Thermo Fisher IMMUNODAY Lausanne, December 1 st Diagnosis and Management of Eosinophilic Esophagitis

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1 Thermo Fisher IMMUNODAY Lausanne, December 1 st 2016 Diagnosis and Management of Eosinophilic Esophagitis Alain Schoepfer, MD, PD + MERClin Division de Gastroentérologie et d Hépatologie CHUV, Lausanne

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4 Outline Definition and diagnosis Pathogenesis Epidemiology Therapeutic options

5 Esophagus: histology

6 Definition JACI 2011;128:3-20 Eosinophilic esophagitis represents a chronic, immune/antigenmediated esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil predominant inflammation

7 EoE diagnosis Symptoms Histology Exclusion of other conditions

8 EoE diagnosis Symptoms Histology Exclusion of other conditions

9 Symptoms related to esophageal dysfunction Adults and Adolescents - Dysphagia for solids 100% ( slow-eaters and drinkers ) - Long lasting food impaction (>35%; 148/414) - Non-swallowing related retrosternal pain (>50%) Children - Food refusal - Failure to thrive - Vomiting, Regurgitation - Chest Pain, abdominal Pain - Diarrhea 1. Attwood SE et al. Dig Dis Sci Straumann A et al. SMW Furuta GE et al. Gastroenterol Lıacouras CA et al. JACI 2011

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13 Mechanisms causing symptoms Cramps of muscle layer Narrowing

14 EoE diagnosis Symptoms Histology Exclusion of other conditions

15 Squamous Epithelium with features of EoE compared with normal findings

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17 EoE diagnosis Symptoms Histology Exclusion of other conditions

18 Esophageal eosinophilia GERD Eosinophilic esophagitis PPI-responsive esophageal eosinophilia (PPI-REE) others: - eosinophilic gastrointestinal diseases - celiac disease - Crohn s disease - infection (eg. Herpes, candida, anisakis) - hypereosinophilic syndrome - achalasia - drug hypersensitivity - vasculitis - pemphigus - connective tissue diseases

19 How to establish the diagnosis Esophageal eosinophilia EoE PPI-REE GERD PPI trial for 8 weeks, then re-scope Eosinophils persist Decrease in eos and symptoms Eosinophils disappear

20 PPI-REE EoE: a-c PPI-REE: d-f EoE and PPI-REE cannot be discriminated based on symptoms, endoscopic, and histologic features Dellon ES et al. Am J Gastroenterol 2013;108: Moawad FJ, et al. APT 2014;39:603-8

21 Where is endoscopy? symptoms Histology Exclusion of other conditions

22 Normal esophagus

23 Endoscopic features of EoE 23

24 Conclusions for EoE diagnosis symptoms Histology Exclusion of other conditions

25 Outline Definition and diagnosis Pathogenesis Epidemiology Therapeutic options

26 Schoepfer AM, et al. Dig Dis 2016

27 Outline Definition and diagnosis Pathogenesis Epidemiology Therapeutic options

28 Epidemiology Prof. Alex Straumann Olten, Switzerland Swiss Medical Weekly 1994 Prof. Stephen Atttwood Durham University, UK Dig Dis 1993

29 Mayo Clinics, Rochester, USA Olten County, Switzerland Prevalence 55/100,000 => 1/1818 Prevalence 43/100,000 => 1/2325 Prasad G, et al. Clin Gastroenterol Hepatol 2009 Hruz P, et al. JACI 2011

30 EoE in Canton of Vaud Giriens B, et al., Allergy 2015

31 EoE in Canton of Vaud Prevalence in Canton of Vaud: 1/4000 Giriens B, et al., Allergy 2015

32 Eosinophilic Oesophagitis affects individuals in westernized countries with an increasing prevalence and incidence Olmsted County Minnesota-USA 55/ Olten County Switzerland-Europe 43/ Vaud Switzerland-Europe 24/ Hamilton County Ohio-USA 43/ Townsville County Queensland-Australia 9/ Eosinophilic Oesophagitis affects individuals of all age groups from 1 to 98 years of age 6 80% of pts = males 80% of pts have allergies 1. Croese et al. Gastro Intest Endos Noel et al NEJM Hruz P. et al. JACI Cherian et al. Arch Dis Child Prasad et al Clin Gastroenterol Hepatol Kapel et al. Gastroenterology Giriens et al. Allergy 2015

