1 Eosinophilic Esophagitis (EoE) Conceptual Definition EoE is a - PDF document

The EoE 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 GERD, EoE, and PPI-REE.  Understand the mechanism of PPI response in PPI-REE patients.  Evaluate and treat a patient with esophageal eosinophilia. 1

Eosinophilic Esophagitis (EoE) Conceptual Definition EoE 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. EoE 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 $0.5 ‐ 1.4 billion per year Jensen E. Am J Gastroenterol 2015. Common Symptoms of EoE •Dysphagia •Odynophagia •Food Impaction Adults Children • Vomiting •Chest Pain • Feeding intolerance •Heart burn • Feeding aversion •Epigastric pain • Failure to Thrive •Refractory “ GERD ” 2

EoE Endoscopic Reference Score (EREFS) • E xudates (plaques) • R ings (trachealization) Esophagus appears • E dema (pallor) normal in ~10% • F urrows (vertical lines) • S trictures Endoscopic findings are not specific for EoE. Hirano I. Gut 2013;62:489. Histological Findings  Esophageal Eosinophilia Eosinophilia ( ≥ 15 intraepithelial eos/HPF)  Eosinophil Microabscesses Epithelium  Basal Zone Hyperplasia Subepithelial  Dilated Intercellular Spaces fibrosis Basal zone Hyperplasia  Subepithelial Fibrosis (>20%) Histological findings are not specific. Eosinophilic Esophagitis Pathogenesis Model (Genetically-Susceptible Individual) eotaxin-3 Esophageal Epithelium Mast Cells Food Allergen IL-13 IL-4 IL-5 APC Th2 cell 3

There Is No Diagnostic “Gold Standard” for Eosinophilic Esophagitis No single clinical, laboratory, endoscopic, or histological feature establishes the diagnosis of EoE. Diseases Associated with Esophageal Eosinophils • EoE • GERD • Eosinophilic gastroenteritis • Crohn’s disease • Infections • Connective tissue diseases • Vasculitis • Hypereosinophilic syndrome History of Esophageal Eosinophilia Esophageal Eosinophilia GERD EoE 1980s 1990s Histologic marker for GERD EoE, a distinct entity Leape et al. J Pediatr Surg 1981. Attwood et al. Dig Dis Sci 1993. Winter et al. Gastroenterology 1982. Straumann et al. Schweiz Med Wochenschr 1994. Brown et al. Am J Surg Pathol 1984. Kelly et al. Gastroenterology 1995. Hyams et al. J Pediatr Gastroenterol Nutr 1988. 4

GERD or EoE? Response to Proton Pump GERD EoE Inhibitors = GERD EoE and GERD Share a Complex Relationship GERD EoE • Acid and bile upregulate • Inflammation and adhesion molecules and remodeling alter chemoattractants involved esophageal motility  in eosinophil trafficking. delayed acid clearance, reduced lower esophageal • Disrupted esophageal sphincter pressure. barrier function may increase esophageal • Inflammation may disrupt permeability to swallowed barrier and increase antigens. hypersensitivity to acid. Cheng E. Current Treatment Options in Gastroenterology 2015. History of Esophageal Eosinophilia Esophageal Eosinophilia +PPI Response GERD EoE 2000 - 2010 5

Most Patients with Symptomatic Esophageal Eosinophilia Respond to PPIs 712 patients with UGI symptoms ≥ 4 biopsies from mid-esophagus 677 ( <15 eos/hpf) 35 ( ≥ 15 eos/hpf) 9 (25%) 26 (75%) Rabeprazole 20mg BID No Remission Remission 4 EoE 5 EoE + GERD 24 2 no evidence 2 endoscopic acid damage 12 endoscopic acid damage no evidence of GERD and and of GERD 3 pathologic pH monitoring 12 pathologic pH monitoring Patients who have EoE symptoms and histology EoE and GERD can co-exist but no evidence of GERD can respond to PPIs. Molina-Infante. Clin Gastroenterol Hepatol 2011;9:110. PPIs Induce Histologic Remission in Symptomatic Esophageal Eosinophilia 50.5% (95%CI, 42.2-58.7%) Lucendo, Arias, Molina-Infante. Clin Gastroenterol Hepatol 2015. “PPI-Responsive Esophageal Eosinophilia” Reflux • Have typical EoE symptoms and histology • No evidence of GERD by endoscopy or pH monitoring • Exhibit a clinical and histological response to PPIs Liacouras et al. J Allergy Clin Immunol 2011. 6

