Glenn T. Furuta Digestive Health Institute Children’s Hospital Colorado, Aurora, CO

1. Eosinophilic Esophagitis:All That Burns is Not GERD May 19, 2012 AGA Spring Postgraduate Course Glenn T. Furuta Digestive Health Institute Children’s Hospital Colorado, Aurora, CO National Jewish Health, Denver, CO Gastrointestinal Eosinophilic Diseases Program University of Colorado Denver School of Medicine

2. Do patients with EoE complain of heartburn? YES!

3. “Practical Solutions for Your Everyday Clinical Management Problems” • Diagnostic “criteria” • Diagnostic clues • Therapeutic approach

4. “Practical Solutions for Your Everyday Clinical Management Problems” • Diagnostic “criteria” • Distinguish between GERD and EoE • Diagnostic clues • Therapeutic approach

5. Eosinophilic Esophagitis (EoE) “Eosinophilic esophagitis represents a chronic, immune / antigen mediated, esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.” Liacouras C et al, J Allergy Clin Immunol 2011

6. How were Consensus Recommendations developed? Authorship 13 new authors Furuta GT et al, Gastroenterology 2007 Liacouras C et al, J All Clin Immunol 2011

7. 2011 Updated Consensus Report • EoE is a clinico-pathologic disease • Clinically characterized by esophageal dysfunction • Pathologically 1 or more biopsies show eosinophil predominant inflammation (15+ eos in peak hpf) • Histopathology is isolated to esophagus • Other causes need to be excluded • “PPI responsive esophageal eosinophilia” • Diagnosis made by clinicians • Rarely < 15 eos/hpf (if other clinicopathologic features present) Liacouras C et al, J Allergy Clin Immunol 2011

8. “PPI responsive esophageal eosinophilia” • Gastroesophageal Reflux Disease • Eosinophilic Esophagitis • Something else? Spechler S et al 2007 Cheng E et al Gut 2012 and DDW 2012

9. Other changes • “EE” to “EoE” • Chronic • Immune / antigen driven Liacouras C et al, J Allergy Clin Immunol 2011

10. Exclude other causes of esophageal eosinophilia Liacouras, et al, J Allergy Clin Immunol 2011

11. “Practical Solutions for Your Everyday Clinical Management Problems” • Diagnostic “criteria” • Diagnostic clues • Heartburn / “coping mechanisms” • Therapeutic approach

12. Clinical Features- Children • “GERD” symptoms • Abdominal pain, vomiting • Feeding dysfunction • Coping mechanisms- avoid highly textured and bulky foods, cut food into small pieces, lubricating foods, extensive chewing / long meals

13. Clinical Features-Adults • Chest pain-”with alcohol” • Food impaction-ask 2 questions • Netherlands- 2 of 59 patients with FBI • van der Sluis et al DDW 2012 • Australia-6.2% to 23% over a decade • Mahesh et al DDW 2012 • Dysphagia- • 10 year period of 1371 cases • EoE increased from 1.6 to 11% • Kidami et al DDW 2012 Straumann A et al, Allergy 2012

14. Histological features Liacouras C et al, J Allergy Clin Immunol 2011

15. “Esophageal epithelial eosinophilia” • Requires clinical dissection • Phenotypes • Quantification • Detection devices Racial differences in EoE? Lee et al DDW 2012 Gupta et al DDW 2012 BohmM et al J Clin Gastroenterol 2011 Molina-Infante et al, Clin Gastroenterol Hepatol 2011 Halsey KD et al, Dis Esophagus 2012 Hurrell JM et al, Am J Gastroenterol 2012 Lee J et al, Clin Gastroenterol Hepatol 2012 Sridhara S et al, Clin Gastroenterol Hepatol 2012 Diniz LO et al, Pediatr Radiol 2012

16. “Esophageal epithelial eosinophilia” • Requires clinical dissection • Clinical phenotypes • Quantification • Detection devices PPI responsiveness Molina-Infante et al, Clin Gastroenterol Hepatol 2011 Bohm M et al J Clin Gastroenterol 2011 Halsey KD et al, Dis Esophagus 2012 Hurrell JM et al, Am J Gastroenterol 2012 Lee J et al, Clin Gastroenterol Hepatol 2012 Sridhara S et al, Clin Gastroenterol Hepatol 2012 Diniz LO et al, Pediatr Radiol 2012

17. “Esophageal epithelial eosinophilia” • Demands pathophysiological investigation • Chemotactic factors • Functional features • Therapeutic targets miR expression patterns in EoE Menard-KatcherC et al DDW 2012 Lu TX et al J Allergy Clin Immunol2012 Kagalwalla AF et al J Allergy Clin Immunol 2012 Lu TX et al Mucosal Immunol 2012 Mavi P AM J Physiol Gastrointest Liver Physiol 2012 Persad R et al J Pediatr Gastroenterol Nutr 2012

18. Diagnostic clues / cautions • Family history of- • Esophageal dilations • Connective tissue diseases • Recalcitrant GERD • “Pretreated mucosa”-i.e. use of topical steroids for other atopic diseases may diminish esophageal inflammation • Alimi et al DDW 2012

19. Diagnostic clues / cautions • Normal endoscopy in past does not rule out EoE. • Or maybe it does? • Hauser et al DDW 2012-Belguim • Le et al DDW 2012-Oklahoma • Abnormal endoscopy / histology is not diagnostic of EoE.

