A Multicenter Long-Term Cohort Study of Eosinophilic Esophagitis Variants and Their Progression to Eosinophilic Esophagitis Over Time

Thomas Greuter; Alex Straumann; Yuniel Fernandez-Marrero; Nina Germic; Aref Hosseini; Apinya Chanwangpong; Shida Yousefi; Dagmar Simon; Margaret H. Collins; Christian Bussmann; Mirna Chehade; Evan S. Dellon; Glenn T. Furuta; Nirmala Gonsalves; Ikuo Hirano; Fouad J. Moawad; Luc Biedermann; Ekaterina Safroneeva; Alain M. Schoepfer; Hans Uwe Simon

doi:10.14309/ctg.0000000000000664

A Multicenter Long-Term Cohort Study of Eosinophilic Esophagitis Variants and Their Progression to Eosinophilic Esophagitis Over Time

Thomas Greuter^*, Alex Straumann, Yuniel Fernandez-Marrero, Nina Germic, Aref Hosseini, Apinya Chanwangpong, Shida Yousefi, Dagmar Simon, Margaret H. Collins, Christian Bussmann, Mirna Chehade, Evan S. Dellon, Glenn T. Furuta, Nirmala Gonsalves, Ikuo Hirano, Fouad J. Moawad, Luc Biedermann, Ekaterina Safroneeva, Alain M. Schoepfer, Hans Uwe Simon

^*Corresponding author for this work

Medicine, Gastroenterology Division

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

INTRODUCTION: Eosinophilic esophagitis (EoE) variants have been recently characterized as conditions with symptoms of esophageal dysfunction resembling EoE, but absence of significant esophageal eosinophilia. Their disease course and severity have yet to be determined. METHODS: Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls. RESULTS: We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6–37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months). DISCUSSION: Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis.

Original language	English (US)
Article number	e00664
Journal	Clinical and translational gastroenterology
Volume	15
Issue number	4
DOIs	https://doi.org/10.14309/ctg.0000000000000664
State	Published - Apr 1 2024

Funding

Financial support: This work was supported by grants from the Swiss National Science Foundation to H.U.-S. (grant no. 310030_184816), A.M.S. (grant no. 32003B_204751/1), A.S. (grant no. 32003B_160115), and T.G. (grant no. P2ZHP3_168561), a young investigator award from the Swiss Society of Gastroenterology to T.G., research grants from the Novartis Foundation for Medical-Biological Research to T.G. and H.U.-S., a research award from the Swiss IBDnet to T.G., and a training grant from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) to T.G. CEGIR (U54 AI117804) is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), and is funded through collaboration between the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and NCATS. CEGIR is also supported by patient advocacy groups including the American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Disease (CURED), and Eosinophilic Family Coalition (EFC). The study was further supported by a research grant from the Swiss EoE Foundation to H.U.-S. (grant no 2021-03) and T.G. (grant no 2023-01).

Keywords

Dysphagia
esophageal eosinophilia
lymphocytic esophagitis
next-generation RNA sequencing

ASJC Scopus subject areas

Gastroenterology

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10.14309/ctg.0000000000000664

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Greuter, T., Straumann, A., Fernandez-Marrero, Y., Germic, N., Hosseini, A., Chanwangpong, A., Yousefi, S., Simon, D., Collins, M. H., Bussmann, C., Chehade, M., Dellon, E. S., Furuta, G. T., Gonsalves, N., Hirano, I., Moawad, F. J., Biedermann, L., Safroneeva, E., Schoepfer, A. M., & Simon, H. U. (2024). A Multicenter Long-Term Cohort Study of Eosinophilic Esophagitis Variants and Their Progression to Eosinophilic Esophagitis Over Time. Clinical and translational gastroenterology, 15(4), Article e00664. https://doi.org/10.14309/ctg.0000000000000664