33 Conclusions on epidemiology EoE is a relevant disease affecting 1/2,000 (compare to IBD = 1/500) EoE is the second leading cause of esophageal inflammation after GERD EoE has a true increase in incidence and prevalence

34 Outline Definition and diagnosis Pathogenesis Epidemiology Therapeutic options

35 Therapeutic Options 2016: DDD Drugs - PPI - Corticosteroids systemically (e.g. prednisone) - Corticosteroids topically (e.g. budesonide, fluticasone) - Anti-Allergens (Leukotriene-Antagonists) - Biologicals (e.g. anti-il5, anti-il13, anti-ige, CRTH2-blocker) - Immunosuppressant s (e.g. azathioprine, 6-mercaptopurine) Diet - Elemental Diet - Elimination Diet (individually, allergy-testing based) - Six-Food Elimination Diet Dilation

36 Proton pump inhibitors Clinical and histologic response Lucendo AJ, et al. Clin Gastroenterol Hepatol 2016

37 Budesonide or fluticasone

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39 Topical Corticosteroids in EoE Esophageal Eosinophilia *NSS Eos/hpf 400X * * Year Cohort Tx 36 Peds 80 Peds 36 Adults 30 Adults 24 Peds Fluticasone Fluticasone Budesonide Fluticasone Budes. 440 mcg BID mcg QID 1 mg BID 440 mcg BID 1-2 mg QD Tx Period 3 mts 4 weeks 15 days 8 weeks 3 mts Control Placebo Prednisone Placebo Esomeprazole Placebo

40 Topical Corticosteroids in EoE Symptom Response *NSS % Symptomatic * Year Cohort Tx 36 Peds 80 Peds 36 Adults 30 Adults 24 Peds Fluticasone Fluticasone Budesonide Fluticasone Budes. 440 mcg BID mcg QID 1 mg BID 440 mcg BID 1-2 mg QD Tx Period 3 mts 4 weeks 15 days 8 weeks 3 mts Control Placebo Prednisone Placebo Esomeprazole Placebo

41 Swallowed topical steroids: what form is best? Spray (NEB) Syrup (OVB) P-value Number of patients Peak eos count before treatment Peak eos count after treatment Mean eos count after treatment 101±85 83± ±94 11± ±37 3± Gastroenterology 2012;321-4

42 Oral viscous budesonide (syrup) Nebulized budesonide (spray) Dellon ES, et al. Gastroenterology 2012;321-4

43 Oral viscous budesonide (syrup) Use budesonide or fluticasone mixed in syrup (sucralose) or powder of Axotide discus, no longer use nebulizers Nebulized budesonide (spray) Dellon ES, et al. Gastroenterology 2012;321-4

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45 Miehlke S, et al. Gut 2016

46 Miehlke S, et al. Gut 2016

47 Median follow-up time 5 years

48 Swallowed budesonide can reduce subepithelial fibrosis Control (esophagus healthy) EoE Patient Pre-treatment EoE Patient Post-treatment A B C EvG D E F EUS Straumann et al. Clin Gastro Hepatol

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50 HEROES study

51 OP325 - A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF A NOVEL RECOMBINANT, HUMANISED, ANTI-INTERLEUKIN-13 MONOCLONAL ANTIBODY (RPC4046) IN PATIENTS WITH ACTIVE EOSINOPHILIC OESOPHAGITIS: RESULTS OF THE HEROES STUDY, Hirano I, et al. USA and Switzerland phase II RCT - efficacy and safety RPC4046 (180 mg, 360 mg IV, then sc. weekly ) vs. PBO [1:1:1] Primary endpoint: histology Wk 16 / secondary end. : symptoms, safety. Results: 90 patients, Eo mean count significantly reduced at wk 16 for both RPC4046 doses compared to PBO. (mean change: PBO 4.4, LD 94.8, and HD 99.9 [both p< vs PBO]). Dysphagia improvement (NS), adverse events (AEs) : 65% PBO/LD, 85% HD. RPC4046 significantly reduces esophageal eosinophilic inflammation and improves endoscopic features at both dose levels. symptom improvement: HD > LD. phase 3 UEGW Vienna 2016