20. “Practical Solutions for Your Everyday Clinical Management Problems” • Diagnostic “criteria” • Diagnostic clues • Therapeutic approach • Balance impact of treatment with quality of life

21. Treatments • Steroids-topical and systemic • Diet exclusions • 6 food elimination • “Tailored” diet • Elemental diet • Dilation • Medical / nutritional pre-treatment • Through the scope vs. Bougie

22. Medical treatments • Fluticasone • Alexander JA et al, Clin Gastroenterol Hepatol 2012 • Lucendo AJ et al, J Allergy Clin Immunol 2011 • Abu-Sultaneh SM et al, Dig Dis Sci 2011 • Peterson KA et al, Dig Dis Sci 2010 • Konikoff MR et al, Gastroenterology 2006 • Teitelbaum J et al, Gastroenterology 2002 • Faubion WA et al, J Pediatr Gastroenterol Nutr 1998 • Budesonide • Straumann A et al, Clin Gastroenterol Hepatol 2011 • Straumann A et al, Gastroenterology 2010 • Dohil R et al, Gastroenterology 2010 • Aceves SS et al, Am J Gastroenterol 2007 • Ciclesonide • Schroeder S et al JACI 2012 • Leukotriene receptor antagonists? • Lexmond et al DDW 2012

23. Fluticasone • 21 FP treated subjects compared to 21 placebo • 6 week trial • Histology significantly improved • Symptoms improved (not significantly) in both groups • Thrush developed in 26% Alexander JA et al Clin Gastro Hepatol 2012

24. Budesonide • “Oral viscous” budesonide • Randomized placebo controlled study • OVB=15, placebo-9 • Significant reduction in symptoms and eosinophilia Dohil et al Gastroenterology 2010

25. Ciclesonide • Converted by epithelial esterases to form the biologically potent desisobutryl-ciclesonide (des-CIC) • Less absorption than other topical steroids

26. Esterases are expressed by esophageal epithelia • 4 children-(4-16 years) • 8 week treatment • Clinicopathological response in all Schroeder S et al J All Clin Immunol 2012

27. Diet exclusions-adults and children • “6” food elimination-75% • Gonsalves N et al, Gastroenterology 2012 • Kagalwalla AF et al, J Pediatr Gastroenterol Nutr 2011 • Kagalwalla AF et al, Clin GastroenterolHepatol 2006 • “Tailored” diet-33%-90% • Molina-Infante et al DDW 2012 • Spergel J et al, Gastrointest Endosc Clin NA 2008 • Elemental diet-95% • Markowitz JE et al, Am J Gastroenterol 2003 • Kelly K et al, Gastroenterology 1995

28. Six food elimination diet (SFED) • 50 adults • 6 weeks • Clinicopathological remission with SFED • Eosinophilia returned when diet liberalized Gonsalves et al, Gastroenterology 2012

29. Treatments • Dilation considerations • Medical / nutritional pre-treatment? • Kavitt et al DDW 2012 • Through the scope or bougie? • Dhalla et al DDW 2012 • Madanick RD et al, Gastrointest Endosc 2011 • Jung KW et al, Gastrointest Endosc 2011 • BohmM et al, Dis Esophagus 2010 • Dellon ES et al, Gastrointest Endosc 2011 • Schoepfer AM et al, Am J Gastroenterol 2010

30. Biological- Reslizumab-(anti-IL-5 antibody) • 226 children (mean age-12 +/1 4) • 3 doses and placebo • 12 weeks • Histological response with treatment • Treatment and placebo symptom response Spergel JM et al, J Allerg Clin Immunol 2012

31. Treatment Strategies • Induce clinical remission-yes • Induce histological remission- • In our experience-yes • What defines histological remission-? • Does this prevent complications-? • Balance benefits of treatment (disease complications) with treatment complications and impact of treatment on quality of life.

32. EoE Complications • Esophageal stricture • Weber et al DDW 2012 • Esophageal food / foreign body impaction • Feeding dysfunction / malnutrition

33. Treatment complications • Topical and systemic steroids • Diet / nutritional exclusions • Malnutrition • Diminished quality of life • Menard-KatcherP et al DDW 2012 • Bajaj et al DDW 2012 • Taft TH et al, Aliment Pharmacol Ther 2011 • Dilation • Perforation • Pain

34. “Practical Solutions for Your Everyday Clinical Management Problems” • Rule out other causes of inflammation • Symptoms may be occult-ask 2 questions • Treatment choices are increasing and endpoints are undergoing definition.

35. Thank you for your attention!