Clinical Features of GERD, EoE, and PPI-REE GERD EoE PPI-REE Heartburn Dysphagia Dysphagia Symptoms Regurgitation Food impaction Food impaction Abdominal pain Atopy/food allergy Atopy/food allergy Erosive White plaques White plaques Endoscopy esophagitis Furrows Hiatal hernia Furrows Rings/Stricture Peptic stricture Rings/Stricture ≥ 15 eos/hpf <15 eos/hpf ≥ 15 eos/hpf Histology No PPI response + PPI response Dellon et al. Clin Gastroenterol Hepatol 2009. Mulder et al. J Pediatr Gastrenterol Nutr 2013. Dellon et al. Am J of Gastroenterol 2013. Schroeder et al. J Pediatr Gastroenterol Nutr 2013. Inflammatory Markers Can Distinguish GERD but not PPI-REE from EoE GERD EoE PPI-REE Major Basic Protein Eotaxin-3 Tryptase Dellon et al. Am J Gastroenterol 2011. Dellon et al. Am J Gastroenterol 2012. Dellon et al. Clin Gastroenterol Hepatol 2014 Esophageal Transcriptome Overlap Between EoE and PPI-REE PPI-REE Normal GERD EoE (Untreated) Esophageal Transcriptome Genes Downregulated (59 EoE genes) Genes Upregulated EoE and PPI-REE are part of the same spectrum of a Th2-mediated esophageal disease. Wen T et al. J Allergy Clin Immunol 2014. 7

Possible Mechanisms for PPI-Responsive Esophageal Eosinophilia • Patients have GERD with acid reflux causing esophageal eosinophilia, even though endoscopy and pH monitoring are normal • Patients have EoE 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 2009. How might an immune/antigen mediated esophageal disease like EoE respond to anti-inflammatory effects of PPIs? 8

Omeprazole Might Have Eosinophil-Reducing Effects Independent of Effects on Gastric Acid Eotaxin-3 is a potent eosinophil chemoattractant. 4000 4000 4000 Eotaxin-3 (pg/ml/250K cells) Baseline 3500 3500 3500 PPI effect was entirely OME (50 μ M) independent of effects on IL-13 (50ng/ml) 3000 3000 3000 IL-4 (10ng/ml) gastric acid secretion. 2500 2500 2500 IL-13+OME 2000 2000 2000 IL-4+OME * # 1500 1500 1500 1000 1000 1000 PPI PPI # 500 500 500 * PPI PPI 0 0 0 EoE1-T EoE2-T * p<0.05 compared to IL-13 alone Cheng et al. Gut 2013. # p<0.05 compared to IL-4 alone PPIs Reduced Th2 Cytokine Gene Profile in Adult Esophageal Eosinophilia Patients Eotaxin ‐ 3 IL ‐ 13 IL ‐ 5 PPI ‐ REE Distal Proximal Distal Proximal Distal Proximal Subjects N=23 PPI therapy Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Eotaxin ‐ 3 IL ‐ 13 IL ‐ 5 EoE Subjects Distal Proximal Distal Proximal Distal Proximal N=30 steroid or diet therapy Pre 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 PPI Responder PPI Responder Non-Responder Non-Responder Non-Responder Proximal Esophagus Distal Esophagus Anti-inflammatory rather than antisecretory effect of PPIs predominates in the proximal esophagus. Park et al. Plos One 2014. 9

PPIs Reversed EoE Genes on Eosinophil Diagnostic Panel PPI-REE PPI-REE Normal GERD EoE (Untreated) (PPI Treated) Esophageal Transcriptome (59 EoE genes) PPI treatment alone reversed allergic Th2 inflammatory signature in PPI-REE. Wen T et al. J Allergy Clin Immunol 2014. 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 2014. Approach to Esophageal Eosinophilia Clinically suspect EoE Allergy-driven? Or Reflux-induced? Both? Endoscopy + Allergy eval/testing biopsy ( ≥ 15 eos/hpf) pH/impedance monitoring future tests (immunostaining, EDP) High-dose PPI <15 eos/hpf ≥ 15 eos/hpf Symptoms resolved Symptoms persist PPI monotherapy Dietary Therapy Topical Steroid ≥ 15 eos/hpf ≥ 15 eos/hpf Symptoms persist Symptoms persist Restrict diet further Increase dose ≥ 15 eos/hpf Symptoms persist Consider adding 2 nd agent: Evaluate Evaluate Consider Consider Consider adherence for remodeling switching therapy: systemic Topical Steroid + PPI, investigational (stricture/narrowing) Dietary → Topical Steroid steroid Dietary + PPI, drug trials ± Dilation Topical Steroid → Dietary Topical Steroid + Dietary 10

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