What’s New in Eosinophilic Esophagitis and PPI-Responsive Esophageal Eosinophilia? Stuart Jon Spechler, M.D. Chief, Division of Gastroenterology, VA North Texas Healthcare System; Co-Director, Esophageal Diseases Center, Professor of Medicine, Berta M. and Cecil O. Patterson Chair in Gastroenterology, UT Southwestern Medical Center

Eosinophilic Esophagitis (EoE) Eosinophils infiltrate esophageal squamous epithelium, releasing secretory products that mediate: Tissue damage Tissue remodeling Symptoms

Incidence of Eosinophilic Esophagitis (EoE) in Olmsted County, Minnesota 12 10 8 Incidence per 100,000 (Age and Sex Adjusted) 6 4 2 1976- 1980 1981- 1985 1986- 1990 1991- 1995 1996- 2000 2001- 2005 Prasad. Clin Gastroenterol Hepatol 2009;7:1055.

EoE in the United States Prevalence 50-100 per 100,000 - Similar to ulcerative colitis Dellon E. Clin Gastroenterol Hepatol 2014;12:589. Most common cause of food impaction in patients seen in ER Sperry S. Gastrointest Endosc 2011;74:985. Health-care cost $0.5-1.4 billion per year Jensen E. Am J Gastroenterol 2015;110:626.

EoE Symptoms Symptoms are not specific. Adults Dysphagia Children Food Impaction Children Vomiting Feeding intolerance Feeding aversion Failure to thrive Chest Pain Heartburn Upper abdominal pain (CLICK) The most common clinical manifestations of EoE are dysphagia, or odynophagia. (CLICK) Many EoE patients experience food impaction. The other clinical manifestations of EoE vary between children and adults. (CLICK) In children, because they can not verbalize their symptoms, often times they have vomiting, feeding intolerance or feeding aversion, and failure to thrive. (CLICK) In adults, their symptoms are often chest pain, heartburn, epigastric pain; symptoms that all are very similar to GERD. These patients are often diagnosed with refractory “GERD” . Symptoms are not specific.

EoE Endoscopic Reference Score (EREFS) Exudates (plaques) None of these findings are specific for EoE Rings (trachealization) Esophagus appears normal in ~10% Edema (pallor) Furrows (vertical lines) Strictures Hirano I. Gut 2013;62:489.

EoE Histology ≥15 eosinophils per HPF Eosinophil microabscesses Basal zone hyperplasia Dilated intercellular spaces Epithelium Subepithelial fibrosis Subepithelial fibrosis The finding of ≥15 eosinophils per HPF has no established biological importance. Histological findings are not specific.

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

EoE Affects Both Sexes Male:Female = 3:1

Eosinophilic Esophagitis Conceptual Definition 2011 Eosinophilic esophagitis is a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Liacouras CA et al. J Allergy Clin Immunol 2011;128:3-20.

Eosinophilic Esophagitis Consensus Diagnostic Guideline 2011 EoE is a clinicopathologic disease. Clinico: Symptoms related to esophageal dysfunction Pathologic: ≥1 esophageal biopsy shows eosinophil-predominant inflammation with ≥15 eos per HPF (recommend 2-4 biopsy specimens from both proximal and distal esophagus) Disease should be isolated to the esophagus Disease should remit with treatments of dietary exclusion, topical corticosteroids or both Liacouras CA et al. J Allergy Clin Immunol 2011;128:3-20.

Evidence that Eosinophilic Esophagitis is an Allergic Disorder 50-60% of patients have history of atopic disease (rhinitis, asthma, atopic dermatitis) Most patients exhibit sensitization to food and/or aeroallergens 15% have food anaphylaxis During oral immunotherapy for food allergy, 3% of patients develop EoE In animal models, EoE can be induced by allergen sensitization Dramatic response to elemental diet

If EoE is caused by food allergy, then why do eosinophils home to the esophagus?

RNA Microarray Analysis of Esophageal Biopsies 230 Genes Downregulated 344 Genes Upregulated Eotaxin-3 (↑ >50-Fold) A potent eosinophil chemoattractant 1 2 3 4 5 6 1 2 3 4 5 6 7 8 9 10 11 12 13 Controls Pts. with EoE Blanchard. J Clin Invest 2006;116:536

