Thermo Fisher IMMUNODAYS 2015 Lucerne, November 5 th EOSINOPHILIC ESOPHAGITIS: An emerging disease

Transcription

1 Thermo Fisher IMMUNODAYS 2015 Lucerne, November 5 th 2015 EOSINOPHILIC ESOPHAGITIS: An emerging disease Alain Schoepfer, MD, PD + MER1 Divison de Gastroentérologie et d Hépatologie CHUV, Lausanne

2

3 Outline Definition and diagnosis Pathogenesis Epidemiology Natural history Therapy in 2015

4 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

5 clinically by 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

6 Squamous Epithelium with features of EoE compared with normal findings

7 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

8 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

9 PPI-REE Definition: - Symptoms of esophageal dysfunction - esophageal eosinophilia - clinical and histologic response to PPI* * response not defined yet Liacouras CE, et al. JACI 2011;128:3-20 Dellon ES et al. Am J Gastroenterol 2013;108:

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

11 How many biopsies to diagnose EoE? Take 2-4 bx from each distal and proximal esophagus Take additional bx from suspicious findings take also duodenal and gastric biopsies (eosinophilic gastrointestinal disease?) with 6-9 bx the diagnostic sensitivity approaches 100% take deep biopsies to get submucosal layer (fibrosis?) JACI 2011 guidelines: cutoff 15 eosinophils/hpf Dellon ES, et al. Am J Gastroenterol 2013;108: Gonsalves N, et al. Gastrointest Endosc 2006;64:

12 Endoscopic manifestation 12

13 JACI 2012;130:461-7

14 JACI 2012;130:461-7

15 JACI 2012;130:461-7

16 SPT APT

17 Combined SPT + APT JACI 2012;130:461-7

18 JACI 2012;130:461-7

19 Conclusions on Dx 2 diagnostic pillars: symptoms and histology EoE = patchy disease PPI-trial for 8 wks take 2-4 bx from prox. + distal esophagus 15 eos/hpf as diagnostic cutoff limited accuracy of allergy tests in detecting offending foods Straumann A et al. Digestion 2004 Peery A et al. Clin Gastroenterol Hepatol 2011

20 Outline Definition and diagnosis Pathogenesis Epidemiology Natural history Therapy in 2015

21

22 Outline Definition and diagnosis Pathogenesis Epidemiology Natural history Therapy in 2015

23 Epidemiology Is EoE a relevant disease or a rarity? Prof. Alex Straumann Olten, Switzerland

24 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

25 EoE in Canton of Vaud Giriens B, et al., submitted

26 EoE in Canton of Vaud Giriens B, et al., submitted

27 Eosinophilic Oesophagitis affects individuals in westernized countries with an increasing prevalence and incidence 3 Olmsted County Minnesota-USA 55/ Olten County Switzerland-Europe 43/ 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 2008

28 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

29 Outline Definition and diagnosis Pathogenesis Epidemiology Natural history Therapy in 2014

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

31 Schoepfer AM, et al. Dig Dis 2015, in press

32 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:

33 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

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

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

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

37 Outline Definition and diagnosis Pathogenesis Epidemiology Natural history Therapy in 2015

38 Therapeutic Options 2015: DDD Drugs - PPI - Corticosteroids systemically (e.g. prednisone) - Corticosteroids topically (e.g. budesonide, fluticasone) - Anti-Allergens (Leukotriene-Antagonists, CRTH2-Blocker) - Biologicals (e.g. anti-il5, anti-il13, anti-ige) - Immunosuppressant s (e.g. azathioprine, 6-mercaptopurine) Diet - Elemental Diet - Elimination Diet (individually, allergy-testing based) - Six-Food Elimination Diet Dilation

39 Efficacy of Proton Pump Inhibitor Drugs for Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal Eosinophilia: A Systematic Review and Meta- Analysis Methods A search in MEDLINE, EMBASE, and SCOPUS databases, and the American Gastroenterological Association Institute, American College of Gastroenterology, and United European Gastroenterology meetings abstract books, was performed. Primary outcomes were clinical response and histologic remission (<15 eos/high-power field) after PPI therapy. Secondary outcomes were the influence on the response to PPIs of age group, study design/quality, PPI type, doses and interval dosing, and ph monitoring results. Data were pooled using a random-effects model. Results Thirty-three studies (11 prospective studies) comprising 619 patients with symptomatic esophageal eosinophilia (188 children and 431 adults) were included. PPI therapy led to a clinical response in 60.8% (95% confidence interval, 48.38% 72.2%; I 2 = 80.2) and histologic remission in 50.5% (95% confidence interval, 42.2% 58.7%; I 2 = 67.5) of patients. No differences were observed regarding the study population (children vs adults), the type of publication, or its quality. PPIs were nonsignificantly more effective in prospective studies (52.6% vs 39.1%) administered twice daily compared with once daily (55.9% vs 49.7%), and with pathologic ph monitoring (65.4% vs 49.3%). A significant publication bias in favor of studies reporting histologic responses to PPIs was observed. Conclusions PPI therapy induces clinicohistologic remission in half of patients with symptomatic esophageal eosinophilia. This finding should be interpreted with caution because of poor-quality evidence, heterogeneity, and publication bias. Lucendo AJ, et al. Clin Gastroenterol Hepatol, in press

40 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

41 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

42 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

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

44 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

45 Median follow-up time 5 years

46 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

47

48 DIETS

49 Prevalence of food allergies Allergen Prevalence Remarks Refer. All 6-8% at one year 3-4% at age Higher prevalence for IgE compared to symptoms 1,2 Cow milk 2-3% until age 2 yrs Most often outgrown, high IgE correlated to lower chance for outgrow Hen s egg 1-2% until age 2 yrs Mostly outgrown with childhood 3 4 Peanut / tree nut % of children 0.5-1% of general pop. Mostly lifelong disorder 5 wheat 0.4-1% of children Mostly outgrown in childhood 6 1 Osborne NJ, et al. JACI 2011;127:668 2 Sicherer SH, et al. JACI 2006;117:470 3 Venter C, et al. JACI 2006;117: Nickel R, et al. JACI 1997;99:613 5 Sicherer SH, et al. JACI 1999;103:559 6 Keet CA, et al. Ann All Asthm Immunol 2009;102:410

50 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

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

52 Which is the best diet? Straumann A, Schoepfer A. Gut 2014;epub

53 Dellon E. Gastroenterology 2014;147:

54 Esophageal Dilation

55 APT 2013

56

57

58 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)

59 Take home messages EoE prevalence 1/2000, increasing incidence typical pattern: young male, dysphagia, allergies Allergy tests have limited performance in identifying offending foods untreated inflammation leads to strictures and food bolus impactions => perforation risk reasons to treat EoE: QoL, prevention of esophageal remodeling and food bolus impactions treatment options: diets, drugs, dilation

60 Thank you!