      Active eosinophilic esophagitis is characterized by epithelial barrier defects and eosinophil extracellular trap formation.
      and TSLP is highly expressed in esophageal epithelium in areas infiltrated by basophils.
      • Iwakura N.
      • Fujiwara Y.
      • Tanaka F.
      • et al.
      Basophil infiltration in eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia.
      TSLP therefore contributes to EoE pathophysiology by acting as an upstream regulator of type 2 inflammation and may also have potential as a biomarker.

      Current Therapeutic Options for EoE

      Current treatment options for EoE are limited and have variable rates of remission induction and long-term maintenance therapy.
      • DeBrosse C.W.
      • Franciosi J.P.
      • King E.C.
      • et al.
      Long-term outcomes in pediatric-onset esophageal eosinophilia.
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      • Laserna-Mendieta E.J.
      • Casabona S.
      • Savarino E.
      • et al.
      Efficacy of therapy for eosinophilic esophagitis in real-world practice.
      Although treatment recommendations for eosinophilic esophagitis continue to evolve, first-line approaches in patients with EoE include dietary therapy, proton pump inhibitors (PPIs), and swallowed topical corticosteroids.
      • Dellon E.S.
      • Liacouras C.A.
      • Molina-Infante J.
      • et al.
      Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.
      ,
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      ,
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias A.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      Endoscopic dilation of the esophagus is often performed on patients with advanced disease resulting in esophageal strictures or narrow-caliber esophagus. Dilation is used for stricturing disease, but it does not treat the underlying type 2 inflammation; therefore, repeat dilations may be required because of restricturing.
      • Arias Á.
      • Lucendo A.J.
      Molecular basis and cellular mechanisms of eosinophilic esophagitis for the clinical practice.
      Understanding how each treatment impacts EoE pathophysiology is key to tailoring therapy to EoE patients of different phenotypes or endotypes to increase the chance of therapeutic success.

      Dietary Therapy

      Three main categories of dietary therapy have been described: elemental diets, consisting of exclusive feeding with nonallergenic, amino acid–based formulas
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      ,
      • Arias A.
      • González-Cervera J.
      • Tenias J.M.
      • et al.
      Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis.
      ; empiric diets, based on removal of the 1, 2, 4, or 6 common food antigens (cow’s milk, wheat, egg, soy, peanut/tree nuts, fish/shellfish)
      • Chehade M.
      • Brown S.
      Elimination diets for eosinophilic esophagitis: making the best choice.
      • De Vlieger L.
      • Smolders L.
      • Nuyttens L.
      • et al.
      A clinical perspective on the dietary therapies for pediatric eosinophilic esophagitis: the gap between research and daily practice.
      • Molina-Infante J.
      • Arias Á.
      • Alcedo J.
      • et al.
      Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 study.
      • Wechsler J.B.
      • Schwartz S.
      • Arva N.C.
      • et al.
      A single food milk elimination diet is effective for treatment of eosinophilic esophagitis in children.
      ; and specific food allergy test–directed elimination diets.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias A.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      Specific food allergy testing using standard allergy tests for IgE-mediated reactions is poorly predictive of food triggers in EoE, making test-directed elimination diets the least effective dietary therapy option.
      • Lucendo A.J.
      • Molina-Infante J.
      • Arias A.
      • et al.
      Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults.
      Dietary therapy can eliminate or prevent the need for chronic medication by identifying and removing trigger foods and reducing inflammation systemically rather than locally.
      • Chehade M.
      • Brown S.
      Elimination diets for eosinophilic esophagitis: making the best choice.
      Although empiric dietary therapy options are generally effective in achieving and maintaining EoE remission, they can be challenging to maintain.

      PPI Therapy

      PPI therapy is effective in a subgroup of EoE patients that are clinically indistinguishable from non-PPI responsive patients,
      • Lucendo A.J.
      • Arias Á.
      • Molina-Infante J.
      Efficacy of proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis.
      with a reported pooled histologic response rate of 42%.
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      In responsive patients, PPI therapy is associated with reduced Th2 inflammation, gene expression,
      • Cavalli E.
      • Brusaferro A.
      • Pieri E.S.
      • et al.
      Eosinophilic esophagitis in children: doubts and future perspectives.
      and endoscopic features of fibrosis.
      • Navarro P.
      • Laserna-Mendieta E.J.
      • Guagnozzi D.
      • et al.
      Proton pump inhibitor therapy reverses endoscopic features of fibrosis in eosinophilic esophagitis.
      PPIs have been shown to inhibit Th2-induced eotaxin-3 mRNA and protein expression in esophageal epithelial cells in a mechanism dependent on STAT6,
      • Cheng E.
      • Zhang X.
      • Huo X.
      • et al.
      Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.
      ,
      • Zhang X.
      • Cheng E.
      • Huo X.
      • et al.
      Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells.
      highlighting a novel role for PPIs independent of gastric acid reduction.