52 DIETS

53 Most common food allergens 90% of IgE mediated allergies in young adults are caused by - Cow s milk - egg -soy - peanut / tree nuts - wheat - seafood Sicherer SH, et al. JACI 2006;117:470

54 Elimination Diet Effectively Treats Eosinophilic Esophagitis in Adults; Food Reintroduction Identifies Causative Factors Gonsalves N, et al. Gastroenterology Volume 142, Issue e1

55 Which is the best diet? Straumann A, Schoepfer A. Gut 2014

56 Elemental diet Allergy-testing based elimination diet Outcome: histologic remission Arias et al, Gastroenterology 2014

57 6-food elimination diet Outcome: histologic remission Arias et al, Gastroenterology 2014

58 OP323 - STEP-UP EMPIRIC ELIMINATION DIET FOR PEDIATRIC AND ADULT EOSINOPHILIC ESOPHAGITIS: THE STUDY. Molina-Infante J, et al. Spain 6 Food elimination diet = high level of dietary restriction 4 Food 2 Food E-Diet? Pop: 93 EoE adults and children in 12 spanish hospital with lack of PPI response. 2 Food elimination diet = animal milks and gluten-containing cereals Reponse : symptom improvement and < 15 eos/hpf, If non responders = > 4 FED => 6 weeks reintroduction histologic reevaluation. Results : 2-Food 40% remission (38 patients), 4- food = 52%, 6 food 65% 35% recuction of endoscopic procedures A step-up empiric diet strategy (2-4-6) might be a cost-effective dietary strategy for EoE. 2 Food elimination diet (milk & Gluten) = 40% remission / 35% less endoscopies UEGW Vienna 2016

59 DILATION Dellon E. Gastroenterology 2014

60 APT 2013

61 APT 2013

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63 Pro / Cons of different therapies Modality Advantages Shortcomings Drugs - STC Effective No dietary restriction - Biologic Favorable safety profile therapies Diets Non-pharmacologic, effective treatment option Antifibrotic Dilation Long-lasting symptom improvement No FDA-approved drugs yet on the market Long-term side effects / safety unknown Costs, availability, limited clinical efficacy Repetitive EGDs may be necessary (up to 10x) Needs motivated patient No influence on underlying inflammation Post-dilational pain (safety)

64 Therapeutic principles in EoE in 2016

65 Key points on EoE increasing frequency typical patient: young male with trouble swallowing worst case scenario: bolus impaction and esophageal perforation therapeutic goals: - restore swallowing, - avoid impactions therapy options: drugs, diets, dilations

66 Merci bien!

67 Backup slides

68 NATURAL HISTORY OF EOE Questions to answer 1. What happens without therapy? 2. What are the long term consequences Organ damage? Dysplasia?

69 What happens without therapy? Intensity of Dysphagia and Inflammation over Time 30 Adults followed for a mean of 7.2 years % of Baseline Dysphagia Eosinophilia Dysphagia (linear) Eosinophilia (linear) Years between diagnosis and follow up Straumann A, et al. Gasroenterol 2003;125:

70 The story of two phenotypes Inflammation Stenosis Schoepfer AM, et al. Am J Gastroenterol 2010;105: Straumann A, et al. Clin Gastroenterol Hepatol 2008;6: Straumann A, et al. Clin Gastroenterol Hepatol 2011;9:400-9

71 Stricture risk over time (n=200) Schoepfer AM, et al, Gastroenterology 2013; 145:

72 Endoscopic features at EoE Dx (n=200) Schoepfer AM, et al, Gastroenterology 2013; 145:

73 Consequences of remodeling Straumann A, et al. Clin Gastroenterol Hepatol 2008;6:

74 Is EoE a precancerous lesion? IBD EoE Cancer risk (%) 116 studies 6 CR of Barrett esophagus and concomitant EoE (1 of them with low-grade dysplasia) Time since diagnosis (years) EoE not considered as a precancerous condition (further data awaiting) Eaden JA, et al. Gut 2001,48: Liacouras CA, et al. JACI 2011;128:3-20