Update on Basic and Clinical Aspects of Eosinophilic Esophagitis
Update on Basic and Clinical Aspects of Eosinophilic Esophagitis
More than 10 years have passed since the first natural history study demonstrated that EoE is a chronic disease with persistence of symptoms and inflammation over years. Meanwhile, basic science and clinical studies have accordingly confirmed that a chronic eosinophil-predominant oesophageal inflammation leads to deposition of subepithelial fibrous tissue (figure 1A). This so-called 'remodelling' induces histological, endoscopic, radiological and even functional alterations of the oesophagus, but unfortunately there is currently no standardised method of assessing properly the degree of this process. In contrast, much more is known regarding the molecular, cellular and tissue features of this process. Several cytokines play a role in the oesophageal remodelling. Interleukin 5 (IL-5) has been shown to mediate subepithelial collagen deposition and remodelling processes. Patients with EoE were found to have an increased expression of fibroblast growth factor 9 and other profibrogenic cytokine genes such as CCL 18 in the subepithelial layer, which suggests that these factors also contribute to the oesophageal remodelling. Oesophageal remodelling has clinical relevance as it is associated with stricture formation (figure 1B) which, in turn, leads to dysphagia and bolus impaction. Two questions are important regarding this process: (1) is remodelling a process that can be prevented by proper anti-inflammatory treatment; and (2) is subepithelial collagen deposition a one-way process or can an already established fibrosis be reversed by therapeutic interventions?
(Enlarge Image)
Figure 1.
Histological and endoscopic signs of remodelling in eosinophilic oesophagitis. (A) Oesophageal epithelium from a patient with long-standing eosinophilic oesophagitis showing a marked increase of fibrotic tissue in the subepithelial layer (HE staining, original magnification 400×). (B) Endoscopic photograph from a patient with eosinophilic oesophagitis showing a non-inflamed mucosa but marked rings leading to a severe stenosis of the lumen.
The first long-term maintenance trial using the topical corticosteroid budesonide has demonstrated that, after 1 year of treatment, the amount of subepithelial fibrosis significantly decreased compared with placebo. Aceves and colleagues found a significant reduction of oesophageal remodelling in children, even after 3 months of swallowed topical budesonide. Lucendo and colleagues have confirmed these findings using fluticasone and demonstrated additionally that topical corticosteroid treatment led to a downregulation of profibrogenic cytokine gene expression. Finally, Chehade and colleagues have demonstrated that, in children, elimination diet reduces subepithelial fibrosis.
In conclusion, long-standing eosinophilic inflammation leads to oesophageal remodelling with subsequent stricture formation. There is strong evidence indicating that swallowed topical corticosteroids as well as dietary allergen avoidance can both prevent and even reverse this oesophageal remodelling process. Remodelling is therefore probably not an inevitable destiny. These findings are of clinical relevance as they support the initiation of a consistent anti-inflammatory therapy.
Natural History
Remodelling in EoE: An Inevitable Destiny or a Preventable Risk?
More than 10 years have passed since the first natural history study demonstrated that EoE is a chronic disease with persistence of symptoms and inflammation over years. Meanwhile, basic science and clinical studies have accordingly confirmed that a chronic eosinophil-predominant oesophageal inflammation leads to deposition of subepithelial fibrous tissue (figure 1A). This so-called 'remodelling' induces histological, endoscopic, radiological and even functional alterations of the oesophagus, but unfortunately there is currently no standardised method of assessing properly the degree of this process. In contrast, much more is known regarding the molecular, cellular and tissue features of this process. Several cytokines play a role in the oesophageal remodelling. Interleukin 5 (IL-5) has been shown to mediate subepithelial collagen deposition and remodelling processes. Patients with EoE were found to have an increased expression of fibroblast growth factor 9 and other profibrogenic cytokine genes such as CCL 18 in the subepithelial layer, which suggests that these factors also contribute to the oesophageal remodelling. Oesophageal remodelling has clinical relevance as it is associated with stricture formation (figure 1B) which, in turn, leads to dysphagia and bolus impaction. Two questions are important regarding this process: (1) is remodelling a process that can be prevented by proper anti-inflammatory treatment; and (2) is subepithelial collagen deposition a one-way process or can an already established fibrosis be reversed by therapeutic interventions?
(Enlarge Image)
Figure 1.
Histological and endoscopic signs of remodelling in eosinophilic oesophagitis. (A) Oesophageal epithelium from a patient with long-standing eosinophilic oesophagitis showing a marked increase of fibrotic tissue in the subepithelial layer (HE staining, original magnification 400×). (B) Endoscopic photograph from a patient with eosinophilic oesophagitis showing a non-inflamed mucosa but marked rings leading to a severe stenosis of the lumen.
The first long-term maintenance trial using the topical corticosteroid budesonide has demonstrated that, after 1 year of treatment, the amount of subepithelial fibrosis significantly decreased compared with placebo. Aceves and colleagues found a significant reduction of oesophageal remodelling in children, even after 3 months of swallowed topical budesonide. Lucendo and colleagues have confirmed these findings using fluticasone and demonstrated additionally that topical corticosteroid treatment led to a downregulation of profibrogenic cytokine gene expression. Finally, Chehade and colleagues have demonstrated that, in children, elimination diet reduces subepithelial fibrosis.
In conclusion, long-standing eosinophilic inflammation leads to oesophageal remodelling with subsequent stricture formation. There is strong evidence indicating that swallowed topical corticosteroids as well as dietary allergen avoidance can both prevent and even reverse this oesophageal remodelling process. Remodelling is therefore probably not an inevitable destiny. These findings are of clinical relevance as they support the initiation of a consistent anti-inflammatory therapy.
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