      Topical Corticosteroid Therapy

      As in many chronic inflammatory conditions, steroids are a common and effective treatment for many EoE patients.
      • Chuang M.Y.
      • Chinnaratha M.A.
      • Hancock D.G.
      • et al.
      Topical steroid therapy for the treatment of eosinophilic esophagitis (EoE): a systematic review and meta-analysis.
      Swallowed topical corticosteroids induce histologic remission in approximately two-thirds of patients
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      and are generally well tolerated in both short- and long-term studies.
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      ,
      • Andreae D.A.
      • Hanna M.G.
      • Magid M.S.
      • et al.
      Swallowed fluticasone propionate is an effective long-term maintenance therapy for children with eosinophilic esophagitis.
      ,
      • Dellon E.S.
      • Collins M.H.
      • Rothenberg M.E.
      • et al.
      Long-term efficacy and tolerability of RPC4046 in an open-label extension trial of patients with eosinophilic esophagitis.
      A meta-analysis demonstrated no clear trends in symptom reduction with topical steroids.
      • Chuang M.Y.
      • Chinnaratha M.A.
      • Hancock D.G.
      • et al.
      Topical steroid therapy for the treatment of eosinophilic esophagitis (EoE): a systematic review and meta-analysis.
      However, more recent studies report an improvement in dysphagia symptoms.
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      ,
      • Dellon E.S.
      • Collins M.H.
      • Katzka D.A.
      • et al.
      Long-term treatment of eosinophilic esophagitis with budesonide oral suspension.
      Topical corticosteroids may reverse remodeling due to edema or fibrosis; however, alleviation of established fibrosis may require mechanical dilation.
      • Arias Á.
      • Lucendo A.J.
      Molecular basis and cellular mechanisms of eosinophilic esophagitis for the clinical practice.
      ,
      • Lieberman J.A.
      • Morotti R.A.
      • Konstantinou G.N.
      • et al.
      Dietary therapy can reverse esophageal subepithelial fibrosis in patients with eosinophilic esophagitis: a historical cohort.
      EoE is a progressive disease, with long-term challenges that impact patients’ health-related quality of life across multiple parameters. Repeated endoscopies, including those used to establish diagnosis and monitor response to therapy, involve considerable cost.
      • Watts A.
      • Alexander J.A.
      • Gupta S.K.
      Eosinophilic esophagitis: search for noninvasive techniques for long-term monitoring.
      Although each of the currently available therapies is effective to a certain extent, or in a subgroup of patients, significant unmet needs remain, including the ability to predict who will respond to a given therapy, the role and safety of chronic maintenance therapy, and how best to approach patients who fail to respond to a given class of therapy. Importantly, many patients are unable to control their disease with currently available therapies, and significant variation in adherence to guidelines regarding treatment choice and assessment of response have been documented.
      • Peery A.F.
      • Shaheen N.J.
      • Dellon E.S.
      Practice patterns for the evaluation and treatment of eosinophilic oesophagitis.
      • Spergel J.M.
      • Book W.M.
      • Mays E.
      • et al.
      Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States.
      • Huang K.Z.
      • Jensen E.T.
      • Chen H.X.
      • et al.
      Practice pattern variation in pediatric eosinophilic esophagitis in the Carolinas EoE Collaborative: a research model in Community and Academic Practices.
      • Vermeulen B.D.
      • Bogte A.
      • Verhagen M.A.
      • et al.
      Management of eosinophilic esophagitis in daily clinical practice.

