Scientific journey to the first FDA-approved drug for eosinophilic esophagitis
2022; Elsevier BV; Volume: 150; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2022.09.027
ISSN1097-6825
Autores Tópico(s)IL-33, ST2, and ILC Pathways
ResumoWhen eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid–based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus. When eosinophilia was first associated with esophagitis, it was thought to reflect gastroesophageal reflux disease, especially given the efficacy of reflux medications to abate esophageal eosinophilia in many individuals. Subsequent studies demonstrated disease remittance with amino acid–based formulas and conversely induction of esophageal eosinophilia in mice following allergen challenge. These results, along with the finding that proton pump inhibitors alleviated esophageal eosinophilia by an anti-inflammatory mechanism, turned attention away from an acid-induced pathogenesis and established eosinophilic esophagitis (EoE) as a separate disease entity driven by allergic inflammation. The disease underpinnings were elucidated by analysis of esophageal transcriptomic profiling, revealing gene signatures orchestrated by type 2 cytokine signaling, mainly IL-13. Preclinical studies showed that IL-13 overproduction was sufficient to induce EoE-like changes in mice and human ex vivo systems and conversely that inhibiting IL-13 signaling attenuated these processes. An early proof-of-principle study with a humanized anti–IL-13 mAb in patients with EoE revealed correction of the EoE transcriptome and attenuation of esophageal eosinophilia, providing a rationale for advancing anti–type 2 cytokine therapy for EoE. Dupilumab, a precision therapeutic mAb that blocks the shared IL-13 and IL-4 receptor, is the first drug to advance through clinical trials and receive US Food and Drug Administration approval for EoE. The ability of dupilumab to improve clinical, histologic, endoscopic, and molecular features of EoE and garner US Food and Drug Administration approval is a victory for science, rare diseases, patients, and advocacy and provides a framework for developing additional EoE treatments and approved treatments for eosinophilic gastrointestinal disease beyond the esophagus. The main tissue reservoir for eosinophils is the gastrointestinal tract, yet the esophagus is the only gastrointestinal segment devoid of eosinophils.1Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1278) Google Scholar As such, detection of esophageal eosinophilia nearly always denotes pathology.2Weller P.F. Spencer L.A. Functions of tissue-resident eosinophils.Nat Rev Immunol. 2017; 17: 746-760Crossref PubMed Scopus (300) Google Scholar When I was in training, the early views were that esophageal eosinophilia was diagnostic for gastroesophageal reflux disease.3Winter H.S. Madara J.L. Stafford R.J. Grand R.J. Quinlan J.E. Goldman H. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis.Gastroenterology. 1982; 83: 818-823Abstract Full Text PDF PubMed Scopus (407) Google Scholar However, the finding that the proximal esophagus was prominently involved and the subsequent ability of amino acid–based formulas to reduce esophageal eosinophilia prompted consideration of a nonallergic disease etiology, perhaps involving glucocorticoid-responsive immunologic hypersensitivity to food.4Kelly K.J. Lazenby A.J. Rowe P.C. Yardley J.H. Perman J.A. Sampson H.A. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.Gastroenterology. 1995; 109: 1503-1512Abstract Full Text PDF PubMed Scopus (918) Google Scholar, 5Furuta G.T. Eosinophils in the esophagus: acid is not the only cause.J Pediatr Gastroenterol Nutr. 1998; 26: 468-471Crossref PubMed Scopus (56) Google Scholar, 6Liacouras C.A. Wenner W.J. Brown K. Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids.J Pediatr Gastroenterol Nutr. 1998; 26: 380-385Crossref PubMed Scopus (463) Google Scholar, 7Walsh S.V. Antonioli D.A. Goldman H. Fox V.L. Bousvaros A. Leichtner A.M. et al.Allergic esophagitis in children: a clinicopathological entity.Am J Surg Pathol. 