Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids

Abstract

Background: Esophageal remodeling occurs in eosinophilic esophagitis (EE) patients but whether the components of remodeling in the subepithelium are reversible by administration of topical oral corticosteroids is unknown.

Methods: We quantitated the degree of lamina propria remodeling in esophageal biopsies obtained before and after at least 3 months of therapy with budesonide in 16 pediatric EE subjects. In addition, we investigated whether corticosteroid therapy modulated vascular activation (expression of VCAM-1; level of interstitial edema), TGFbeta(1) activation (levels of TGFbeta(1), phosphorylated Smad2/3), and performed a pilot analysis of a polymorphism in the TGFbeta(1) promoter in relation to EE subjects who had reduced remodeling with budesonide therapy.

Results: EE subjects were stratified based on the presence (n = 9) or absence (n = 7) of decreased epithelial eosinophilia following budesonide. Patients with residual eosinophil counts of <or=7 eosinophils per high power field in the epithelial space (responders) demonstrated significantly reduced esophageal remodeling with decreased fibrosis, TGFbeta(1) and pSmad2/3 positive cells, and decreased vascular activation in association with budesonide therapy. Responders were more likely to have a CC genotype at the -509 position in the TGFbeta(1) promoter.

Conclusions: Reductions in epithelial eosinophils following budesonide therapy were associated with significantly reduced esophageal remodeling.

Figure 1

Epithelial eosinophils and epithelial changes in EE patients treated with budesonide. The peak epithelial eosinophil count prior to (Pre) and following (Post) therapy among responders (RESP, ≤ 7eos/hpf) and non-responders is shown (NON-RESP, >20eos/hpf) (A). Epithelial scores grade the severity of basal zone hyperplasia and presence of epithelial desquamation among responders (RESP, ≤ 7eos/hpf) vs non-responders (NON-RESP, >20eos/hpf) prior to (Pre) and following (Post) budesonide therapy (B). Bars represent means. Representative images of hematoxylin/eosin stained biopsy in responder patient shows epithelial basal zone hyperplasia, dilated intercellular spaces, eosinophils and degranulation (C, E), lamina propria fibrosis with eosinophils prior to therapy (C, G) and resolution following therapy (D, H, F).

Figure 2

Lamina propria fibrosis and pro-fibrotic mediators in EE patients in response to budesonide therapy. Lamina propria eosinophils (A), fibrosis scores (B), TGFβ₁ (C) and phosphorylated Smad2/3 (pSmad2/3) expressing cells (D) in the lamina propria (LP) of EE patients who have decreased (RESP, ≤ 7eos/hpf) and continued (NON-RESP, >20eos/hpf) epithelial eosinophils prior to (Pre) and following (Post) therapy. Bars represent means. Representative images of TGFβ₁ positive (brown) (E) and pSmad2/3 (F) positive (red) cells prior to (left panels) and following therapy (right panels) in a responder patient.

Figure 3

Lamina propria (LP) vascular activation and dilated intercellular spaces among responders and non-responders. LP VCAM-1 positive vessels (A) and epithelial dilated intercellular spaces (B) in patients who have decreased (RESP, ≤ 7eos/hpf) and continued (NON-RESP, >20eos/hpf) epithelial eosinophils prior to (Pre) and following (Post) therapy. Bars represent means.

Figure 4

TGFβ₁ cell numbers are lower in patients with CC promoter genotype. Numbers of lamina propria TGFβ₁ positive cells in patients with −509 CC or CT/TT genotype in the TGFβ₁ promoter. R = Responders, patients with CT or TT genotype who had ≤ 7eos/hpf following budesonide therapy. Bars represent means.