The EoE Hunger Games: PPI-REE is Catching Fire!

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1 The Hunger Games: PPI-REE is Catching Fire! Edaire Cheng, M.D. Assistant Professor of Pediatrics University of Texas Southwestern Esophageal Diseases Center Children s Medical Center I have no conflict of interests to disclose. Learning Objectives Recognize the similarities, differences, and relationship between,, and PPI-REE. Understand the mechanism of PPI response in PPI-REE patients. Evaluate and treat a patient with esophageal eosinophilia. 1

2 Eosinophilic Esophagitis () Conceptual Definition is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Liacouras et al. J Allergy Clin Immunol 2011;128:3-20. in the United States Prevalence 56.7 per 100,000 (1 in 2,000) Similar to pediatric inflammatory bowel diseases Dellon E. Clin Gastroenterol Hepatol 2014;12:589. Most common cause of food impaction in patients seen in ER Sperry S. Gastrointest Endosc 2011;74:985. Health care cost $ billion per year Jensen E. Am J Gastroenterol Common Symptoms of Dysphagia Odynophagia Food Impaction Children Vomiting Feeding intolerance Feeding aversion Failure to Thrive Adults Chest Pain Heart burn Epigastric pain Refractory 2

3 Endoscopic Reference Score (EREFS) Exudates (plaques) Rings (trachealization) Esophagus appears Edema (pallor) normal in ~10% Furrows (vertical lines) Strictures Endoscopic findings are not specific for. Hirano I. Gut 2013;62:489. Histological Findings Esophageal Eosinophilia ( 15 intraepithelial eos/hpf) Eosinophil Microabscesses Basal Zone Hyperplasia Dilated Intercellular Spaces Subepithelial Fibrosis Epithelium Eosinophilia Subepithelial Basal fibrosis zone Hyperplasia (>20%) Histological findings are not specific. Eosinophilic Esophagitis Pathogenesis Model (Genetically-Susceptible Individual) Mast Cells Esophageal Epithelium eotaxin-3 Food Allergen APC IL-13 IL-4 Th2 cell IL-5 3

4 There Is No Diagnostic Gold Standard for Eosinophilic Esophagitis No single clinical, laboratory, endoscopic, or histological feature establishes the diagnosis of. Diseases Associated with Esophageal Eosinophils Eosinophilic gastroenteritis Crohn s disease Infections Connective tissue diseases Vasculitis Hypereosinophilic syndrome History of Esophageal Eosinophilia Esophageal Eosinophilia 1980s Histologic marker for Leape et al. J Pediatr Surg Winter et al. Gastroenterology Brown et al. Am J Surg Pathol Hyams et al. J Pediatr Gastroenterol Nutr s, a distinct entity Attwood et al. Dig Dis Sci Straumann et al. Schweiz Med Wochenschr Kelly et al. Gastroenterology

5 or? Response to Proton Pump Inhibitors = and Share a Complex Relationship Acid and bile upregulate adhesion molecules and chemoattractants involved in eosinophil trafficking. Disrupted esophageal barrier function may increase esophageal permeability to swallowed antigens. Inflammation and remodeling alter esophageal motility delayed acid clearance, reduced lower esophageal sphincter pressure. Inflammation may disrupt barrier and increase hypersensitivity to acid. Cheng E. Current Treatment Options in Gastroenterology History of Esophageal Eosinophilia Esophageal Eosinophilia +PPI Response

6 Most Patients with Symptomatic Esophageal Eosinophilia Respond to PPIs 677 (<15 eos/hpf) 712 patients with UGI symptoms 4 biopsies from mid-esophagus 35 ( 15 eos/hpf) 9 (25%) No Remission Rabeprazole 20mg BID 26 (75%) Remission no evidence of 2 endoscopic acid damage and 3 pathologic ph monitoring Molina-Infante. Clin Gastroenterol Hepatol 2011;9: endoscopic acid damage and 12 pathologic ph monitoring no evidence of and Patients who can have co-exist symptoms and histology but no evidence of can respond to PPIs. PPIs Induce Histologic Remission in Symptomatic Esophageal Eosinophilia 50.5% (95%CI, %) Lucendo, Arias, Molina-Infante. Clin Gastroenterol Hepatol PPI-Responsive Esophageal Eosinophilia Reflux Have typical symptoms and histology No evidence of by endoscopy or ph monitoring Exhibit a clinical and histological response to PPIs Liacouras et al. J Allergy Clin Immunol

