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Update on Eosinophilic EsophagitisUpdate on Eosinophilic Esophagitis

Stuart Jon Spechler, M.D.Chief, Division of Gastroenterology; Co-Director, Center for Esophageal Diseases,

Baylor University Medical Center at DallasCo-Director, Center for Esophageal Research

Baylor Scott and White Research Institute

Disclosures

• Consultant – Ironwood, Takeda

• Off label – Proton pump inhibitors and topical steroids for eosinophilic esophagitis

Eosinophilic Esophagitis(EoE)

• Tissue damage

Eosinophils infiltrate esophageal squamous epithelium, releasing secretory products mediating:

• Tissue remodeling

• Symptoms

Incidence of Eosinophilic Esophagitis (EoE)in Olmsted County, Minnesota

Prasad. Clin Gastroenterol Hepatol 2009;7:1055.

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1976-1980

1981-1985

1986-1990

1991-1995

1996-2000

2001-2005

EoE in the United States

• Prevalence 50-100 per 100,000- Similar to ulcerative colitis

Dellon E. Clin Gastroenterol Hepatol 2014;12:589.

• Health-care cost $0.5-1.4 billion per yearJensen E. Am J Gastroenterol 2015;110:626.

• Most common cause of food impaction in patients seen in ERSperry S. Gastrointest Endosc 2011;74:985.

EoE Affects Children and Adults of All Ages in All Racial and Ethnic Groups

• Reports of EoE from US, Canada, Australia, New Zealand, Europe, Mexico, India, Israel,

Saudi Arabia, Iran, Japan, China

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EoE Affects Both SexesMale:Female = 3:1

Evidence that Eosinophilic Esophagitis is an Allergic Disorder

• 50-60% of patients have history of atopic disease (rhinitis, asthma, atopic dermatitis)

• In animal models, EoE can be induced by allergen sensitization

• Dramatic response to elemental diet

• Most patients exhibit sensitization to food and/or aeroallergens- 15% have food anaphylaxis

• During oral immunotherapy for food allergy, 3% of patients develop EoE

If EoE is caused by food allergy, then why do eosinophils

home to the esophagus?

RNA Microarray Analysis of Esophageal Biopsies

Controls Pts. with EoE

230 GenesDownregulated

344 GenesUpregulated

Eotaxin-3 (↑ >50-Fold)

Blanchard. J Clin Invest 2006;116:536

1 2 3 4 5 6 1 2 3 4 5 6 7 8 9 10 11 12 13

A potent eosinophil chemoattractant

Down-regulated

Up-regulated

Immune System ActivationTh1 and Th2 Differentiation

Antigen

Activate Immune SystemNaive CD4+ T Cells

Th1(T-helper 1)

Th2(T-helper 2)

TNF-β, IFN-Ɣ IL-4, IL-5, IL-13

Antigen Presenting Cell

AllergicDisorders

UnstimulatedIL-4 (10 ng/ml)

*

IL-4 (a Th2 cytokine) Stimulates Eotaxin-3 Secretion in Esophageal Cells from EoE Patients

EoE1-T EoE2-T

*p<0.001

Eo

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(pg

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ells

)

Eotaxin-3 is a potent eosinophil chemoattractant*

Cheng E et al. Gut 2013;62:824.

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Eosinophilic Esophagitis Pathogenesis Model(Genetically-Susceptible Individual)

Food allergen activates immune system

Th2 Response↑ IL-5

↑ eosinophil production, activation, recruitment

↑ IL-13↑ IL-4

↑↑↑ esophageal production of

eotaxin-3

↑↑↑eotaxin-3

EoE Symptoms

Adults

• Dysphagia

• Food Impaction

Children

• Vomiting

• Feeding intolerance

• Feeding aversion

• Failure to thrive

• Chest Pain

• Heartburn

• Upper abdominal pain

These also can be symptoms of GERD.