      Novel Targeted Therapies

      A variety of novel therapies that target the underlying type 2 inflammatory pathophysiology of EoE detailed previously are now in various stages of development (Tables 1 and 2).
      Table 2Novel Targeted Therapies for EoE
      DrugTargetMOAReference
      OmalizumabIgELowers free IgE levelsClayton 2014
      • Clayton F.
      • Fang J.C.
      • Gleich G.J.
      • et al.
      Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.
      MepolizumabIL-5Stops IL-5 from binding to its receptor on the surface of eosinophils and decreases eosinophil accumulationStraumann 2010
      • Straumann A.
      • Conus S.
      • Grzonka P.
      • et al.
      Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial.
      ; Assa’ad 2011
      • Assa’ad A.H.
      • Gupta S.K.
      • Collins M.H.
      • et al.
      An antibody against IL-5 reduces numbers of oesophageal intraepithelial eosinophils in children with eosinophilic esophagitis.
      ; Otani 2013
      • Otani I.M.
      • Anilkumar A.A.
      • Newbury R.O.
      • et al.
      Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis.
      ReslizumabIL-5Blocks IL-5 signaling on eosinophils and eosinophil accumulationSpergel 2012
      • Spergel J.M.
      • Rothenberg M.E.
      • Collins M.H.
      • et al.
      Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial.
      ; Markowitz 2018
      • Markowitz J.E.
      • Jobe L.
      • Miller M.
      • et al.
      Safety and efficacy of reslizumab for children and adolescents with eosinophilic esophagitis treated for 9 years.
      BenralizumabIL-5 receptor alphaBlocks IL-5 signaling; induces eosinophil apoptosis via NK cell–mediated antibody-dependent cellular cytotoxicityBleecker 2016
      • Bleecker E.R.
      • FitzGerald J.M.
      • Chanez P.
      • et al.
      Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial.
      ; Kolbeck 2010
      • Kolbeck R.
      • Kozhich A.
      • Koike M.
      • et al.
      MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function.
      Cendakimab (RPC4046)IL-13Binds to the IL-13 ligand, inhibits binding to IL-13Rα1 and IL-13Rα2 subunitsHirano 2019
      • Hirano I.
      • Collins M.H.
      • Assouline-Dayan Y.
      • et al.
      RPC4046, a monoclonal antibody against IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis.
      ; Dellon 2021
      • Dellon E.S.
      • Collins M.H.
      • Rothenberg M.E.
      • et al.
      Long-term efficacy and tolerability of RPC4046 in an open-label extension trial of patients with eosinophilic esophagitis.
      DupilumabIL-4 receptor alphaBlocks signaling of IL-4 and IL-13 that contribute to type 2 inflammation in EoEHirano 2020
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      Lirentelimab (AK002)Siglec8Blocks Siglec8 signaling, leading to eosinophil depletion and mast cell inhibitionDellon 2020
      • Dellon E.S.
      • Peterson K.A.
      • Murray J.A.
      • et al.
      Anti-Siglec-8 antibody for eosinophilic gastritis and duodenitis.
      EtrasimodS1P receptorModulates S1P receptor signaling to block lymphocyte trafficking to sites of inflammation
      S1P, sphingosine 1 phosphate; Siglec8, sialic acid–binding Ig-like lectin 8.
      Clinical trials investigating the IL-5-targeting agents mepolizumab and reslizumab, commonly prescribed for asthma, support a role for IL-5 in terms of eosinophil accumulation in the epithelium, including in pediatric patients. However, only a small group of patients achieved complete histologic remission, and clinical improvement was inconsistent. Although mepolizumab and reslizumab were generally well tolerated, small patient numbers and a lack of control groups (only 2 studies were placebo controlled) preclude any definitive conclusions.
      • Straumann A.
      • Conus S.
      • Grzonka P.
      • et al.
      Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial.
      • Assa’ad A.H.
      • Gupta S.K.
      • Collins M.H.
      • et al.
      An antibody against IL-5 reduces numbers of oesophageal intraepithelial eosinophils in children with eosinophilic esophagitis.
      • Spergel J.M.
      • Rothenberg M.E.
      • Collins M.H.
      • et al.
      Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial.
      • Otani I.M.
      • Anilkumar A.A.
      • Newbury R.O.
      • et al.
      Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis.
      A randomized, placebo-controlled, phase 2 study of mepolizumab is currently ongoing (NCT03656380).
      Benralizumab is a humanized anti-IL-5 receptor alpha monoclonal antibody used for the treatment of eosinophilic asthma.
      • Bleecker E.R.
      • FitzGerald J.M.
      • Chanez P.
      • et al.
      Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial.
      Benralizumab acts by blocking IL-5 signaling and also by inducing eosinophil apoptosis via natural killercell–mediated antibody-dependent cellular cytotoxicity.
      • Kolbeck R.
      • Kozhich A.
      • Koike M.
      • et al.
      MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function.
      A randomized, placebo-controlled phase 3 trial of benralizumab in adults and adolescents with EoE without esophageal strictures preventing passage of a standard adult endoscope is currently ongoing (NCT04543409).
