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New Treatment Paradigms in EoE

Seema Aceves MD, PhDAssociate Professor, Pediatrics and Medicine

Director, EGID ClinicUniversity of California, San DiegoRady Children’s Hospital, San Diego

Disclosures

• Intellectual Property: Co‐Inventor oral viscous budesonide• NIH: NIAID, NIDDK, NCATS grant• Medical Advisory Committee: APFED

Learning Objectives

• Understand how to diagnose and manage EoE• Understand and be able to choose the appropriate treatment regimen

• Know the advantages, disadvantages, and management strategies of various EoE therapeutic regimens including the current state of the art regarding dietary eliminations, testing, topical corticosteroids, and biologics

EoE is a Clinicopathologic Diagnosis

Liacouras et al, 2011 Updated Consensus Recommendations, JACI

Liacouras et al, JACI 2011

What is the Best Outcome Measure?

Symptoms and Clinical Features

Noel et al, NEJM 2004

Symptoms in Children

Symptoms: Validated Indexes

Schoepfer et al, Gastro 2014

Liacouras et al, JACI 2011

Endoscopy: Validated Indexes

Hirano et al, Gut 2012

Histologic Features>15 eosinophils per hpfEosinophil DegranulationBasal Zone Hyperplasia

Dilated Intercellular Spaces

Histologic Features

Liacouras et al, 2011 Updated Consensus Recommendations, JACI

Validated Histology Scoring Tool

Collins et al, Dis Esophagus 2016

Do These Features Correlate with One Another?

The search for surrogate markers

Symptoms

• Food Impactions

• Dysphagia

• Vomiting

Martin et al, JACI 2015

Inflammation Endoscopy Symptom

Epithelial:Average Epithelial Score

Prox+Mid+Distal

Thickened/Furrows r=0.82*White Plaques, r =0.64*

Pallor r=0.62* Dysphagia + Anorexia/Early

Satietyr=0.32*

Lamina Propria:Fibrosis + Eosinophils

Thickened/Furrows r=0.64*Dysphagia

r= 0.45*

*p<0.05Aceves et al, Annals of All Immunol 2009

Inflammation Can Correlate with Endoscopy, Symptoms

Other Outcome Measures?

FunctionalFibrotic

Esophageal Rigidity

Nicodeme et al, Clin Gastro Hepatol 2013

Eosinophilia and Rigidity Rigidity and Food Impactions

Novel Endpoints: Functional Outputs

Menard‐Katcher et al, DDW 2016

Topical Corticosteroid and Barrier Function

van Rhijn et al, Am J Gastro 2015

Diet Effects on Functional Outputs

Warners et al, DDW 2016

PAI‐1 in EoE

Rawson et al, JACI 2016

Therapeutic Options

DietTopical Corticosteroids

Biologics

Elimination Diet Options• Testing Based

– Skin Prick Testing– Serum IgE Testing – Skin Patch Testing

• Empiric Food Elimination–Six food –Four food

Elemental Formula

• 429 Patients in Total– 411 children– 18 adults

• Overall 91% Efficacy• Challenges

– Adherence– Cost– Route of ingestion

Arias et al, Gastro 2014

Elemental Formula


Empiric Elimination Diets

EoE Food Triggers in Adults

Gonsalves et al, Gastroenterology 2012

Wheat: 60%Milk: 50%

Milk Elimination

• Adults (1 study, prospective): 27% Response (Molina‐Infante et al 2014)

• Children (3 studies, 2 retrospective, 1 prospective)– 30% response (Spergel et al 2012)– 65% response (Kagalwalla et al 2012)– 64% response (Erwin et al, 2015)

Empiric Elimination


Prick and Patch Testing

Allergy Testing Based Diets: Resolutions Rates

Pediatric • Directed Elimination Diet

• 53‐65%

• Combination Directed + Empiric– Directed + Empiric Milk: 77%

• Adult– 25‐35% resolution rates

Henderson et al, JACI 2012Spergel et al, JACI 2012

Testing Based Diets


Food Desensitization Trials

• Onset of EoE with food desensitization– Peanut trials– Milk trials

• Underscores distinct disease mechanisms

Kim et al, JACI 2011Wasserman et al, JACI 2011

Imperfections with Testing

• SPT– Immediate Hypersensitivity

• APT– Is there an immunologic infiltrate at the APT test?

Imperfections with Testing

• SPT– Immediate Hypersensitivity

• APT– Is there an immunologic infiltrate at the APT test?

We Need Standardization, Validation and Trials to Show What Tests Mean in the Context of EoE

Long Term Dietary Management

• Most children have to avoid at least some foods forever

• <10% of children gain tolerance to foods

Spergel et al, JPGN 2009Henry et al, JACI 2011

Dietary Algorithm

• Food Avoidance • Food Reintroduction• Endoscopy after each food or food groups• Each eliminated and reintroduced food potentially equivalent to one endoscopy

PPI Responsive Esophageal Eosinophilia

• 50% of adult patients responded to PPI– Symptoms of EoE– Eosinophils >15 per hpf

• 40% of pediatric patients who responded to PPI– Endoscopic features of EoE– Eosinophils >15 per hpf

Molina-Infante et al, Clin Gastro Hepatol 2010Dranove et al, JPGN 2010

Topical Corticosteroids

• Multiple randomized controlled trials• Pediatric and Adult data• Use of MDI

– Puff and forcefully swallowed

• Use of viscous suspension • Swallowed to coat esophagus

– Use of nebulizer– Large vs Small particle?