0=absent, 1=mild, 2=moderate, 3=severe

EoE Endoscopic Reference Score (EREFS)

• Exudates (plaques)

• Rings (trachealization)

• Edema (pallor)

• Furrows (vertical lines)

• StricturesHirano I. Gut 2013;62:489.Dellon E. CGH 2016;14:31.

Esophagus appears normal in 5-10%

0=absent, 1=mild, 2=severe

0=absent, 1=present

0=absent, 1=mild, 2=severe

0=absent, 1=present

Strictures can be GERD complications

EoE Histology

• ≥15 eosinophils per HPF

• Eosinophil microabscesses

• Basal zone hyperplasia

• Dilated intercellular spaces

• Subepithelial fibrosis

GERD also can cause esophageal eosinophilia.

Epithelium

Subepithelialfibrosis

EoE or GERD?

GERD EosinophilicEsophagitis

A primary disorder of the esophagus characterized by UGI symptoms, esophageal biopsy ≥15 eos/hpf,

AGA Institute 2007 Definition of EoEGastroenterology 2007;133:1342.

and the absence of pathologic GERD

EoE GERD

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Possible Reasons for the Association of GERD and Esophageal Eosinophils

• GERD causes mild eosinophilia (<7 eos/hpf)

Spechler, Genta, Souza. Am J Gastroenterol 2007;102:1301.

• GERD and EoE co-exist but are unrelated

• EoE contributes to or causes GERD– Eosinophil secretory products alter esophageal

motility and permeability, and induce remodeling

• GERD contributes to or causes EoE– Reflux might cause esophageal mucosa to

produce chemokines that attract eosinophils– Increased esophageal permeability might expose

deep layers of esophageal epithelium to antigens

GERD

GERD

GERD

EoE

EoE

EoE

2007 Rationale for a Diagnostic Trial of PPI Therapy for Patients with

Esophageal Symptoms and Eosinophilia

Response to PPIs = GERD

PPIs only affect gastric acid secretion

Only acid-peptic disease can respond to PPIs

PPI-Responsive Esophageal Eosinophilia(PPI-REE)

• Have typical EoE symptoms and histology

• Do not have GERD by endoscopy or pH monitoring

• Exhibit a clinical and histological response to PPIs

Reflux

30% to 50% of patients with symptomatic esophageal eosinophilia respond to PPIs

Possible Explanations for PPI-Responsive Esophageal Eosinophilia (PPI-REE)

1) Pts have subclinical GERD, not Ag-driven eosinophilia Responds to anti-secretory and ?anti-inflammatory effects of PPIs

2) Pts have Ag-driven eosinophilia (EoE), not GERDResponds to anti-inflammatory effects of PPIs

Non-ErosiveReflux Disease

(NERD)

3) Patients have GERD exacerbating Ag-driven EoEResponds to both anti-secretory and anti-inflammatory effects of PPIs

0

500

1000

1500

2000

2500

3000

3500

4000

0

500

1000

1500

2000

2500

3000

3500

4000

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500

1000

1500

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2500

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3500

4000

Eo

tax

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(pg/

ml/2

50K

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ls)

EoE1-T EoE2-T

UnstimulatedOmeprazole (50μM)

IL-13 (50ng/ml)

IL-13+Omeprazole (OME)IL-4+Omeprazole (OME)

IL-4 (10ng/ml)

* #

*

*p<0.05 compared to IL-13 alone# p<0.05 compared to IL-4 alone

#

Omeprazole Blocks Th2 Cytokine-Stimulated Eotaxin-3 Secretion in Squamous Cells from EoE Patients

Cheng E et al. Gut 2013;62:824.

OME OME

OMEOME

EoE and PPI-REE Have Similar Esophageal Transcriptome

Wen T et al. J Allergy Clin Immunol 2015;135:187.