      Given the important role of IL-13 in mediating tissue remodeling, fibrosis, and smooth muscle contractility (as discussed in the prior section), several studies have examined the targeting of IL-13 signaling.
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      ,
      • Dellon E.S.
      • Collins M.H.
      • Rothenberg M.E.
      • et al.
      Long-term efficacy and tolerability of RPC4046 in an open-label extension trial of patients with eosinophilic esophagitis.
      ,
      • Hirano I.
      • Collins M.H.
      • Assouline-Dayan Y.
      • et al.
      RPC4046, a monoclonal antibody against IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis.
      ,
      • Rothenberg M.E.
      • Wen T.
      • Greenberg A.
      • et al.
      Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis.
      In a placebo-controlled phase 2 trial, the anti-IL-13 antibody cendakimab (formerly RPC4046) reduced esophageal eosinophil counts and endoscopic and histologic scores at week 16 and week 52 in a long-term open-label extension analysis of adult patients with EoE without esophageal stricture preventing passage of a standard adult endoscope.
      • Dellon E.S.
      • Collins M.H.
      • Rothenberg M.E.
      • et al.
      Long-term efficacy and tolerability of RPC4046 in an open-label extension trial of patients with eosinophilic esophagitis.
      ,
      • Hirano I.
      • Collins M.H.
      • Assouline-Dayan Y.
      • et al.
      RPC4046, a monoclonal antibody against IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis.
      Importantly, comparable responses were observed in both nonsteroid-refractory and steroid-refractory subgroups, suggesting this biologic therapy may be beneficial to this group of patients who currently have no suitable pharmacological options. However, cendakimab did not reduce dysphagia symptom severity and frequency, although the study was not powered to assess these outcomes. Furthermore, the study is potentially limited by the inability of approximately 25% of patients to complete the 52-week long-term extension study. Cendakimab was well tolerated with a consistent safety profile across the induction and long-term extension periods. Most adverse events were mild or moderate, with upper respiratory tract infection (21%) and nasopharyngitis (14%) most commonly reported through week 52.
      • Dellon E.S.
      • Collins M.H.
      • Rothenberg M.E.
      • et al.
      Long-term efficacy and tolerability of RPC4046 in an open-label extension trial of patients with eosinophilic esophagitis.
      ,
      • Hirano I.
      • Collins M.H.
      • Assouline-Dayan Y.
      • et al.
      RPC4046, a monoclonal antibody against IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis.
      A randomized, double-blind, placebo-controlled phase 3 trial of this drug is currently ongoing (NCT04753697).
      As both IL-4 and IL-13 upregulate the expression of chemokines that promote eosinophil migration to the site of inflammation, several studies have investigated the targeting of IL-4/13 signaling in patients with EoE.
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      ,
      • Nicodème F.
      • Hirano I.
      • Chen J.
      • et al.
      Esophageal distensibility as a measure of disease severity in patients with eosinophilic esophagitis.
      In a randomized, placebo-controlled phase 2 trial dupilumab, a fully human monoclonal antibody that inhibits the signaling of the shared receptor component for IL-4 and IL-13, reduced dysphagia, histologic features of disease including esophageal eosinophils, and abnormal esophageal endoscopic features compared with placebo in adults with active EoE and without esophageal stricture preventing passage of a standard endoscope.
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      Dupilumab also increased esophageal distensibility, with reduced distensibility being associated with food impaction and need for dilation, and was generally well tolerated. The most common adverse events reported by patients who received dupilumab or placebo during the 12-week study period were nonserious injection-site erythema (35% and 8%, respectively) and nasopharyngitis (17% and 4%).
      • Hirano I.
      • Dellon E.S.
      • Hamilton J.D.
      • et al.
      Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis.
      ,
      • Nicodème F.
      • Hirano I.
      • Chen J.
      • et al.
      Esophageal distensibility as a measure of disease severity in patients with eosinophilic esophagitis.
      Data from the phase 3 LIBERTY-EoE-TREET study (NCT03633617) demonstrate that patients who received dupilumab achieved clinically meaningful improvements in histologic, symptomatic, and endoscopic aspects of EoE at week 24, which were sustained to week 52, with an acceptable safety profile.
      • Dellon E.S.
      • Rothernberg M.E.
      • Collins M.H.
      • et al.
      Dupilumab efficacy and safety up to 52 weeks in adult and adolescent patients with eosinophilic esophagitis: results from part a and c of a randomized, placebo-controlled, three-part, phase 3 liberty eoe treet study.
      Placebo-treated patients who switched to dupilumab experienced similar outcomes to dupilumab-treated patients. These findings were confirmed in a larger sample size of adolescents and adults with EoE.