1999; 23: 390-396Crossref PubMed Scopus (214) Google Scholar A definitive role for allergic inflammation in the etiology of eosinophilic esophagitis (EoE) was supported by our finding that allergen exposure in mice was sufficient to experimentally induce an EoE-like response.8Mishra A. Hogan S.P. Brandt E.B. Rothenberg M.E. An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest. 2001; 107: 83-90Crossref PubMed Scopus (544) Google Scholar Disease pathology was eotaxin and IL-5 dependent, and an intimate connection between respiratory and esophageal inflammation was demonstrated. In parallel, clinical studies suggested the involvement of T cells and IL-5 in human esophageal biopsy specimens from patients with EoE.9Straumann A. Bauer M. Fischer B. Blaser K. Simon H.U. Idiopathic eosinophilic esophagitis is associated with a TH2-type allergic inflammatory response.J Allergy Clin Immunol. 2001; 108: 954-961Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar These collective findings shifted attention away from an acid-induced mechanism to the role of type 2 immunity. Our early work demonstrated that intratracheal delivery of IL-13 was sufficient to induce esophageal eosinophilia in mice.10Mishra A. Rothenberg M.E. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.Gastroenterology. 2003; 125: 1419-1427Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar The effect of IL-13 was dose and concentration dependent; it involved a mechanism dependent on STAT6, IL-5, and eotaxin-1 and was relatively specific, as other cytokines tested (IL-4, IL-9, and IL-10) did not elicit this response.10Mishra A. Rothenberg M.E. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.Gastroenterology. 2003; 125: 1419-1427Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar Conversely, we showed that allergen-induced experimental EoE was attenuated in mice engineered to be deficient in these type 2 cytokines and/or stat6.11Akei H.S. Brandt E.B. Mishra A. Strait R.T. Finkelman F.D. Warrier M.R. et al.Epicutaneous aeroallergen exposure induces systemic TH2 immunity that predisposes to allergic nasal responses.J Allergy Clin Immunol. 2006; 118: 62-69Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Putting these murine findings together, we then demonstrated that a human anti–human IL-13 mAb (CAT-354) could reverse EoE-like changes induced by human IL-13 in mice.12Blanchard C. Mishra A. Saito-Akei H. Monk P. Anderson I. Rothenberg M.E. Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody (CAT-354).Clin Exp Allergy. 2005; 35: 1096-1103Crossref PubMed Scopus (172) Google Scholar CAT-354 is now approved for atopic dermatitis under the name tralokinumab.13Duggan S. Tralokinumab: first approval.Drugs. 2021; 81: 1657-1663Crossref PubMed Scopus (23) Google Scholar Furthermore, we discovered that mice genetically engineered to overexpress IL-13 using a lung promoter developed profound EoE-like changes.14Zuo L. Fulkerson P.C. Finkelman F.D. Mingler M. Fischetti C.A. Blanchard C. et al.IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway.J Immunol. 2010; 185: 660-669Crossref PubMed Scopus (173) Google Scholar IL-13 kinetically accumulated in the esophagus of these mice (following induction of transgene expression), and over the course of only several weeks, it was associated with esophageal eosinophilia, epithelial hyperplasia, collagen deposition, and angiogenesis, features that occur in human EoE (Fig 1). Interestingly, the effect of IL-13 was so profound that there were visible changes of esophageal edema and lengthening of the esophageal circumference, reminiscent of the gross endoscopic findings seen in patients with EoE. Mechanistically, esophageal eosinophilia was eotaxin-1–dependent, but interestingly, both eosinophils and eotaxin-1 were dispensable for the pathologic features of the disease, consistent with subsequent studies, which have so far failed to demonstrate clinical benefit of anti-eosinophil therapy in human EoE.15Assa'ad A.H. Gupta S.K. Collins M.H. Thomson M. Heath A.T. Smith D.A. et al.An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis.Gastroenterology. 2011; 141: 1593-1604Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar,16Spergel J.M. Rothenberg M.E. Collins M.H. Furuta G.T. Markowitz J.E. Fuchs 3rd, G. et al.Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2012; 129 (63.e1-3): 456-463Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar Furthermore, the activity of proton pump inhibitors in EoE was recognized to work by a mechanism beyond inhibiting acid production and instead by a mechanism mediated by its anti-inflammatory effect, including by inhibiting eotaxin production, and it was most recently demonstrated to be mediated by the aryl hydrocarbon receptor.17Zhang X. Cheng E. Huo X. Yu C. Zhang Q. Pham T.H. et al.Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells.PLoS One. 2012; 7e50037Google Scholar, 18Cheng E. Zhang X. Huo X. Yu C. Zhang Q. Wang D.H. et al.Omeprazole blocks eotaxin-3 expression by oesophageal squamous cells from patients with eosinophilic oesophagitis and GORD.Gut. 2013; 62: 824-832Crossref PubMed Scopus (236) Google Scholar, 19Rochman M. Xie Y.M. Mack L. Caldwell J.M. Klingler A.M. Osswald G.A. et al.Broad transcriptional response of the human esophageal epithelium to proton pump inhibitors.J Allergy Clin Immunol. 2021; 147: 1924-1935Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Collectively, these studies drew significant attention to the role of type 2 immunity, particularly IL-13, in the potential pathoetiology of EoE. Furthermore, these studies suggested that eosinophils may be a byproduct of the type 2 immune response rather than a key orchestrator of esophageal pathobiology. These studies focused attention on the epithelial expression and signaling of the IL-13 receptor, composed of the type 2 IL-4 receptor (IL-4 receptor α-chain [IL-4Rα] and IL-13Rα1), and IL-13Rα2, the latter being inhibitory in the esophagus (Fig 2).14Zuo L. Fulkerson P.C. Finkelman F.D. Mingler M. Fischetti C.A. Blanchard C. et al.IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway.J Immunol. 2010; 185: 660-669Crossref PubMed Scopus (173) Google ScholarFig 2Schematic diagram of IL-4 and IL-13 receptors and the impact of dupilumab. IL-4 and IL-13 receptors and the effect of dupilumab as an antibody that blocks IL-4Rα are shown. The IL-4 receptor is composed of 2 transmembrane proteins. IL-4Rα binds IL-4 with high affinity, leading to dimerization with either the common γ-chain (γC) or IL-13Rα1, forming the type I or type II receptor complex, respectively. IL-13 binds to IL-13Rα1 with lower affinity, followed by heterodimerization with IL-4Rα to form a high-affinity complex. IL-13 also binds to IL-13Rα2, which is thought to serve as a "decoy receptor" in the esophagus. The interaction of the receptor components with the Janus kinase (JAK) signaling molecules is shown.View Large Image Figure ViewerDownload Hi-res image Download (PPT) EoE provided an opportunity to probe human allergic inflammation at a level not previously achieved, as biopsy specimens were readily available for research investigation. Prior studies had primarily researched biologic specimens from a remote tissue (the blood), difficult-to-obtain bronchoalveolar lavage fluid, or biopsy specimens from the lung or skin. The ability to safely and routinely obtain millimeter-sized endoscopic biopsy specimens from the esophagus, even from children, allowed us to apply early genome-wide expression profiling technologies to study human allergic inflammation.20Blanchard C. Wang N. Stringer K.F. Mishra A. Fulkerson P.C. Abonia J.P. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (740) Google Scholar Computational analysis of more than 50,000 esophageal transcripts identified dysregulated expression of approximately 1% of the human genome in active biopsy specimens. I was convinced of the value of this approach when our initial analysis discovered that eotaxin-3, a potent chemoattractant and activating factor for eosinophils, was the most upregulated gene in the whole human genome in the esophagus of patients with active disease.20Blanchard C. Wang N. Stringer K.F. Mishra A. Fulkerson P.C. Abonia J.P. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (740) Google Scholar We were struck by the finding that the EoE transcriptome was enriched for known IL-13–regulated genes, including eotaxin-3. Using primary esophageal epithelial cells derived from EoE biopsy specimens (or an immortalized esophageal epithelial cell line), we were able to show that this single cytokine (IL-13) was sufficient to induce a substantial segment of the EoE transcriptome ex vivo, including eotaxin-3 as the most strongly upregulated gene.21Blanchard C. Stucke E.M. Burwinkel K. Caldwell J.M. Collins M.H. Ahrens A. et al.Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis.J Immunol. 