Immune System Activation Th1 and Th2 Differentiation Antigen Antigen Presenting Cell Activate Immune System Naive CD4+ T Cells EoE is due to the infiltration of the esophagus by eosinophils. A number of cytokines have been indentified as chemotactic signals for eosinophils. Cytokines are produced from inflammatory cells. (CLICK) Infection, injury, allergens activate (CLICK) the immune system including CD4 lymphocytes. If these lymphocytes secret (CLICK) predominantly TNF-b, IFN-g, they are classified (CLICK) as Th1 cells. However if these same CD4+ helper cells secrete (CLICK) predominantly IL-4 or IL-13 they are classified (CLICK) as Th2 cells which are often involved in allergic disease. In EoE, (CLICK) the secretion of IL-4 and IL-13 by Th2 cells is thought to play a role. Allergic Disorders Th1 (T-helper 1) Th2 (T-helper 2) TNF-β, IFN-Ɣ IL-4, IL-5, IL-13

* IL-13 (a Th2 cytokine) Stimulates Eotaxin-3 Secretion in Esophageal Cells from EoE Patients Eotaxin-3 is a potent eosinophil chemoattractant Unstimulated IL-13 (10 ng/ml) * (pg/ml per 250,000 cells) Eotaxin-3 *p<0.001 * Recently, our group published these data on how the Th2 cytokine IL-13 and IL-4 stimulates eotaxin-3 secretion in esophageal squamous cells from EoE patients. EoE1-T and EoE2-T are esophageal squamous cell lines established from biopsy specimens taken from EoE patients. Unstimulated, these cells secrete very little eotaxin-3. But when you treat them with IL-13, their production of eotaxin-3 increases dramatically. EoE1-T EoE2-T Cheng E et al. Gut 2013;62:824.

IL-4 (a Th2 cytokine) Stimulates Eotaxin-3 Secretion in Esophageal Cells from EoE Patients Eotaxin-3 is a potent eosinophil chemoattractant * Unstimulated IL-4 (10 ng/ml) *p<0.001 (pg/ml per 250,000 cells) Eotaxin-3 Similarly, when you treat the EoE cells with IL-14, their production of eotaxin-3 also increases dramatically. * EoE1-T EoE2-T Cheng E et al. Gut 2013;62:824.

Eosinophilic Esophagitis Pathogenesis Model (Genetically-Susceptible Individual) Food allergen activates immune system Th2 Response ↑↑↑ esophageal production of eotaxin-3 ↑ IL-5 ↑ IL-13 ↑ IL-4 ↑ eosinophil production, activation, recruitment ↑↑↑eotaxin-3

GERD Eosinophilic Esophagitis AGA Institute 2007 Definition of EoE Gastroenterology 2007;133:1342. A primary disorder of the esophagus characterized by UGI symptoms, esophageal biopsy ≥15 eos/hpf, and the absence of pathologic GERD GERD Eosinophilic Esophagitis EoE GERD

help these EoE patients Possible Reasons for the Association of GERD and Esophageal Eosinophils GERD causes mild eosinophilia (<7 eos/hpf) GERD and EoE co-exist but are unrelated GERD EoE EoE contributes to or causes GERD Eosinophil secretory products alter esophageal motility and permeability, and induce remodeling GERD EoE 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 EoE PPIs might help these EoE patients Spechler, Genta, Souza. Am J Gastroenterol 2007;102:1301.

“A trial of PPI therapy is recommended for patients with eosinophilic esophagitis, even if the diagnosis seems clear-cut.” Spechler S, Genta R, Souza R. Am J Gastroenterol 2007;102:1301.

Only acid-peptic disease can respond to PPIs Rationale for a Trial of PPI Therapy in Patients with Esophageal Eosinophilia PPIs only affect gastric acid secretion Only acid-peptic disease can respond to PPIs Response to PPIs = GERD

PPI-Responsive Esophageal Eosinophilia (PPI-REE) Reflux Have typical EoE symptoms and histology Do not have GERD by endoscopy or pH monitoring Exhibit a clinical and histological response to PPIs 30% to 50% of patients with symptomatic esophageal eosinophilia respond to PPIs

Possible Explanations for PPI-Responsive Esophageal Eosinophilia (PPI-REE) Pts have subclinical GERD, not Ag-driven eosinophilia Responds to anti-secretory effects of PPIs Non-Erosive Reflux Disease (NERD) Pts have Ag-driven eosinophilia (EoE), not GERD Responds to anti-inflammatory effects of PPIs Patients have GERD exacerbating Ag-driven EoE Responds to both anti-secretory and anti-inflammatory effects of PPIs

