Eosinophilic Esophagitis: Eosinophilic Esophagitis: Diagnosis, Clinical Diagnosis, Clinical Implications, and Implications, and

TreatmentTreatmentSeema S. Aceves, M.D., Ph.D.Seema S. Aceves, M.D., Ph.D.

Assistant Professor, Pediatrics and MedicineAssistant Professor, Pediatrics and MedicineDirector, EGID ClinicDirector, EGID Clinic

University of California, San DiegoUniversity of California, San DiegoRady ChildrenRady Children’’s Hospital, San Diegos Hospital, San Diego

Faculty DisclosureFaculty Disclosure

The University of California, San Diego has a financial interest in Meritage Pharma, the University of California may financially benefit (patent royalties) from this interest if the company is successful in developing and marketing its own product related to oral viscous budesonide. Dr Aceves is a co-inventor of OVB to which UCSD owns the patent. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.Research funding from GlaxoSmithKlineSome slides are from CDHNF, TIGERS and received funding from Takeda

Eosinophilic Esophagitis Eosinophilic Esophagitis (EoE): A Clinicopathological (EoE): A Clinicopathological

DiagnosisDiagnosis

Histologic FeaturesHistologic FeaturesEndoscopic FeaturesEndoscopic Features

Clinical FeaturesClinical FeaturesDistinctions from GERDDistinctions from GERD

Making the DiagnosisMaking the Diagnosis

Clinical FeaturesClinical Features

Atypical EoE Presenting SymptomsAtypical EoE Presenting Symptoms

CoughCough

HoarsenessHoarseness

PostPost--tussivetussive emesisemesis

““AnaphylaxisAnaphylaxis”” to every food to every food

DemographicsDemographics

0

10

20

30

40

50

60

70

80

90

EE

GI

AI

PA

Caucasian Male

EoE

GIAI

PA EoE

GI

AI

PA

Franciosi et al Clin Gastro Hepatol, 2009

Making the DiagnosisMaking the Diagnosis

Endoscopic FeaturesEndoscopic Features

EndoscopicEndoscopic FeaturesFeatures

PallorPallorLichenificationLichenificationLinear FurrowsLinear FurrowsWhite PlaquesWhite PlaquesConcentric RingsConcentric RingsStrictures and NarrowingsStrictures and Narrowings

Furuta et al, Gastroenterology 2007Fox et al, GI Endoscopy 2005

Normal

EoE

Vomiting

Abdominal Pain

Dysphagia

Esophageal Stricture

Age

50%

50%

30% (Pediatric)97% (Adults)

10% (Pediatric)37% (Adult)

Food Impaction

13% (Pediatric)51% (Adult)

Feeding Disorder

13% ??

SymptomsSymptoms

Making the DiagnosisMaking the Diagnosis

Histologic FeaturesHistologic Features

HistologyHistology>15 eosinophils per hpf >15 eosinophils per hpf especially with acid blockadeespecially with acid blockadeTypical Accompanying Typical Accompanying Features:Features:

Basal Zone HyperplasiaBasal Zone HyperplasiaDilated Intercellular SpacesDilated Intercellular SpacesEosinophil Clusters, Eosinophil Clusters, DegranulationDegranulationSubepithelial FibrosisSubepithelial Fibrosis

Furuta et al, Gastroenterology 2007

Making the DiagnosisMaking the Diagnosis

Distinguishing Distinguishing Features from GERDFeatures from GERD

Symptom ComparisonSymptom ComparisonSymptomSymptom Not at allNot at all Mild: No Mild: No

interference with interference with daily activities, daily activities, Meds as neededMeds as needed

Severe: Regularly Severe: Regularly interferes with daily interferes with daily activities or requires activities or requires daily medsdaily meds

Does your child ever have burning in the Does your child ever have burning in the chest?chest?Does your child ever feel food coming back Does your child ever feel food coming back up into his/her throat?up into his/her throat?

Not at all=0, Mild=1, Severe=2Not at all=0, Mild=1, Severe=2

Does your child complain about stomach Does your child complain about stomach pains?pains?Is your child often irritable for no apparent Is your child often irritable for no apparent reason?reason?

How often does your child complain about How often does your child complain about feeling like throwing up?feeling like throwing up?

How often does your child throw up?How often does your child throw up?