Normal EoE

Esophageal Transcriptome (59 EoE genes)

PPI-REEGERD

Red=Upregulated Blue=Downregulated

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Eosinophilic Esophagitis (EoE) vs. PPI-Responsive Esophageal Eosinophilia (PPI-REE)

• Clinical, endoscopic, histologic and gene expression features of EoE and PPI-REE are virtually identical.

• Multivariate analyses have not identified any feature that distinguishes EoE from PPI-REE.

Dellon ES. Am J Gastroenterol 2013;108:1854.Wen T. J Allergy Clin Immunol 2015;135:187.

Patients with PPI-REE Can Respond to Elimination Diets and Topical Steroids

• 9 patients with typical EoE history, histology, endoscopy

• 4 had normal pH monitoring, responded to elimination diet (no PPI trial), specific food triggers identified in 3– Started on PPIs and unrestricted diet, symptoms and

eosinophilia did not return

Lucendo AJ et al. J Allergy Clin Immunol 2016;137:931.

• 4 had PPI-REE on unrestricted diet– 3 PPIs stopped, disease remitted on elimination diet,

food triggers identified on subsequent challenge

– 1 PPIs stopped, disease remitted on topical steroids

• 1 responded to topical steroids– Steroids stopped, disease remitted on PPIs

Irrespective of the mechanism, patients with an antigen-driven esophageal eosinophilia can respond to PPIs!

• Early investigators were compelled to use rigid criteria to distinguish EoE from GERD to establish that EoE was a new disease.

• The notion that PPIs can only benefit an acid-driven esophageal disease (GERD) and not an antigen-driven esophageal disease (EoE) is untenable.– Irrespective of the mechanism, patients with an antigen-driven

esophageal eosinophilia can respond to PPIs.– Patients with the antigen-driven, clinicopathologic syndrome

that we recognize as EoE can respond to PPIs.

Conclusions about PPI-REE

• Use of the term “PPI-REE” is artificial, potentially impeding progress, and should be abandoned.

• 29 year-old man with heartburn and dysphagia for 8 years– Treated empirically with PPIs for suspected GERD, with partial relief

– Endoscopy when symptoms increased over 6 months

Consequence of Confusion about PPI-REE and EoE

Distal narrowing(?peptic stricture vs.

achalasia?)

Dilated

18mmballoon

Mucosal tear?EoE?

Biopsy

– Incomplete relief of dysphagia

– Esophageal manometry: 100% failed peristalsis, IRP 12.4 mm Hg

– Sent to surgeon for Heller myotomy, surgeon refers for further evaluation

– History of asthma and seasonal allergies, PPIs not stopped for endoscopy

– Stop PPIs, repeat endoscopy 4 weeks later

Endoscopy performed with patient on PPIs cannot rule out EoE

Stop PPIs for 3-4 weeks before diagnostic endoscopy

if EoE is a consideration

Odiase E, Schwartz A, Souza RF, Martin J,

Konda V, Spechler SJ. Gastroenterology 2018 [Epub ahead of print] >50 eos/hpf

Approaches to Diet Therapy for EoE

• Directed elimination diet– Based on skin prick testing– 46% success (95% CI, 35-56%)

• Empiric elimination diet– Prohibit most common food allergens

(milk, wheat, eggs, soy, nuts, seafood)– 72% success (95% CI, 66-78%)

Arias A. Gastroenterology 2014;146:1639.

• Elemental diet– Uses amino acid-based formulas– 91% success (95% CI, 85-96%)

Six Food Group Elimination Diet (SFGED)[milk, wheat, eggs, soy/legumes, nuts, seafood]

• For EoE patients who respond to SFGED (~70%):– Reintroduce food groups one at a time for 6 weeks,

assess symptom response, repeat endoscopy with biopsy– At least 7 endoscopies performed over 42 weeks

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Step-Up (2-4-6) Elimination Diet

• Start with two food group elimination diet (TFGED) – Eliminates 2 most common food triggers - milk and wheat

(gluten-containing cereal grains – wheat, barley, rye, oats)

• Step up to four food group elimination diet (FFGED)– Eliminates milk, wheat, eggs, soy/legumes)

• Step up to a six food group elimination diet (SFGED)– Eliminates milk, wheat, eggs, soy/legumes, nuts, seafood

• For patients who respond to diet– Reintroduce food groups one at a time for 6 weeks – Repeat endoscopy and esophageal biopsy

Molina-Infante. J Allergy Clin Immunol 2018 [Epub ahead of print].

