Alain Schoepfer, MD, PD + MERClin Division de Gastroentérologie et d’Hépatologie

CHUV, Lausanne

Diagnosis and Management of Eosinophilic Esophagitis

Thermo Fisher IMMUNODAY

Lausanne, December 1st 2016

Outline

• Definition and diagnosis

• Pathogenesis

• Epidemiology

• Therapeutic options

Esophagus: histology

Eosinophilic esophagitis represents a chronic, immune/antigen-mediated esophageal disease, characterized clinically bysymptoms related to esophageal dysfunction and histologicallyby eosinophil predominant inflammation

Definition JACI 2011;128:3-20

EoE diagnosis

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EoE diagnosis

Sym

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Exc

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1. Attwood SE et al. Dig Dis Sci 19932. Straumann A et al. SMW 19943. Furuta GE et al. Gastroenterol 20074. Lıacouras CA et al. JACI 2011

- Dysphagia for solids 100% (“slow-eaters” and “drinkers”)

- Long lasting food impaction (>35%; 148/414)

- Non-swallowing related retrosternal pain (>50%)

- Food refusal

- Failure to thrive

- Vomiting, Regurgitation

Adults and Adolescents

Children

Symptoms related to esophageal dysfunction

- Chest Pain, abdominal Pain

- Diarrhea

Mechanisms causing symptoms

Cramps of muscle layer

Narrowing

EoE diagnosis

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Squamous Epithelium with features of EoE compared with normal findings

EoE diagnosis

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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

How to establish the diagnosis

Esophageal eosinophilia

EoE PPI-REE GERD

PPI trial for 8 weeks, then re-scope

Eosinophilspersist

Decrease in eos and

symptoms

Eosinophilsdisappear

Dellon ES et al. Am J Gastroenterol 2013;108:679-692Moawad FJ, et al. APT 2014;39:603-8

PPI-REE EoE: a-c

PPI-REE: d-f

EoE and PPI-REE cannot be discriminatedbased on symptoms, endoscopic, and

histologic features

Where is endoscopy?

sym

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Normal esophagus

23

Endoscopic features of EoE

Conclusions for EoE diagnosis

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Outline

• Definition and diagnosis

• Pathogenesis

• Epidemiology

• Therapeutic options

Schoepfer AM, et al. Dig Dis 2016

Outline

• Definition and diagnosis

• Pathogenesis

• Epidemiology

• Therapeutic options

Epidemiology

Prof. Alex Straumann

Olten, Switzerland

Swiss Medical Weekly 1994

Prof. Stephen Atttwood

Durham University, UK

Dig Dis 1993

0.35

9.45

Prasad G, et al. Clin Gastroenterol Hepatol 2009

Prevalence 55/100,000 => 1/1818 Prevalence 43/100,000 => 1/2325

Hruz P, et al. JACI 2011

Mayo Clinics, Rochester, USA

Olten County, Switzerland

Giriens B, et al., Allergy 2015

EoE in Canton of Vaud

Giriens B, et al., Allergy 2015

EoE in Canton of Vaud

Prevalence in Canton of Vaud: 1/4000

1. Croese et al. Gastro Intest Endos 20032. Noel et al NEJM 20043. Hruz P. et al. JACI 20114. Cherian et al. Arch Dis Child 20065. Prasad et al Clin Gastroenterol Hepatol 2009 6. Kapel et al. Gastroenterology 2008 7. Giriens et al. Allergy 2015

Eosinophilic Oesophagitis affects individuals in westernized countries with an increasing prevalence and incidence

Eosinophilic Oesophagitis affects individuals of all age groups from 1 to 98 years of age6

Townsville CountyQueensland-Australia

9/100‘000

Olmsted CountyMinnesota-USA

55/100‘000

Hamilton CountyOhio-USA

43/100‘000

Olten CountySwitzerland-Europe

43/100‘000

80% of pts = males

80% of pts have allergies

Vaud Switzerland-Europe

24/100‘000

• EoE is a relevant disease affecting ≈ 1/2,000(compare to IBD = 1/500)

• EoE is the second leading cause of esophagealinflammation after GERD

• EoE has a true increase in incidence and prevalence

Conclusions on epidemiology

Outline

• Definition and diagnosis

• Pathogenesis

• Epidemiology

• Therapeutic options

Therapeutic Options 2016: DDD

Diet- Elemental Diet- Elimination Diet (individually, allergy-testing based)- Six-Food Elimination Diet

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)

Dilation

Proton pump inhibitors

Clinical and histologic response

Lucendo AJ, et al. Clin Gastroenterol Hepatol 2016

Budesonide or fluticasone

http://www.ibdnet.ch/about-eoenet.html

Eos/

hpf

400X

Year 2006 2008 2008 2009 2010 Cohort 36 Peds 80 Peds 36 Adults 30 Adults 24 Peds Tx Fluticasone Fluticasone Budesonide Fluticasone Budes.

440 mcg BID 220-440 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

Topical Corticosteroids in EoE Esophageal Eosinophilia

*NSS

**

% S

ympt

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*

Year 2006 2008 2008 2009 2010Cohort 36 Peds 80 Peds 36 Adults 30 Adults 24 Peds Tx Fluticasone Fluticasone Budesonide Fluticasone Budes.

