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Transcript of New Treatment Paradigms in EoE · New Treatment Paradigms in EoE ... Arias et al, Gastro 2014....
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
Arias et al, Gastro 2014
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
Arias et al, Gastro 2014
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
Arias et al, Gastro 2014
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
Rajan et al, JACI 2015
Long Term Response to Topical Steroids
Rajan et al, JACI 2015
Rajan et al, JACI 2015
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
Rajan et al, JACI 2015
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
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?