20180427 0800 spechler eoe.ppt...achalasia?) dilated 18mm balloon mucosal tear?eoe? biopsy –...
TRANSCRIPT
4/16/2018
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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.
Inci
den
ce p
er 1
00,0
00(A
ge
an
d S
ex
Ad
jus
ted
)
0
2
4
6
8
10
12
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
taxi
n-3
(pg
/ml
pe
r 2
50
,00
0 c
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
0
500
1000
1500
2000
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3500
4000
Eo
tax
in-3
(pg/
ml/2
50K
cel
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