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abstract = "INTRODUCTION: Eosinophilic esophagitis (EoE) variants have been recently characterized as conditions with symptoms of esophageal dysfunction resembling EoE, but absence of significant esophageal eosinophilia. Their disease course and severity have yet to be determined. METHODS: Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls. RESULTS: We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6–37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months). DISCUSSION: Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis.",

keywords = "Dysphagia, esophageal eosinophilia, lymphocytic esophagitis, next-generation RNA sequencing",

author = "Thomas Greuter and Alex Straumann and Yuniel Fernandez-Marrero and Nina Germic and Aref Hosseini and Apinya Chanwangpong and Shida Yousefi and Dagmar Simon and Collins, {Margaret H.} and Christian Bussmann and Mirna Chehade and Dellon, {Evan S.} and Furuta, {Glenn T.} and Nirmala Gonsalves and Ikuo Hirano and Moawad, {Fouad J.} and Luc Biedermann and Ekaterina Safroneeva and Schoepfer, {Alain M.} and Simon, {Hans Uwe}",

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year = "2024",

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day = "1",

doi = "10.14309/ctg.0000000000000664",

language = "English (US)",

volume = "15",

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Greuter, T, Straumann, A, Fernandez-Marrero, Y, Germic, N, Hosseini, A, Chanwangpong, A, Yousefi, S, Simon, D, Collins, MH, Bussmann, C, Chehade, M, Dellon, ES, Furuta, GT, Gonsalves, N, Hirano, I, Moawad, FJ, Biedermann, L, Safroneeva, E, Schoepfer, AM & Simon, HU 2024, 'A Multicenter Long-Term Cohort Study of Eosinophilic Esophagitis Variants and Their Progression to Eosinophilic Esophagitis Over Time', Clinical and translational gastroenterology, vol. 15, no. 4, e00664. https://doi.org/10.14309/ctg.0000000000000664

TY - JOUR

T1 - A Multicenter Long-Term Cohort Study of Eosinophilic Esophagitis Variants and Their Progression to Eosinophilic Esophagitis Over Time

AU - Greuter, Thomas

AU - Straumann, Alex

AU - Fernandez-Marrero, Yuniel

AU - Germic, Nina

AU - Hosseini, Aref

AU - Chanwangpong, Apinya

AU - Yousefi, Shida

AU - Simon, Dagmar

AU - Collins, Margaret H.

AU - Bussmann, Christian

AU - Chehade, Mirna

AU - Dellon, Evan S.

AU - Furuta, Glenn T.

AU - Gonsalves, Nirmala

AU - Hirano, Ikuo

AU - Moawad, Fouad J.

AU - Biedermann, Luc

AU - Safroneeva, Ekaterina

AU - Schoepfer, Alain M.

AU - Simon, Hans Uwe

PY - 2024/4/1

Y1 - 2024/4/1

N2 - INTRODUCTION: Eosinophilic esophagitis (EoE) variants have been recently characterized as conditions with symptoms of esophageal dysfunction resembling EoE, but absence of significant esophageal eosinophilia. Their disease course and severity have yet to be determined. METHODS: Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls. RESULTS: We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6–37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months). DISCUSSION: Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis.

AB - INTRODUCTION: Eosinophilic esophagitis (EoE) variants have been recently characterized as conditions with symptoms of esophageal dysfunction resembling EoE, but absence of significant esophageal eosinophilia. Their disease course and severity have yet to be determined. METHODS: Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls. RESULTS: We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6–37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months). DISCUSSION: Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis.

KW - Dysphagia

KW - esophageal eosinophilia

KW - lymphocytic esophagitis

KW - next-generation RNA sequencing

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DO - 10.14309/ctg.0000000000000664

M3 - Article

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AN - SCOPUS:85185260087

SN - 2155-384X

VL - 15

JO - Clinical and translational gastroenterology

JF - Clinical and translational gastroenterology

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A Multicenter Long-Term Cohort Study of Eosinophilic Esophagitis Variants and Their Progression to Eosinophilic Esophagitis Over Time

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