2-4-6 Elimination Diet Results220 EoE patients eligible

130 patients 2 food group elimination diet

56 (43%) remission 74 (57%) no remission

54 step up to 4 food group elimination diet

20 refuse more diet

10 (19%) remission 44 (81%) no remission

27 step up to 6 food group elimination diet

17 refuse more diet

8 (30%) remission 19 (70%) no remission

90 refuse diet

74respond

2 food group elimination

diet identified

56/74 (76%) responders

4 food group elimination

diet identified

66/74 (89%) responders

Molina-Infante J et al. J Allergy Clin Immunol 2018

[Epub ahead of print]

127refuse

Food Triggers Identified by Food ReintroductionFood triggers identified in 64 of 73 patients (88%) who achieved clinico-histologic remission on diets

Milk Grains(Gluten-Containing)

Egg Soy/Legumes

Fish/Seafood

Nuts

81%

43%

15%9% 5%

Molina-Infante. J Allergy Clin Immunol 2018 [Epub ahead of print].

Proportion of Patients with Food Triggers Identified

Responders With 1 or 2 

Food Triggers

Molina-Infante J et al. J Allergy Clin Immunol 2018

[Epub ahead of print]

1

2

1

2

3 3 4

5

1 2 3 4 5

TFGED FFGED SFGED

My Take on EoE Diet Therapy• Start with two food group elimination diet

– Success rate ~40%– Identifies ~75% of patients who will respond to diet

• Proceed to four food group elimination diet for motivated non-responders– Success rate ~60%– Identifies ~90% of patients who will respond to diet

• Identifies ~90% of patients who have 1 or 2 food triggers

• Proceed to six food group elimination diet only for exceptionally motivated patients– Identifies few additional responders, most of whom

will have ≥3 food triggers

Biologic Agents for EoE• IL-5 monoclonal antibodies

– Mepolizumab– Reslizumab

• IL-13 monoclonal antibodies– QAX576– Lebrikizumab

• IL-4/IL-13 receptor monoclonal antibodies– Dupilumab (IL-4Rα1)– RPC4046 (IL-13Rα1 and IL-13Rα2)

• Future targets– Anti-IL-5Rα (benralizumab)– Anti-integrin (vedolizumab)– Chemokine receptor CCR3 antagonist (GW766994)– Anti-Siglec-8 [sialic acid-binding immunoglobulin-like

inhibitory receptor, found on mast cells and eosinophils] (AK002)

– Anti-TSLP– Anti-IL-9

• Agents that don’t work– Anti-IgE Omalizumab– Anti-TNFα Infliximab

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Management of EoE 2018Patient with EoE symptoms and

esophageal eosinophilia (>15 eos/hpf)

Exclude non-EoE disorders that can cause esophageal eosinophilia(e.g. vasculitis, eosinophilic gastroenteritis, Crohn’s, connective tissue disease)

Two FoodElimination Diet

Continue dietreintroduce foods,Identify triggers

PPIs

Steroids PRNIf chronic use required, consider annual serum cortisol, plasma ACTH

Dysphagia Persists

Esophageal Dilationstart low and go slow

Remission

Topical Steroids6-8 weeks

No

RemissionRemission

Considerfour food

eliminationdiet

Remission

ContinuePPIs

Consider six food elimination

diet only forexceptionally

motivated

NoRemission

No

Remission

EoE diagnosis established

or or