Omeprazole Blocks Th2 Cytokine-Stimulated Eotaxin-3 Secretion in Squamous Cells from EoE Patients Unstimulated Omeprazole (50μM) *p<0.05 compared to IL-13 alone # p<0.05 compared to IL-4 alone IL-13 (50ng/ml) IL-4 (10ng/ml) IL-13+Omeprazole (OME) Eotaxin-3 (pg/ml/250K cells) IL-4+Omeprazole (OME) * # OME OME Recently, we published data showing that PPIs might have direct eosinophil-reducing effects in the esophagus. Esophageal squamous cells can produce eotaxin-3, which is a potent eosinophil chemoattractant that draws eosinophils to the esophagus in EoE. This slide shows eotaxin-3 secretion by EoE1-T and EoE2-T, which are two esophageal squamous cell lines from EoE patients. At baseline, these cells make very little eotaxin-3, and omeprazole treatment, shown here in yellow, has no apparent effect on their eotaxin-3 production. When the cells are stimulated with Th2 cytokines, IL-13 and IL-4, their expression of eotaxin-3 increases dramatically. However, that cytokine-stimulated eotaxin-3 secretion can be blocked by treatment with the PPI omeprazole. We have proposed that this acid-independent PPI effect of blocking Th2 cytokine-stimulated eotaxin-3 production by esophageal squamous cells might explain the phenomenon of PPI-responsive esophageal eosinophilia. # * OME OME EoE1-T EoE2-T Cheng E et al. Gut 2013;62:824.

Effects of Lansoprazole on IL-4-Stimulated Eotaxin-3 Protein Secretion in EoE Squamous Cell Lines EoE1-T + * EoE2-T * Inhibition of IL-4-stimulated eotaxin-3 secretion may be a class effect of PPIs. Eotaxin-3 (pg/ml) To see if this inhibitory effect was unique to omeprazole, we treated our EoE cell lines with another PPI, lansoprazole. Similar to omeprazole, lanoprazole at concentrations of 10 and 50 uM significantly decreased IL-4-stimulated eotaxin-3 protein secretion. This suggests that the inhibition of IL-4-stimulated eotaxin-3 secretion may be a class effect of the PPIs. + + Control IL-4 10 µM 50 µM Control IL-4 10 µM 50 µM IL-4 +Lansoprazole IL-4 +Lansoprazole Zhang X et al. PLoS One 7:e50037, 2012

PPIs and Esophageal Eosinophilia in GERD and in EoE Reflux PPIs have anti-secretory (gastric acid inhibitory) effects that might be beneficial both for GERD and for EoE. PPIs have anti-inflammatory effects (independent of their anti-secretory effects) that might be beneficial both for GERD and for EoE. For patients with esophageal symptoms and eosinophilia, a clinical and/or histological response to PPIs… - Does not rule in GERD - Does not rule out EoE

A trial of PPI therapy is recommended for patients with symptomatic esophageal eosinophilia, even if the diagnosis of eosinophilic esophagitis seems clear-cut. A trial of PPI therapy is recommended for patients with eosinophilic esophagitis, even if the diagnosis seems clear-cut. Cheng E, Souza R, Spechler S. Gastroenterol Clin North Am 2014;43:243. Spechler S, Genta R, Souza R. Am J Gastroenterol 2007;102:1301.

Topical Steroid Therapy for EoE (Fluticasone, Oral Viscous Budesonide) RCTs show that topical steroids significantly reduce esophageal eosinophil levels Most patients experience symptomatic relief during treatment with steroids Symptoms recur frequently when steroids are stopped Limited data on efficacy and safety of long-term steroid therapy for EoE

Topical Steroid Therapy for EoE in Adults Fluticasone 2-4 puffs (220μg/puff) BID, after breakfast and dinner Do not use spacer (designed for lung delivery) Inspire deeply first, depress inhaler, swallow Do not eat or drink for at least 30 minutes

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, soy, eggs, wheat, nuts, seafood) 72% success (95% CI, 66-78%) Prohibit 4 foods – 54% success Molina-Infante. Rev Esp Enferm Dig 2015;107:1639. Elemental diet Use amino acid-based formulas 91% success (95% CI, 85-96%) Arias A. Gastroenterology 2014;146:1639.

Management of EoE 2015 Patient with Esophageal Symptoms and Esophageal Eosinophilia Symptoms Resolve Trial of PPI BID 4-8 weeks Dx: GERD or PPI-REE Continue PPI Rx Symptoms Persist Dx: EoE Empiric Elimination Diet Symptoms Resolve Symptoms Persist Patient Declines Diet Therapy Continue Diet Rx Topical Steroids 6-8 weeks Symptoms Resolve Symptoms Persist Follow, Resume Steroids PRN Rule Out Infection (Candida, HSV) Dysphagia Persists Esophageal Stenosis Esophageal Dilation Modified from Aceves, Furuta, Spechler. Gastrointest Endosc Clin N Am 2008;18:195

Photo by S. Spechler