440 mcg BID 220-440 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

*NSS

Topical Corticosteroids in EoE Symptom Response

Swallowed topical steroids: what form is best?

Gastroenterology 2012;321-4

Spray (NEB) Syrup (OVB) P-value

Number of patients 11 11

Peak eos count beforetreatment

101±85 83±89 0.62

Peak eos count after treatment

89±94 11±23 0.02

Mean eos count aftertreatment

21±37 3±7 0.02

Oral viscous budesonide

(syrup)

Nebulized budesonide

(spray)

Dellon ES, et al. Gastroenterology 2012;321-4

Oral viscous budesonide

(syrup)

Nebulized budesonide

(spray)

Dellon ES, et al. Gastroenterology 2012;321-4

Use budesonide or fluticasone mixed in syrup (sucralose) or powder of Axotide discus, no

longer use nebulizers

Miehlke S, et al. Gut 2016

Miehlke S, et al. Gut 2016

Median follow-up time 5 years

48

EoE PatientPre-treatment

EoE PatientPost-treatment

EvG

EUS

E F

B C

Control(esophagus healthy)

D

A

Straumann et al. Clin Gastro Hepatol 2011

Swallowed budesonide can reduce subepithelial fibrosis

HEROES study

RPC4046 significantly reduces esophageal eosinophilic inflammationand improves endoscopic features at both dose levels. symptom improvement: HD > LD. phase 3

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<0.0001 vs PBO]).Dysphagia improvement (NS), adverse events (AEs) : 65% PBO/LD, 85% HD.

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

UEGW Vienna 2016

DIETS

Most common food allergens

Sicherer SH, et al. JACI 2006;117:470

90% of IgE mediated allergies in young adults are caused by

- Cow‘s milk

- egg

- soy

- peanut / tree nuts

- wheat

- seafood

Gonsalves N, et al. Gastroenterology Volume 142, Issue 7 2012 1451 - 1459.e1

Elimination Diet Effectively Treats Eosinophilic Esophagitis in Adults; Food Reintroduction Identifies Causative Factors

Which is the best diet?

Straumann A, Schoepfer A. Gut 2014

Elemental diet Allergy-testing based elimination diet

Arias et al, Gastroenterology 2014

Outcome: histologic remission

6-food elimination diet

Arias et al, Gastroenterology 2014

Outcome: histologic remission

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 dietarystrategy for EoE. 2 Food elimination diet (milk & Gluten) = 40% remission / 35% less endoscopies

OP323 - STEP-UP EMPIRIC ELIMINATION DIET FOR PEDIATRIC AND ADULT EOSINOPHILIC ESOPHAGITIS: THE 2-4-6 STUDY. Molina-Infante J, et al. Spain

UEGW Vienna 2016

Dellon E. Gastroenterology 2014

DILATION

APT 2013

APT 2013

Pro / Cons of different therapies

Modality Advantages Shortcomings

Drugs- STC

- Biologictherapies

• Effective• No dietary restriction

• Favorable safety profile

• No FDA-approved drugsyet on the market

• Long-term side effects / safety unknown

• Costs, availability, limited clinical efficacy

Diets • Non-pharmacologic, effective treatment option

• Antifibrotic

• Repetitive EGDs may benecessary (up to 10x)

• Needs motivated patientDilation • Long-lasting symptom

improvement• No influence on underlying

inflammation• Post-dilational pain• (safety)

Therapeutic principles in EoE in 2016

Key points on EoE

• increasing frequency • typical patient: young male with trouble swallowing• worst case scenario: bolus impaction andesophageal perforation

• therapeutic goals: - restore swallowing, - avoid impactions

• therapy options: drugs, diets, dilations

Merci bien!

Backup slides

NATURAL HISTORY OF EOE

1. What happens without therapy?

Questions to answer

2. What are the long term consequences

Organ damage? Dysplasia?

0 5 10 15 20 25

Years between diagnosis and follow up

300

250

200

150

100

50

0

DysphagiaEosinophiliaDysphagia (linear)Eosinophilia (linear)

% o

f Bas

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Straumann A, et al. Gasroenterol 2003;125:1660-69.

Intensity of Dysphagia and Inflammation over Time30 Adults followed for a mean of 7.2 years

What happens without therapy?

Inflammation Stenosis

Schoepfer AM, et al. Am J Gastroenterol 2010;105:1062-70

Straumann A, et al. Clin Gastroenterol Hepatol 2008;6:598-600

Straumann A, et al. Clin Gastroenterol Hepatol 2011;9:400-9

The story of two phenotypes

Stricture risk over time (n=200)

Schoepfer AM, et al, Gastroenterology 2013; 145:1230-1236

Endoscopic features at EoE Dx (n=200)

Schoepfer AM, et al, Gastroenterology 2013; 145:1230-1236

Consequences of remodeling

Straumann A, et al. Clin Gastroenterol Hepatol 2008;6:598-600

Is EoE a precancerous lesion?

Liacouras CA, et al. JACI 2011;128:3-20Eaden JA, et al. Gut 2001,48:526-35

Time since diagnosis(years)

116 studies

Can

cerr

isk

(%)

IBD EoE

6 CR of Barrett esophagus and concomitant EoE (1 of them with

low-grade dysplasia)

EoE not considered as a precancerous condition

(further data awaiting)