4/16/2018 1 Update on Eosinophilic Esophagitis Update on Eosinophilic Esophagitis Stuart Jon Spechler, M.D. Chief, Division of Gastroenterology; Co-Director, Center for Esophageal Diseases, Baylor University Medical Center at Dallas Co-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. Incidence per 100,000 (Age and Sex Adjusted) 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 year Jensen E. Am J Gastroenterol 2015;110:626. • Most common cause of food impaction in patients seen in ER Sperry 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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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
• 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
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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