7 Clinical Features of,, and PPI-REE Symptoms Heartburn Dysphagia Regurgitation Food impaction Abdominal pain Atopy/food allergy Endoscopy Erosive esophagitis White plaques Hiatal hernia Furrows Peptic stricture Rings/Stricture Histology <15 eos/hpf 15 eos/hpf No PPI response PPI-REE Dysphagia Food impaction Atopy/food allergy White plaques Furrows Rings/Stricture 15 eos/hpf + PPI response Dellon et al. Clin Gastroenterol Hepatol Mulder et al. J Pediatr Gastrenterol Nutr Dellon et al. Am J of Gastroenterol Schroeder et al. J Pediatr Gastroenterol Nutr Inflammatory Markers Can Distinguish but not PPI-REE from PPI-REE Major Basic Protein Eotaxin-3 Tryptase Dellon et al. Am J Gastroenterol Dellon et al. Am J Gastroenterol Dellon et al. Clin Gastroenterol Hepatol 2014 Esophageal Transcriptome (59 genes) Esophageal Transcriptome Overlap Between and PPI-REE Normal Wen T et al. J Allergy Clin Immunol PPI-REE (Untreated) Genes Downregulated Genes Upregulated and PPI-REE are part of the same spectrum of a Th2-mediated esophageal disease. 7

8 Possible Mechanisms for PPI-Responsive Esophageal Eosinophilia Patients have with acid reflux causing esophageal eosinophilia, even though endoscopy and ph monitoring are normal Patients have that responds to anti inflammatory effect of PPIs independent of effects on acid inhibition PPIs Do More Than Just Inhibit Gastric Acid Production Potential Anti-Inflammatory Effects Anti-oxidant properties Inhibitory effects on neutrophil function Decrease cytokine production by endothelial and epithelial cells Decrease adhesion molecule production by endothelial cells and neutrophils Kedika, Souza, Spechler. Dig Dis Sci How might an immune/antigen mediated esophageal disease like respond to anti-inflammatory effects of PPIs? 8

9 Eotaxin-3 (pg/ml/250k cells) Omeprazole Might Have Eosinophil-Reducing Effects Independent of Effects on Gastric Acid Eotaxin-3 is a potent eosinophil chemoattractant Cheng et al. Gut Baseline PPI effect was entirely OME (50μM) IL-13 (50ng/ml) independent of effects on IL-4 (10ng/ml) gastric acid secretion. IL-13+OME IL-4+OME PPI 1-T * PPI *p<0.05 compared to IL-13 alone # # p<0.05 compared to IL-4 alone PPI * 2-T PPI # PPIs Reduced Th2 Cytokine Gene Profile in Adult Esophageal Eosinophilia Patients PPI REE Subjects N=23 PPI therapy Eotaxin 3 IL 13 IL 5 Pre Distal Proximal Distal Proximal Distal Proximal Post Pre Post Pre Post Pre Post Pre Post Pre Post Subjects N=30 steroid or diet therapy Eotaxin 3 IL 13 IL 5 Pre Distal Proximal Distal Proximal Distal Proximal Post Pre Post Pre Post Pre Post Pre Post Pre Post Molina-Infante et al. Aliment Pharmacol Ther 2014 PPI reduced Eotaxin-3 + Epithelial Cells in the Proximal Esophagus of Pediatric Esophageal Eosinophilia Patients PPI Responder Non-Responder Proximal Esophagus Anti-inflammatory rather than antisecretory effect of PPIs predominates in the proximal esophagus. Park et al. Plos One Distal Esophagus 9

10 Esophageal Transcriptome (59 genes) PPIs Reversed Genes on Eosinophil Diagnostic Panel Normal Wen T et al. J Allergy Clin Immunol PPI-REE PPI-REE (Untreated) (PPI Treated) PPI treatment alone reversed allergic Th2 inflammatory signature in PPI-REE. A trial of PPI therapy is recommended for patients with symptomatic esophageal eosinophilia, even if the diagnosis of eosinophilic esophagitis seems clear-cut. Cheng E, Souza RF, Spechler SJ. Gastroenterology Clinics of North America Approach to Esophageal Eosinophilia Clinically suspect Endoscopy + biopsy ( 15 eos/hpf) High-dose PPI Allergy-driven? Or Reflux-induced? Both? Allergy eval/testing ph/impedance monitoring future tests (immunostaining, EDP) <15 eos/hpf Symptoms resolved 15 eos/hpf Symptoms persist PPI monotherapy Dietary Therapy 15 eos/hpf Symptoms persist Topical Steroid 15 eos/hpf Symptoms persist Restrict diet further Increase dose 15 eos/hpf Symptoms persist Evaluate adherence Evaluate for remodeling (stricture/narrowing) ± Dilation Consider switching therapy: Dietary Topical Steroid Topical Steroid Dietary Consider systemic steroid Consider adding 2 nd agent: Topical Steroid + PPI, Dietary + PPI, Topical Steroid + Dietary Consider investigational drug trials 10

11 Where are we now? Esophageal Eosinophilia PPI-Responsive May the EOS be ever in your favor. 11