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
Sym
ptom
s
His
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Exc
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f oth
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EoE diagnosis
Sym
ptom
s
His
tolo
gy
Exc
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f oth
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cond
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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
Sym
ptom
s
His
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Exc
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Squamous Epithelium with features of EoE compared with normal findings
EoE diagnosis
Sym
ptom
s
His
tolo
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Excl
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n of
ot
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cond
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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
ptom
s
His
tolo
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Exc
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f oth
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cond
ition
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Normal esophagus
23
Endoscopic features of EoE
Conclusions for EoE diagnosis
sym
ptom
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His
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Exc
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f oth
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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
omat
ic
*
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
elin
e
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)
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