How often does your child eat too little or get How often does your child eat too little or get full before finishing his/her meal?full before finishing his/her meal?

How often does your child wake up during How often does your child wake up during the night from belly pain?the night from belly pain?

How often has your child noticed blood in How often has your child noticed blood in his/her stool in the last 3 months?his/her stool in the last 3 months?

Does your child have difficulty swallowing?Does your child have difficulty swallowing?

0

1

2

ANOREXIAEARLY SATIETY DYSPHAGIA

NormalAllergy NonEEGERDEE

***

* **

*

SCO

RE

Aceves et al, Ann of Allergy 2009

Making The DiagnosisMaking The Diagnosis

Other Distinguishing EoE Other Distinguishing EoE FeaturesFeatures

EpitheliumEpithelium

Blanchard, C. et al. J. Clin. Invest. 2006;116:536-547

EotaxinEotaxin--33

53-fold increase in Eotaxin-3 gene expression in EE versus GERD pediatric patients

Thymic Stromal Thymic Stromal LymphopoetinLymphopoetin

Increased TSLP expression in EoEIncreased TSLP expression in EoEGenetic variants in TSLP and EotaxinGenetic variants in TSLP and Eotaxin--3 3 associate with EoEassociate with EoE

Rothenberg et al, Nature Genetics 2010

Adaptive Immune SystemAdaptive Immune System

B CellsB CellsT CellsT Cells

B Cells and Local IgE ProductionB Cells and Local IgE Production

Increased B cells in :•Epithelium•Vascular Papillae•Lamina Propria

Increased IgE Class Switch

Genes

Vicario et al, Gut 2009Vicario et al, Gut 2009

T CellsT Cells

Increased CD3+Increased CD3+Increased CD8+Increased CD8+Murine EoE Induction Relies on T cellsMurine EoE Induction Relies on T cells

Lucendo et al, 2007Mishra et al, 2007Zhu et al, 2009

InterleukinsInterleukins

ILIL--55 ILIL--1313

ILIL--1515

ILIL--55EoE patients have Increased ILEoE patients have Increased IL--55ILIL--5 Deficient Mice are Protected from 5 Deficient Mice are Protected from EoEEoEILIL--5 5 miniosmoticminiosmotic pump promotes murine pump promotes murine EoEEoE

Straumann et al, JACI 2001Mishra et al, 2008

ILIL--1313

Mishra & Rothenberg, Gastroenterology 2003Blanchard et al, Clin Exp Allergy 2005

••Instilling ILInstilling IL--13 Causes 13 Causes Murine EEMurine EE••Resolved with antiResolved with anti--ILIL--13 13 AntibodyAntibody

••ILIL--13 treatment promotes 13 treatment promotes EoE transcriptomeEoE transcriptome••ILIL--13 induces the Eotaxin13 induces the Eotaxin--3 3 promoterpromoter

ILIL--1515Increased ILIncreased IL--15 on EoE Gene Chip15 on EoE Gene ChipILIL--15R15Rαα Deficient Mice: Protected from experimental Deficient Mice: Protected from experimental EoEEoEILIL--15 Increased in Human Esophageal biopsies15 Increased in Human Esophageal biopsies

Rayapudi et al, Gastroenterology 2010

Mast CellsMast Cells

Mast CellsMast Cells

•Increased Mast Cells:•Epithelium

•Smooth muscle•Increased degranulated Mast Cells in EE versus GERD

Lucendo, 2007 Aceves, 2009

Kirsch et al, JPGN 2007Konikoff et al, Gastroenterology 2006Lucendo et al, Am J Surg Path 2007

SubepitheliumSubepithelium

Lamina Propria: Lamina Propria: Esophageal RemodelingEsophageal Remodeling

Esophageal Remodeling: FibrosisEsophageal Remodeling: Fibrosis

Human subjects have increased fibrosis

Animal EE Models have increased fibrosis

0

1

2

3

EENormal

Fibr

osis

Sco

re

****

GERD

Fibrosis Score

Aceves et al, JACI 2007Mishra et al, Gastroenterology 2008

Esophageal Remodeling: Esophageal Remodeling: ProPro--Fibrotic FactorsFibrotic Factors

