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Multicenter Study
. 2024 Apr 1;15(4):e00664.
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  1   2   3 , Alex Straumann  1 , Yuniel Fernandez-Marrero  4 , Nina Germic  4 , Aref Hosseini  4 , Apinya Chanwangpong  4 , Shida Yousefi  4 , Dagmar Simon  5 , Margaret H Collins  6 , Christian Bussmann  7 , Mirna Chehade  8 , Evan S Dellon  9 , Glenn T Furuta  10 , Nirmala Gonsalves  11 , Ikuo Hirano  11 , Fouad J Moawad  12 , Luc Biedermann  1 , Ekaterina Safroneeva  13 , Alain M Schoepfer  2 , Hans-Uwe Simon  4   14
Affiliations
Multicenter Study

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

Thomas Greuter et al. Clin Transl Gastroenterol. .

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.

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Conflict of interest statement

Guarantors of the article: Thomas Greuter, MD, Alex Straumann, MD, and Hans-Uwe Simon, MD, PhD.

Specific author contributions: T.G., A.S., and H.U.-S.: study concept and design. T.G., A.S., M.H.C., C.B., M.C., E.S.D., G.T.F., N.G., I.H., F.J.M., E.S., and A.M.S.: acquisition of data. M.H.C. and C.B.: histological examination. T.G., A.S., Y.F.M., N.G., A.H., S.Y., D.S., M.H.C., C.B., and H.U.-S.: analyses and interpretation of data: T.G., A.S., and H.U.S.: drafting of manuscript. Y.F.-M., N.G., S.Y., D.S., M.H.C., C.B., M.C., E.S.D., G.T.F., N.G., I.H., F.J.M., E.S., and A.M.S.: critical revision of the manuscript for intellectual content. T.G., A.S., and H.U.-S: supervision.

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).

Potential competing interests: T.G. has consulting contracts with Sanofi-Regeneron, Janssen, BMS, Takeda, AbbVie, and Falk Pharma GmbH, received travel grants from Falk Pharma GmbH and Vifor, speaker's fee from Norgine, and an unrestricted research grant from Novartis. A.S. has consulting contracts with Actelion, Celgene-Receptos, Falk Pharma GmbH, Roche-Genentech, GSK, Novartis, Nutricia, and Sanofi-Regeneron. E.S. is a consultant for Celgene Corp., Regeneron Pharmaceuticals Inc, and Novartis. A.M.S. is a consultant for Falk Pharma GmbH, Adare Pharmaceuticals Inc, Celgene-Receptos, and Sanofi-Regeneron. M.H.C. is a consultant for AstraZeneca, Allakos, Arena, Celgene, EsoCap, GlaxoSmithKline, Regeneron, and Shire and has received research funds from Regeneron and Shire. L.B. reports fees for consulting/advisory board from AbbVie, Amgen, BMS, MSD, Vifor, Falk, EsoCap, Janssen, Calypso, Ferring, Pfizer, Takeda, Janssen, and Sanofi. G.T.F. is a consultant for Takeda, has received research support from Holoclara and Arena/Pfizer, and is Chief Medical Officer of EnteroTrack. M.C. has received consulting fees from Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, Bristol Myers Squibb, Allakos, Shire/Takeda, Phathom, and Recludix and has received research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, and Danone. I.H. has received consulting fees from Receptos, Regeneron, Shire, and Roche. N.G. has received consulting fees from AstraZeneca, Allakos, Regeneron, BMS, and Knopp and is on speakers bureau for Regeneron. E.S.D. has received research funding Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda, has received consulting fees from Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nextstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio, and has received educational grants from Allakos, Holoclara, and Invea. H.U.-S. is a consultant for AstraZeneca, GlaxoSmithKline, and EsoCap. The other authors have no competing interests to declare. No company representative was involved in conception, writing, or financing of this study.

RNA-seq: RNA-seq was performed by the Next-Generation Sequencing (GS) Platform of the University of Bern. RNA-seq data have been deposited in the Gene Expression Omnibus (GEO), accession number GSE148381.

Figures

Figure 1.
Figure 1.
(a) Flow chart of study patients. (b) Kaplan-Meier analysis showing progression of EoE-like esophagitis to EoE over time. (c) Transition from one variant to another variant during the follow-up period with numbers between pies indicating the number of patients (and percentage) transitioning from one variant to another variant. (d) Patients with more than one additional variant during follow-up (n = 5) and one additional patient with transition from EoE-like esophagitis to nonspecific esophagitis and then progression to EoE. Blue color indicates EoE-like esophagitis, orange color indicates lymphocytic esophagitis, yellow color indicates nonspecific esophagitis, and green color indicates EoE. EoE, eosinophilic esophagitis.
Figure 2.
Figure 2.
(a) ingenuity pathway analysis (IPA) pathway analysis of patients with newly developed EoE during the follow-up, with the top pathways ranked by −log10 P value. Boxes on the right show the most upregulated genes in the 3 top pathways (ranked by log2 fold change). (b) Heatmap of the mRNA profile of newly developed EoE vs classical EoE. Red color indicates upregulation, and blue color indicates downregulation. (c) Vulcano plot for differentially expressed genes during progression from EoE-like esophagitis to newly developed EoE. Red colors indicate a significant change during progression defined by a log2 fold change of at least 2 and an false detection rate (FDR) of <0.05. (d) Comparative pathway analysis in patients with progression from EoE-like esophagitis (on the left) to newly developed EoE (on the right). Orange color indicates upregulation, and blue color indicates downregulation. EoE, eosinophilic esophagitis.
Figure 3.
Figure 3.
Esophageal expression of TSG6 (green) and EPX (red) in the upper line, and ALOX15 (green) and EPX (red) in the lower line, as assessed by immunofluorescence, in patients with EoE-like esophagitis at baseline (a), time of newly developed EoE (b), esophagus healthy controls (c), and classic EoE (d). Hoechst H3570 was used for nuclear staining. Panels on the right show quantification in epithelial cells for TSG6 (e), ALOX15 (f), and EPX (g). EoE, eosinophilic esophagitis.
Figure 4.
Figure 4.
Esophageal T-bet and GATA-3 expression as assessed by immunofluorescence analysis in patients with EoE-like esophagitis at baseline (a), time of newly developed EoE (b), esophagus healthy controls (c), and classic EoE (d). Hoechst H3570 was used for nuclear staining. Panels on the right show quantification of T-bet (e), GATA3 (f), and the GATA3 to T-bet ratio in EoE-like esophagitis at baseline vs at the time of eosinophil infiltration (g). AU, arbitrary units; EoE, eosinophilic esophagitis.
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