      Rothenberg M, Dellon E, Bredenoord A, et al. Dupilumab improves clinical and histologic aspects of disease in adult and adolescent patients with eosinophilic esophagitis at week 24: results from part B of the 3-part LIBERTY EoE TREET study. Presented at: AAAAI 2022 Annual Meeting; February 25-28, 2022; Phoenix, Arizona. Abstract L02.

      ,

      Hirano I, Dellon E, Collins M, et al. Dupilumab reduces biomarkers of type 2 inflammation in adult and adolescent patients with eosinophilic esophagitis: results from parts A and C of a three-part, phase 3 LIBERTY EoE TREET study. Presented at: AAAAI 2022 Annual Meeting; February 25-28, 2022; Phoenix, Arizona. Abstract 633.

      In addition, a separate randomized, placebo-controlled phase 3 study in pediatric patients with active EoE (NCT04394351) is ongoing.
      Lirentelimab, (AK002), is an investigational, monoclonal antibody targeting Siglec8, a cell-surface protein expressed exclusively on eosinophils and mast cells
      • Dellon E.S.
      • Peterson K.A.
      • Murray J.A.
      • et al.
      Anti-Siglec-8 antibody for eosinophilic gastritis and duodenitis.
      that leads to eosinophil depletion and mast cell stabilization. In a recent phase 2 placebo-controlled trial of AK002 in adult patients with eosinophilic gastritis and/or eosinophilic duodenitis, a subset of patients had concurrent EoE that improved with therapy. Lirentelimab was well tolerated, although higher rates of mild-to-moderate infusion-related reactions were reported in the lirentelimab vs placebo group (60% vs 23%, respectively). Other common adverse events were flushing, feeling of warmth, and headache.
      • Dellon E.S.
      • Peterson K.A.
      • Murray J.A.
      • et al.
      Anti-Siglec-8 antibody for eosinophilic gastritis and duodenitis.
      A randomized, placebo-controlled phase 2/3 trial evaluating lirentelimab in adults and adolescents with EoE is currently underway (NCT04322708).
      Etrasimod is an investigational, oral selective sphingosine 1 phosphate receptor modulator being developed for the treatment of inflammatory and immune-mediated disease and acts, in part, by blocking lymphocyte trafficking to sites of inflammation. Etrasimod is being evaluated in a randomized, placebo-controlled phase 2 trial of adults with EoE (NCT04682639).
      Evidence from clinical trials interrogating pathways of type 2 inflammation suggest that histologic improvement alone, that is, reduction in esophageal-associated eosinophils, may be insufficient to address the complex underlying pathophysiology of EoE and reduce clinical symptoms.
      • Straumann A.
      • Conus S.
      • Grzonka P.
      • et al.
      Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial.
      • Assa’ad A.H.
      • Gupta S.K.
      • Collins M.H.
      • et al.
      An antibody against IL-5 reduces numbers of oesophageal intraepithelial eosinophils in children with eosinophilic esophagitis.
      • Spergel J.M.
      • Rothenberg M.E.
      • Collins M.H.
      • et al.
      Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial.
      • Otani I.M.
      • Anilkumar A.A.
      • Newbury R.O.
      • et al.
      Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis.
      This may reflect differences in eosinophil homing vs activation vs differentiation.

      Conclusion

      EoE is a complex disease, with multiple phenotypes and endotypes emerging that are associated with type 2 inflammation and that may reflect the natural history of EoE disease progression. Although eosinophils are a hallmark feature of the disease, their roles in disease activity and progression remain unclear. Current treatment options, while effective for some patients, leave many with incompletely controlled disease and persistent symptoms. With promising therapeutic options in the pipeline, there is a need for a greater understanding of the underlying inflammatory pathophysiology of EoE and endotypes to enable precision medicine approaches and better tailor treatment for this complex and burdensome disease.

      Acknowledgments:

      The authors would like to thank Linda Williams from Regeneron Pharmaceuticals Inc, and Melissa Auclair, Ledia Goga, and Lila Glotfelty from Sanofi. Research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Medical writing/editorial assistance was provided by Joseph Worrall, PhD, of Excerpta Medica, and was funded by Sanofi and Regeneron Pharmaceuticals, Inc, according to the Good Publication Practice guideline.

      Authors' Contributions:

      Mirna Chehade, Gary W. Falk, Jason K. Lee, Vinay Mehta, John Leung, Seema Aceves, Brad Shumel, Juby A. Jacob-Nara, Yamo Deniz, Paul J. Rowe, Danen Cunoosamy, and Angela Khodzhayev contributed to the concept and design of this review, interpreted the literature, provided critical feedback on the manuscript, approved the final manuscript for submission, and were accountable for the accuracy and integrity of the article.

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