2010; 184: 4033-4041Crossref PubMed Scopus (237) Google Scholar IL-13 was sufficient not only to induce many of the EoE transcripts but also to downregulate esophageal epithelial barrier function, including loss of filaggrin and desmosome genes,21Blanchard C. Stucke E.M. Burwinkel K. Caldwell J.M. Collins M.H. Ahrens A. et al.Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis.J Immunol. 2010; 184: 4033-4041Crossref PubMed Scopus (237) Google Scholar, 22Sherrill J.D. Kc K. Wu D. Djukic Z. Caldwell J.M. Stucke E.M. et al.Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis.Mucosal Immunol. 2014; 7: 718-729Crossref PubMed Scopus (214) Google Scholar, 23Wu L. Oshima T. Li M. Tomita T. Fukui H. Watari J. et al.Filaggrin and tight junction proteins are crucial for IL-13-mediated esophageal barrier dysfunction.Am J Physiol Gastrointest Liver Physiol. 2018; 315: G341-G350Crossref PubMed Scopus (31) Google Scholar processes that are germane to the pathoetiology and genetic susceptibility of EoE.24Shoda T. Kaufman K.M. Wen T. Caldwell J.M. Osswald G.A. Purnima P. et al.Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis.Nat Commun. 2021; 12: 6795Crossref PubMed Scopus (18) Google Scholar The ability to recapitulate the human EoE transcriptome with a single cytokine (IL-13) and a single cell type (esophageal epithelial cells) provided the framework for the eventual view that EoE pathogenesis involved the central interplay of adaptive IL-13+ memory T cells with innate IL-13Rα1+epithelial immunity.25Wen T. Aronow B.J. Rochman Y. Rochman M. Kc K. Dexheimer P.J. et al.Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis.J Clin Invest. 2019; 129: 2014-2028Crossref PubMed Scopus (103) Google Scholar,26Rothenberg M.E. Wen T. Shik D. Cole E.T. Mingler M.M. Munitz A. IL-13 receptor alpha1 differentially regulates aeroallergen-induced lung responses.J Immunol. 2011; 187: 4873-4880Crossref PubMed Scopus (28) Google Scholar Indeed, genome-wide association studies have revealed that the chief EoE susceptibility loci are located at 2p23 and 5q22, regions that encode for the key epithelial gene products calpain-14 and thymic stromal lymphopoietin, respectively.27Rothenberg M.E. Spergel J.M. Sherrill J.D. Annaiah K. Martin L.J. Cianferoni A. et al.Common variants at 5q22 associate with pediatric eosinophilic esophagitis.Nat Genet. 2010; 42: 289-291Crossref PubMed Scopus (369) Google Scholar, 28Kottyan L.C. Davis B.P. Sherrill J.D. Liu K. Rochman M. Kaufman K. et al.Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.Nat Genet. 2014; 46: 895-900Crossref PubMed Scopus (218) Google Scholar, 29Sleiman P.M. Wang M.L. Cianferoni A. Aceves S. Gonsalves N. Nadeau K. et al.GWAS identifies four novel eosinophilic esophagitis loci.Nat Commun. 2014; 5: 5593Crossref PubMed Scopus (163) Google Scholar, 30Kottyan L.C. Trimarchi M.P. Lu X. Caldwell J.M. Maddox A. Parameswaran S. et al.Replication and meta-analyses nominate numerous eosinophilic esophagitis risk genes.J Allergy Clin Immunol. 2021; 147: 255-266Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Calpain-14 is esophageal specific; it regulates barrier function, and importantly, it is transcriptionally activated by IL-13 at extraordinary levels comparable to the activation levels of eotaxin-3.28Kottyan L.C. Davis B.P. Sherrill J.D. Liu K. Rochman M. Kaufman K. et al.Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.Nat Genet. 2014; 46: 895-900Crossref PubMed Scopus (218) Google Scholar,31Miller D.E. Forney C. Rochman M. Cranert S. Habel J. Rymer J. et al.Genetic, inflammatory, and epithelial cell differentiation factors control expression of human calpain-14.G3 (Bethesda). 2019; 9: 729-736Crossref PubMed Scopus (15) Google Scholar Thymic stromal lymphopoietin is a key pro-atopy alarmin released from breached epithelial cells and is overproduced in the esophagus of patients with EoE.27Rothenberg M.E. Spergel J.M. Sherrill J.D. Annaiah K. Martin L.J. Cianferoni A. et al.Common variants at 5q22 associate with pediatric eosinophilic esophagitis.Nat Genet. 2010; 42: 289-291Crossref PubMed Scopus (369) Google Scholar,32Blanchard C. Mingler M.K. Vicario M. Abonia J.P. Wu Y.Y. Lu T.X. et al.IL-13 involvement in eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids.J Allergy Clin Immunol. 2007; 120: 1292-1300Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar,33Shoda T. Wen T. Caldwell J.M. Ben-Baruch Morgenstern N. Osswald G.A. Rochman M. et al.Loss of endothelial TSPAN12 promotes fibrostenotic eosinophilic esophagitis via endothelial cell-fibroblast crosstalk.Gastroenterology. 