0

100

200

Normal EE

****

TGFβ

Pos

itve

Cells

per h

pf

GERD

0

100

200

EENormal

***

pSM

AD

2/3

posit

ive

cells

per h

pf in

LP

GERD

Aceves et al, J All Clin Immunol 2007

Esophageal Remodeling: Esophageal Remodeling: ProPro--Fibrotic FactorsFibrotic Factors

Eosinophils produce Eosinophils produce TGFTGFββ11

Aceves, J All Clin Immunol 2007Mishra, Gastronenterology

2008

Animals that lack Animals that lack eosinophils are protected eosinophils are protected from fibrosisfrom fibrosis

InflammationInflammation EndoscopyEndoscopy SymptomSymptom

Epithelial:Epithelial:Average Epithelial ScoreAverage Epithelial Score

Prox+Mid+DistalProx+Mid+Distal

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

Pallor r=0.62* Pallor r=0.62* Dysphagia + Dysphagia + Anorexia/Early Anorexia/Early

SatietySatietyr=0.32*r=0.32*

Lamina Propria:Lamina Propria:Fibrosis + EosinophilsFibrosis + Eosinophils

Thickened/Furrows r=0.64*Thickened/Furrows r=0.64*DysphagiaDysphagiar= 0.45*r= 0.45*

*p<0.05

Aceves et al, Annals of All Immunol 2009

Inflammation Correlates with Endoscopy and Symptoms

•Severity of Eosinophilic Inflammation in the epithelium and LP can correlate with Endoscopic and Symptom Findings

•Severity of Fibrosis can correlate with Endoscopic and Symptom Findings

Blood VesselsBlood Vessels

AngiogenesisAngiogenesisVascular ActivationVascular Activation

Esophageal Remodeling: VascularityEsophageal Remodeling: Vascularity

Normal GERD EE

0

25

50

75

EENormal

***

VW

F po

sitiv

e ve

ssel

spe

r hpf

GERD0

25

50

75

EENormal

***

VCA

M p

ositi

ve v

esse

lspe

r hpf

GERD

vWF Positive Vessels VCAM-1 Positive Vessels

Diagnosing EoE: ?More Than Diagnosing EoE: ?More Than Eosinophil Numbers??Eosinophil Numbers??

Eosinophil peroxidase footprint in absence of intact eosinophils meeting diagnostic criteriaProtheroe et al, CGH, 2009

Prevalence and Prevalence and EpidemiologyEpidemiology

Disease ChronicityDisease Chronicity

Clinical ImplicationsClinical Implications

TriggersTriggersChronicityChronicity

ComplicationsComplications

EoE and Allergy:EoE and Allergy:

Causal Link or CoincidenceCausal Link or Coincidence

Triggers: AeroallergensTriggers: Aeroallergens

Indoor Allergen SensitizationIndoor Allergen Sensitization

Rayapaudi et al, J Leuko Biol 2010

AerollergensAerollergens

and EoE: Causal Linkand EoE: Causal Link

Instillation of:Instillation of:Intranasal AspergillusIntranasal AspergillusIntranasal HDMIntranasal HDMIntranasal Cockroach Intranasal Cockroach Drives Murine EoEDrives Murine EoE

Mishra et al., J Clin Invest 2001 Rayapaudi et al, J Leuko Biol 2010

Aspergillus

AerollergensAerollergens

and EoE: Causal Linkand EoE: Causal Link

EE during pollen seasonEE during pollen seasonSpontaneous disease resolutionSpontaneous disease resolution

Fogg et al,

JACI 2003

Seasonal EoE?Seasonal EoE?

Moawad et al Alim Pharm Ther 2009 Almansa et al Am J Gastro 2009

Triggers: FoodsTriggers: Foods

ChronicityChronicity

Pediatric EoEPediatric EoE

79% Relapsed21% Resolved 33% No Resolution

Assa’ad et al, JACI 2007

Patients with EE diagnosed at Cincinnati Children’s Hospitaln=57

Duration of Follow up: Median 2.58 years (range 0.18-5.61)

Resolved EEn-=38

Persistent EEN=19Duration of follow up:Median 1.3 (range 0.3-5.7)

Resolved EE,No RelapseN=8Duration of follow-up: Median 0.8 years (range 0.2-3.1)