Therapy Resolves Fibrosis in EoE Children

Aceves et al, Allergy 2010

>20eos/hpf<7eos/hpf

Lieberman et al, Allergy 2012

Children: Opportunity for Control?

Epithelium Sub-Epithelial Fibrosis

Rajan et al, JACI 2016

Adults: Discord Between Epithelium and Sub-epithelium?

Epithelium Sub-Epithelial Fibrosis

Lucendo et al, JACI 2011

TCS Increases Esophageal Diameter

Lee et al, CGH 2012

Kuchen et al, Allergy 2014

TCS Decreases Food Impactions

Need for New Therapies

• Biologics: anti‐IL‐5, anti‐IL‐13

• Small molecules: ruxilitinib

Pediatric EoE: Anti-IL-5

Peak oesophageal eosinophils (mean±SD)

Screening Week 12 Week 240

25

50

75

100

125

150

175

200

2250.55 mg/kg 2.5 mg/kg 10 mg/kg

End of treatment End of follow -up

Cells

/hig

h po

wer

fiel

d

Assa’ad et al, Gastroenteorogy 2011

Anti‐IL‐13

Rothenberg et al, JACI 2014

Anti‐IL‐13Placebo

Effects of Ruxolitinib in Murine GVHD

Spoerl et al, Blood 2014

JAK Inhibitors in Asthma and Ulcerative Colitis

Yoshino et al, JACI 2013

Sandborn et al, NEJM 2012

Cheng et al, DDW 2016

Long Term Therapy

• Need more studies • Pediatric (Fluticasone)

– 1760 daily, 65% remission– 73% Continued remission with dose decrease to 50%– 20% Partial remission with dose decrease

• Adult (Budesonide)– 0.5mg 52 weeks– Increase in eosinophilia but lower than initial

Butz et al, Gastro 2014Straumann et al, CGH 2010

Sustained Responders

Butz et al Gastro 2014

Long Term Response to Topical Steroids


EoE Phenotypes, Genotypes, and Endotypes

Do Different Phenotypes Need Different Therapies?

Phenotypes and Prognostics

Sears JACI 2015

Environmental Risk Factors

– Antibiotic use in infancy– C‐section– Formula feeding

Genes Plus Environment

• Twin Studies

• Genetic: 14.5% with 81% of variation accounted for by environment

Alexander et al, JACI 2014

Other Atopy: Differences in Eosinophilia

Asthmati

c-Bas

eline

Asthmati

c-Ove

rall

Non-asthmati

c-Bas

eline

Non-asthmati

c-Ove

rall

0

20

40

60

80

100

120

140Ep

ithel

ial E

osin

ophi

ls

Baseline vs Overall Epithelial Eosinophilsp=0.001

p=0.171

p=0.015


Aeroallergen Allergies

Molina‐Infante et al AJG 2015

Allergies: Differences in Interleukins

Blanchard et al, JACI 2011

SNPs and Disease Severity

SNPs, Food Sensitization, and Disease Severity

Fibrotic versus Non‐Fibrotic

Schoepfer et al, Gastro 2013

Fibrostenotic EoE

Kwiatek et al, Gastroenterology 2011

Mechanism of Fibrosis Despite Inflammatory Control

Tkachenko… Aceves, JACI In press

Dysmotile versus Non‐Dysmotile

Dysmotile Phentoype

Colizzo et al, Dis Esopahagus 2015

Smooth Muscle Inflammation

Aceves et al, JACI 2010

TGF1 and Esophageal Smooth Muscle Cells

Aceves et al, JACI 2010

TGF1 Induction Phospholamban

Beppu et al, JACI 2014

TGF1‐ Induced Contraction Depends on Phospholamban

Beppu et al, JACI 2014

Mechanisms of Smooth Muscle Hypertrophy

Tkachenko et al JACI 2016

3kPa 48kPa

Cel

l Are

a

24kPa 48kPa0.8kPa 3kPa

Tkachenko et al, JACI 2016

Rigidity

0

2000

4000

6000

8000

10000

12000

2 1 0.5 0.25 0.125 0.06 0.03

TGF1

None

Esophageal Smooth Muscle Cells Increase Traction Force with TGF1

Tkachenko, Aceves unpublished

TGF1

12000

10000

8000

6000

4000

2000

NoneBead Distance (microns)

Intermittent versus Persistent EoE

Pollens and EoE

Fogg et al, JACI 2003

EoE Clinical Trials

Question 1

• The most effective dietary option in EoE is:–A. Elemental formula–B. Milk elimination–C. Milk, Wheat, Egg, Soy elimination–D. Testing based elimination diet

Question 2

• Currently approve therapies for EoE include–A. Elemental formula–B. Oral budesonide suspension–C. Anti‐IL‐5–D. All of the above–E. None of the above

Acknowledgements • Funding Sources: NIAID, NIDDK, NCATS• Lab Members: Renee Rawson BS, Loan Du BS, Kellen Cavagnero

BS, Rebecca Khamishon, Braxton Bell, Lucas Dohil, Iris Otani MD, Lance Hse, Jessica Rajan MD, Ashmi Doshi MD,

• Collaborators: Ranjan Dohil MD, Rob Newbury MD, Richard Kurten PhD, Stacie Jones MD, Ron Marchelletta PhD, Kim Barrett PhD, David Broide MD, Taylor Doherty MD, Eugene Tkachenko PhD

What is the Right Endpoint?