Effects of topical corticosteroids on esophageal epithelial permeability changes and inflammation in patients with eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a recently recognized disorder characterized
by symptoms of dysphagia and esophageal food impaction which typically requires
repeated emergency endoscopies to remove impacted food. Long-term presence of
the disorder leads to fibrotic strictures and diffuse narrowing in the
esophagus that require endoscopic dilatations.
A potential allergic pathway in the pathophysiology of this disorder is
suggested by the observation that a large proportion of EoE patients has an
atopic constitution and by the notion that elementary diets have been shown to
have a beneficial effect. The esophageal biopsy specimens of EoE patient are
characterized by a Th2-type inflammatory process, with increased numbers of
eosinophils, mast cells and lymphocytes. The interplay between these cells
remains largely unknown. Furthermore, it is reported that patients with EoE are
hypersensitive to acid.
Current standard treatment of the disorder consists of topical corticosteroids
to suppress the immune system. Alternatively, acid suppression can be used.
Histological remission (<1 eosinophil per HPF) can be achieved in 50% of EoE
patients after treatment with swallowed fluticasone propionate, as reported in
a recent pediatric randomized controlled trial.

We hypothesize that in EoE a process of impaired epithelial barrier function is
important. In fact, dilated intercellular spaces have previously been described
in a EoE patient. The impaired epithelial barrier could result in a deep
penetration of food antigens into the epithelium and subsequent processing and
activation of antigen presenting cells followed by activation of an
inflammatory Th2 response.
It has been shown that corticosteroid treatment is effective in reducing
symptoms of dysphagia and heartburn in EoE patients. However, the underlying
mechanism is currently unknown. Since corticosteroids reduce heartburn
complaints in these patients a similar effect on esophageal epithelial barrier
function is suggested. We hypothesize that by treating EoE patients with
swallowed fluticasone propionate, the esophageal epithelial barrier function
could be restored. The effect of topical corticosteroid therapy on the
epithelial barrier function has never been investigated before.

Furthermore, we wish to widely investigate the composition of inflammatory
cells present in the esophageal biopsies of EoE patients and characterize them
using flow cytometry.

Primary: We hypothesize that in eosinophilic esophagitis gastro-esophageal
reflux-induced epithelial barrier dysfunction facilitates passage of
food-antigens through the epithelial barrier and subsequent increased exposure
of antigens by dendritic cells activates the Th2 immune response, and that
treatment with corticosteroids improves the epithelial barrier function. This
can be further specified:
- Affected tissue impedance, dilation of intercellular spaces, and increased
mucosal permeability to small molecules are normalized after treatment with 500
µg fluticasone propionate twice daily for 8 weeks;
- Numbers of esophageal intraepithelial eosinophils and mast cells are
normalized after treatment with 500 µg fluticasone propionate twice daily for 8
weeks;
- Normalization of tissue impedance, intercellular spaces and permeability to
small molecules is correlated with normalization of the number of esophageal
intraepithelial mast cells and eosinophils after 8 weeks of topical
corticosteroid therapy.

Secondary Objective: To widely investigate the composition of inflammatory
cells present in the esophageal biopsies of EoE patients and characterize them
using flow cytometry.

Prospective, observational.

Patients will be treated with topical corticosteroids (which are standard
treatment) and will undergo gastroscopy twice.

Patients will be treated with standard treatment. They will undergo a
gastroscopy twice.
The risk of the performed procedures consists of the risk of esophageal
biopsies, namely bleeding and perforation. There is no additional risk involved
with the tissue impedance measurements.