Resolved EE,Subsequent RelapseN=30Duration of follow up: Median 3.2 years (range 0.5-5)

Adult EoEAdult EoED

ysph

agia

or I

nfla

mm

ator

y In

tens

ity

ComplicationsComplications

RemodelingRemodelingStricturesStrictures

ILIL--13 Effects on Murine EoE 13 Effects on Murine EoE RemodelingRemodeling

IL-13 induces eosinophilia, esophageal thickness, and collagen accumulation Zou et al, J Immuol 2010

ILIL--13, TGFb1, and Periostin13, TGFb1, and Periostin

Increased periostin expression induced by TGFβ

Periostin increases eosinophil trafficking and adhesion

Blanchard et al, Mucosal Immunol 2008

ComplicationsComplications

Smooth Muscle DysfunctionSmooth Muscle Dysfunction

Thickened muscular Thickened muscular bundles in EEbundles in EE

Muscular dysfunction Muscular dysfunction with poor relaxationwith poor relaxation

Increased motility Increased motility correlates with correlates with episodes of dysphagiaepisodes of dysphagia Fox et al GI Endoscopy 2003Fox et al GI Endoscopy 2003

KorsapatiKorsapati et al Gastro 2009et al Gastro 2009Nurko et al, Am J Gastro 2009Nurko et al, Am J Gastro 2009

Esophageal Mast Cells Make TGFEsophageal Mast Cells Make TGFββ11

Mast Cells and Smooth Muscle Mast Cells and Smooth Muscle FunctionFunction

Aceves et al, JACI, in press

Food Impaction and Iatrogenic Food Impaction and Iatrogenic ComplicationsComplications

Food Impactions: 35%Food Impactions: 35%Flexible endoscopic bolus Flexible endoscopic bolus removal: 93%removal: 93%Rigid endoscopic bolus Rigid endoscopic bolus removal: 7%removal: 7%Transmural Perforation:Transmural Perforation:

20% Rigid Endoscopy20% Rigid EndoscopySpontaneous rupture in 1 Spontaneous rupture in 1 patientpatient

Straumann et al, Clin Gastroenterol Hepatol 2008

IgE

Mast Cell

TGFβ

B Cell

Remodeling

TreatmentTreatment

Avoiding Triggers: Avoiding Triggers: FoodsFoods

Elemental FormulaElemental FormulaElimination Diet:Elimination Diet:

TargetedTargetedEmpiricEmpiric

FoodsFoodsElimination diets resolve EEElimination diets resolve EE

Empiric: 50% (adults)Empiric: 50% (adults)--74% (pediatric)74% (pediatric)Targeted: 70%Targeted: 70%

Elemental formula resolves EEElemental formula resolves EE>90%>90%

Addition of foods causes EEAddition of foods causes EEAnimal models using ovalbumin cause EE/EGAnimal models using ovalbumin cause EE/EG

Kagalwalla

et al, Clin Gastro Hepatol

2006 Liacouras et al, Clin Gastro HepatolHogan et al, Nature Immunology 2001

Spergel et al, JACI 2008Song et al, Clin Exp Allergy 2009

Elemental Formula Eliminates EoEElemental Formula Eliminates EoE

70

75

80

85

90

95

100

Kelly 1993

Kelly 1993Kelly 1993

Markowitz2003

Liacouras2005

Spergel 2005

Kagalwalla2006

IgE TestingIgE Testing

Use food extracts as for anaphylaxisUse food extracts as for anaphylaxisMost data is from ChildrenMost data is from Children’’s Hospital of s Hospital of PhiladelphiaPhiladelphia

Food Food ImmunoCAPImmunoCAP Testing: Limited data in Testing: Limited data in EGIDsEGIDs

Overall varying success with RAST based Overall varying success with RAST based elimination dietelimination dietPaucity of dataPaucity of data

Food Patch TestFood Patch Test

Delayed/Cellular HypersensitivityDelayed/Cellular HypersensitivityFresh foods or single item baby foodFresh foods or single item baby foodMilk, egg, soy, wheat used as powders in Milk, egg, soy, wheat used as powders in salinesalineApply in large Finn chamberApply in large Finn chamberRemove at 48 hoursRemove at 48 hoursRead at 72 hoursRead at 72 hours