2022; 162: 439-453Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Recent single-cell RNA sequencing analysis of esophageal biopsy specimens, particularly focused on T cells and mast cells, localized IL-13 production to pathogenic effector memory IL-5+IL-13+ CD4+ T cells, which also express the free fatty acid receptor (FFAR3) and GPR15, as well as esophageal resident mast cells.25Wen T. Aronow B.J. Rochman Y. Rochman M. Kc K. Dexheimer P.J. et al.Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis.J Clin Invest. 2019; 129: 2014-2028Crossref PubMed Scopus (103) Google Scholar,34Morgan D.M. Ruiter B. Smith N.P. Tu A.A. Monian B. Stone B.E. et al.Clonally expanded, GPR15-expressing pathogenic effector TH2 cells are associated with eosinophilic esophagitis.Sci Immunol. 2021; 6Crossref Scopus (35) Google Scholar,35Ben-Baruch Morgenstern N. Ballaban A.Y. Wen T. Shoda T. Caldwell J.M. Kliewer K. et al.Single-cell RNA sequencing of mast cells in eosinophilic esophagitis reveals heterogeneity, local proliferation, and activation that persists in remission.J Allergy Clin Immunol. 2022; 149: 2062-2077Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Furthermore, we have shown that IL-13 is able to directly mediate other features of EoE in vitro, including esophageal epithelial cell proliferation, loss of esophageal epithelial differentiation, and profibrotic processes in esophageal endothelial cells, including loss of tetraspan protein 12 (TSPAN12).21Blanchard C. Stucke E.M. Burwinkel K. Caldwell J.M. Collins M.H. Ahrens A. et al.Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis.J Immunol. 2010; 184: 4033-4041Crossref PubMed Scopus (237) Google Scholar,33Shoda T. Wen T. Caldwell J.M. Ben-Baruch Morgenstern N. Osswald G.A. Rochman M. et al.Loss of endothelial TSPAN12 promotes fibrostenotic eosinophilic esophagitis via endothelial cell-fibroblast crosstalk.Gastroenterology. 2022; 162: 439-453Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar,36Rochman M. Travers J. Miracle C.E. Bedard M.C. Wen T. Azouz N.P. et al.Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis.J Allergy Clin Immunol. 2017; 140 (e3): 738-749Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar These collective human translational findings, buttressed with the preclinical murine findings, provided substantial evidence for the key role of IL-13 in the development of EoE. To prove the theory that EoE was mediated, at least in part, by IL-13, I convinced a pharmaceutical company to allow us to study their humanized anti-human IL-13 mAb (QAX576) in patients with EoE. In a single-site study, we treated 23 adult patients with EoE with 3 intravenous doses of QAX576 or placebo over the course of 3 months.37Rothenberg M.E. Wen T. Greenberg A. Alpan O. Enav B. Hirano I. et al.Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis.J Allergy Clin Immunol. 2015; 135: 500-507Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar Patients treated with the drug had statistically reduced esophageal eosinophilia and a trend for improved symptoms, although a non–disease-specific patient-reported outcome metric was used to measure symptoms (the Mayo Dysphagia Questionnaire). At the same time, we examined the EoE transcriptome before and after treatment and were impressed by the profound reversibility of the molecular markers of the disease, even 6 months after cessation of drug therapy. This allowed us to construct a functional map of IL-13–dependent nodes in humans within the context of allergic esophageal inflammation. This map was notably enriched in chemokines, proteases, barrier function, mast cell signature genes, and tissue remodeling pathways, which we attributed to IL-13–induced responses (Fig 3). This relatively small-scale, single-site study, which was carefully planned to examine key molecular biomarkers, provided the proof-of-principle that would propel multiple pharmaceutical companies to pursue larger-scale and eventual registration trials with their relevant drugs. Motivated by the need to find answers for their children with eosinophil-associated gastrointestinal diseases, several patient advocacy groups (PAGs) were formed in the United States; they included the American Partnership for Eosinophilic Diseases, Campaign