Eosinophilic esophagitis (EE) is an emerging vyorldwide disease that mimics gastroesophageal reflux disease (GERD) and can lead to esophageal narrowing and stricture (1-4). EE is differentiated from GERD by the magnitude of mucosal eosinophilia and epithelial thickening, its association with atopy, its much lower incidence (~1:10,000) and the lack of response to add suppression. Attention has been drawn to imderstanding the;etiology and. treatment of EE because there has been a recent surge of newly recognized cases. Over the past decade, the mechanisms and treatment of eosinophil accumulation in the gastrointestinal (Gi) tract, with special attention on the esophagus have begun to be characterized. We have established that the esophagus is normally devoid of eosinophils, and that esophageal eosinophilia occurs in association with T helper type 2 (Th2) allergic responses in the lung and GI tract (5, 6). Employing genome wide microarray expression profile analysis, we recently identified an EE transcriptome that includes the eosinophil chemoattractant and activating factor eotaxin-3 as the single most dysregulated gene in the esophagus of EE patients (7). Furthermore, levels of eotaxin-3 strongly correlated with disease severity and a single nucleotide polymorphism in the eotaxin-3 gene was associated with disease susceptibility. In addition, we have recently completed the first double-blind-plaCebo controlled cHnical trial for EE (8) demonstrating that 880 meg of daily swallowed fluticasone (delivered via an asthma inhaler) induces a complete remission (including reductions in esophageal eotaXin-3 expression) in approximately 50% of patients compared with remission rates of less than 10% in patients randomized to placebo (8, 9). Notably, we have identified factors that correspond with glucocorticoid-resistance induding atopic status and increasing patient age, weight, and height. These and other findings have led us to hypothesize that 1760 meg of daily swallowed fluticasone induces disease remission in EE (compared with placebo). Accordingly/ as part of our RESC-RDCRC grant, we propose a multi-center dinical trial that will test this hypothesis in the following two related aims.
|Butz, Bridget K; Wen, Ting; Gleich, Gerald J et al. (2014) Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. Gastroenterology 147:324-33.e5|
|Fulkerson, Patricia C; Rothenberg, Marc E (2013) Targeting eosinophils in allergy, inflammation and beyond. Nat Rev Drug Discov 12:117-29|
|Simon, Dagmar; Wardlaw, Andrew; Rothenberg, Marc E (2010) Organ-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract. J Allergy Clin Immunol 126:3-13; quiz 14-5|
|Brown-Whitehorn, Terri F; Spergel, Jonathan M (2010) The link between allergies and eosinophilic esophagitis: implications for management strategies. Expert Rev Clin Immunol 6:101-9|