Predictive Values: SPT+APTPredictive Values: SPT+APT

Spergel et al, JACI 2007

Dietary Options: Pros and ConsDietary Options: Pros and ConsElemental Elemental FormulaFormula

Directed Directed EliminationElimination

Empiric Empiric EliminationElimination

ComplianceCompliance DifficultDifficult BetterBetter BetterBetterCostCost ExpensiveExpensive ManageableManageable ManageableManageableInvasive?Invasive? Potentially (GT, Potentially (GT,

NGT)NGT)NoNo NoNo

Number of Number of EGDsEGDs

ManyMany Fewer, every 1Fewer, every 1--2 2 foodsfoods

Fewer, every 1Fewer, every 1--2 2 foods (6 in total)foods (6 in total)

TolerabilityTolerability LowLow BetterBetter BetterBetterComplicationsComplications Oral AversionOral Aversion

CostCostTube relatedTube related

Nutritional Nutritional NutritionalNutritional

Response RateResponse Rate >95%>95% 75%75% 75%75%QOLQOL UnknownUnknown UnknownUnknown UnknownUnknown

MedicationsMedications

Topical CorticosteroidsTopical CorticosteroidsBiologicsBiologics

Oral Viscous BudesonideOral Viscous Budesonide

•

Overall Response Rate to viscous budesonide: 87

•

Overall Response Rate to Placebo + PPI: 0%

Dohil et al, Gastroenterology 2010

0

50

100

150

200

0 2 4 6 8 10 12 14Time (weeks)

Eosi

noph

ils/m

m2

MepolizumabPlacebo

Screening

0

50

100

150

200

0 2 4 6 8 10 12 14Time (weeks)

Eosi

noph

ils/m

m2

MepolizumabPlacebo

Screening

P = 0.387

P = 0.001* - 55.3 %

- 55.3 %

Mean (Mean (±±SD) SD) esophagealesophageal

eosinophils (ECP staining)eosinophils (ECP staining)AntiAnti--ILIL--5 Therapy in EoE5 Therapy in EoE

Straumann et al, Gut 2010

Effects of Therapy on Effects of Therapy on ComplicationsComplications

Topical Fluticasone Reverses Topical Fluticasone Reverses Transcriptome ProfileTranscriptome Profile

Blanchard et al, JACI 2007

Treatment Resolves Pathology: Treatment Resolves Pathology: RemodelingRemodeling

LP Eosinophils Fibrosis Score

Aceves et al, Allergy 2010

Treatment Resolves Pathology: Treatment Resolves Pathology: RemodelingRemodeling

Aceves et al, Allergy 2010

TGFβ pSmad2/3

Decreased Vascular ActivationDecreased Vascular Activation

VCAM-1 Positive Vessels Dilated Intercellular Spaces

Aceves et al, Allergy 2010

Treatment StrategyTreatment Strategy

Aeroallergen Testing: SPT

EoE: >15 eosinophils per hpf despite acid blockade

Food Testing: SPT?APT

Institute Therapy

Elimination Diet

Empiric: 6 Food EliminationDirected: SPT, APT Based

Repeat EGD with Biopsy

Histologic/EGD/Symptom Response

Maintenance

Topical Corticosteroids

>7-10 years old: Fluticasone BID

Budesonide + Sucralose/Maltodexrtin

Food Reintroduction

Histologic/EGD FailureElemental FormulaSystemic corticosteroidsBiologics

ConclusionsConclusions

EoE is a chronic disease of children and adultsEoE is a chronic disease of children and adultsTypical symptoms include dysphagia, abdominal pain, Typical symptoms include dysphagia, abdominal pain, and anorexia/early satietyand anorexia/early satietyPrevalence is increasingPrevalence is increasingSuccessful therapies are diet and topical corticosteroidsSuccessful therapies are diet and topical corticosteroidsComplications: Strictures, RemodelingComplications: Strictures, RemodelingPathogenesis includes EotaxinPathogenesis includes Eotaxin--3, IL3, IL--5, IL5, IL--13, IL13, IL--15, 15, TGFb1 and involves the Epithelium, Innate and TGFb1 and involves the Epithelium, Innate and Adaptive Immunity, Vascularity, and Smooth MuscleAdaptive Immunity, Vascularity, and Smooth MuscleNo surrogate disease markersNo surrogate disease markers