Urging Research for Eosinophilic Diseases, and Eosinophil Family Coalition. These groups have been essential in raising awareness about EoE and related eosinophilic diseases, providing education about these diseases (through their websites, meetings, and media), raising substantial research funds, and promoting legislation (such as medical formula insurance coverage and enactment of National Eosinophil Awareness Week by the US Congress). Medical researchers, PAGs, and other key stakeholders in the EoE field were successful in establishing the Consortium of Eosinophilic Gastrointestinal Disease Researchers, which has been part of the Rare Diseases Clinical Research Network supported by the National Institutes of Health.38Cheng K. Gupta S.K. Kantor S. Kuhl J.T. Aceves S.S. Bonis P.A. et al.Creating a multi-center rare disease consortium - the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).Transl Sci Rare Dis. 2017; 2: 141-155PubMed Google Scholar,39Gupta S.K. Falk G.W. Aceves S.S. Chehade M. Collins M.H. Dellon E.S. et al.Consortium of Eosinophilic Gastrointestinal Disease Researchers: advancing the field of eosinophilic GI disorders through collaboration.Gastroenterology. 2019; 156: 838-842Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Leading clinical investigators, nearly all of whom are associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers, developed key clinical outcome metrics that have provided clinical trial readiness tools for EoE trials. These tools included the following: consensus guidelines for diagnosing EoE (a peak eosinophil count of ≥15 cells/hpf)40Liacouras C.A. Furuta G.T. Hirano I. Atkins D. Attwood S.E. Bonis P.A. et al.Eosinophilic esophagitis: updated consensus recommendations for children and adults.J Allergy Clin Immunol. 2011; 128 (e6; quiz 1-2): 3-20Abstract Full Text Full Text PDF PubMed Scopus (1658) Google Scholar; validated symptom measurement tools, such as the Dysphagia Symptom Questionnaire41Dellon E.S. Irani A.M. Hill M.R. Hirano I. Development and field testing of a novel patient-reported outcome measure of dysphagia in patients with eosinophilic esophagitis.Aliment Pharmacol Ther. 2013; 38: 634-642Crossref PubMed Scopus (116) Google Scholar,42Dellon E.S. Liacouras C.A. Molina-Infante J. Furuta G.T. Spergel J.M. Zevit N. et al.Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference.Gastroenterology. 2018; 155 (e10): 1022-1033Abstract Full Text Full Text PDF PubMed Scopus (624) Google Scholar and Pediatric EoE Symptom Score43Franciosi J.P. Hommel K.A. DeBrosse C.W. Greenberg A.B. Greenler A.J. Abonia J.P. et al.Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods.BMC Gastroenterol. 2011; 11: 126Crossref PubMed Scopus (81) Google Scholar; the EoE Histology Scoring System, which measures stage and grade44Collins M.H. Martin L.J. Alexander E.S. Boyd J.T. Sheridan R. He H. et al.Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring.Dis Esophagus. 2017; 30: 1-8PubMed Google Scholar; a quantitative endoscopy tool, the Endoscopic Reference Score45Hirano I. Moy N. Heckman M.G. Thomas C.S. Gonsalves N. Achem S.R. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system.Gut. 2013; 62: 489-495Crossref PubMed Scopus (562) Google Scholar; and the EoE Diagnostic Panel, which is composed of 96 transcripts (94 differentially expressed and 2 housekeeping controls) that quantify the EoE transcriptome.46Wen T. Stucke E.M. Grotjan T.M. Kemme K.A. Abonia J.P. Putnam P.E. et al.Molecular diagnosis of eosinophilic esophagitis by gene expression profiling.Gastroenterology. 2013; 145: 1289-1299Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar Engagement and dialog with the US Food and Drug Administration (FDA), particularly through the Division of Gastroenterology in the Center for Drug Evaluation and Research, led to several joint EoE public meetings, publications, and an FDA guidance document for EoE drug development.47Rothenberg M.E. Aceves S. Bonis P.A. Collins M.H. Gonsalves N. Gupta S.K. et al.Working with the US Food and Drug Administration: progress and timelines in understanding and treating patients with eosinophilic esophagitis.J Allergy Clin Immunol. 2012; 130: 617-619Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 48Spergel J.M. Aceves S.S. Kliewer K. Gonsalves N. Chehade M. Wech
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