Fibrosis and Remodeling in EoE
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1 Fibrosis and Remodeling in EoE Seema S. Aceves, M.D., Ph.D. Division of Allergy, Immunology University of California, San Diego Rady Children s Hospital, San Diego
2 Faculty Disclosure Co-inventor of OVB Research funding NIH/NIAID DOD TIGERS GlaxoSmithKline No FDA approved therapies for EoE Topical corticosteroids are off label use
3 Question 1 Features associated with esophageal remodeling include A. Fibrosis B. Angiogenesis C. Basal zone hyperplasia D. Muscular hypertrophy E. All of the above
4 Definition of Remodeling Histologic Tissue Changes Fibrosis Angiogenesis Smooth muscle hypertrophy and dysfunction With a Clinical Impact Strictures Dysmotility Stiffness Therapy response May or May not be Reversible Children Adults
5 Histologic Features Fibrosis Angiogenesis Smooth Muscle
6 Increased Subepithelial Fibrosis in EoE 3 ** ** Fibrosis Score Normal GERD EE Aceves et al, JACI 2007
7 Subepithelial Angiogenesis vwf Positive Vessels VWF positive vessels per hpf ** * 0 Normal GERD EE Normal GERD EE
8 Smooth Muscle Thickened muscular bundles Dis-coordinated smooth muscle contraction with poor relaxation Episodes of dysmotility correlate with dysphagia Nurko et al, Am J Gastro, 2009 Korsapaati et al, Gastroenterol 2009 Fox et al, Gastrointest Endosc, 2003
9 Clinical Implications Strictures Muscular Hypertrophy Decreased Compliance Dysmotility and Dysphagia
10 Esophageal Strictures and Compliance Kwiatek et al, Gastroenterology 2011
11 Inflammation Can Correlate with Endoscopy, Symptoms 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 Satiety r=0.32* Lamina Propria: Fibrosis + Eosinophils Thickened/Furrows r=0.64* Dysphagia r= 0.45* *p<0.05 Aceves et al, Annals of All Immunol 2009
12 Question 2 Molecular pathogenesis of remodeling includes: A. Eotaxin-1 B. CD4+ T Cells C. Eosinophils D. Epithelial mucous
13 Molecular Mechanisms
14 Animal Models: Antigenic Intranasal Aspergillus Intraperitoneal OVA Intragastric OVA Increased collagen deposition Triggers Mishra et al, Gastro 2008 Rubinstein et al, JPGN 2011
15 Role of Eosinophils Mishra et al, Gastro 2008 Rubinstein et al, JPGN 2011
16 Role of IL-5 and IL-13 Mishra et al, Gastro 2008 Zou et al, J Immuol 2010
17 Pro-Fibrotic Factors: TGFb1 TGFb Positve Cells per hpf Normal ** ** GERD EE psmad2/3 positive cells per hpf in LP Normal ** GERD * EE MBP+TGFb1 Aceves et al, JACI 2007 Straumann et al, Gastro 2010
18 Pro-Angiogenic Factors Persad et al, JPGN 2012
19 Esophageal Remodeling: Vascular Activation VCAM-1 Positive Vessels VCAM positive vessels per hpf ** * 0 Normal GERD EE Persad et al, JPGN 2012 Aceves et al, JACI 2007
20 Smooth Muscle Inflammation Aceves et al, JACI 2010
21 Smooth Muscle Inflammation Nicholson et al, J Pathology 1997
22 Mast Cells and Smooth Muscle Function Aceves et al, JACI 2010
23 Question 3 Remodeling of the esophagus A. Is reversed only by dietary changes B. Is reversed only by topical corticosteroids C. Is reversible only in children D. Is reversible in a subset of subjects
24 Reversibility?
25 In Children
26 Aceves et al, Allergy 2010 Topical Budesonide Resolves LP Eosinophilia and Fibrosis LP Eosinophils Fibrosis Score <7eos/hpf >20eos/hpf <7eos/hpf >20eos/hpf
27 Topical Budesonide Decreases TGFb and psmad2/3 Cells TGFb psmad2/3 Aceves et al, Allergy 2010
28 Diet or Steroids Effects on Fibrosis Lieberman et al, Allergy 2012
29 In Adults
30 Budesonide in Adults 15 days of swallowed budesonide 75% decrease in TGFb1 Straumann et al, Gastroenterology 2010
31 Long Term Adult Remodeling Control? 52 week extension of 2 week induction Budesonide: Increased eos Placebo: increased eos Less Extensive but: Increases in TGFb Increases in Tenascin Increases in Fibrosis Straumann et al, Clin Gastro Hepatol 2011
32 Adults Treated for 1 Year Lucendo et al, JACI 2011
33 Adults: Discord Between Epithelium and Sub-epithelium? Epithelium Sub-Epithelial Fibrosis Lucendo et al, JACI 2011
34 ? Concordance in Children? Lost in a subset of Adults Aceves, JACI 2011
35 Conclusions Esophageal remodeling consists of: Fibrosis, Angiogenesis, Smooth muscle changes Results in clinical consequences Strictures, Decreased compliance, Dysmotility, Food impactions Is directed by IL-13, IL-5, TGFb1-dependent and TGFb1-independent pathways May be reversible
36 Acknowledgements AAAAI, TIGERS Funding Sources, past and present: NIH/NIAID, DOD, AAAAI, TIGERS, APFED, GSK, Meritage Collaborators, National and International Lab: Lisa Beppu BS, Andrew Anilkumar BS, Iris Otani MD,
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