Finding the Path in Eosinophilic Esophagitis

Page 1

MIRNA CHEHADE, MD

Associate Professor of Pediatrics and Medicine Director, Mount Sinai Center for Eosinophilic Disorders Icahn School of Medicine at Mount Sinai New York, New York

IKUO HIRANO, MD

Professor of Medicine (Gastroenterology and Hepatology) Northwestern University Feinberg School of Medicine Chicago, Illinois

JONATHAN SPERGEL, MD

Chief, Allergy Program, Children’s Hospital of Philadelphia Stuart E. Starr Chair of Pediatrics Professor of Pediatrics Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania

LEARNING OBJECTIVES After completing of this activity, participants will be better prepared to: • Describe the pathophysiologic mechanisms underlying EoE development, with a focus on potential therapeutic targets • Comprehensively assess pediatric and adult patients with suspected EoE to accelerate differential diagnoses and establish appropriate multidisciplinary care

Americans with Disabilities Act Event staff will be glad to assist you with any special needs (ie, physical, dietary, etc). Please contact Integritas prior to the live event at info@ exchangecme.com. There is no registration fee for attending this NonCME Corporate Forum; however, seating is limited. Preregistration does not guarantee seating. We recommend arriving at the meeting room early.

• Longitudinally manage pediatric and adult patients with EoE based on symptoms, comorbidities, updated clinical guidelines, and therapeutic responses

This activity is supported by an independent grant from Sanofi Genzyme and Regeneron Pharmaceuticals.

• Communicate with patients, caregivers, and members of the multidisciplinary team to ensure continuity of care and promote shared clinical decision-making

The Non-CME Corporate Forum content and views expressed therein do not necessarily reflect the views, policies or position of the American College of Allergy, Asthma & Immunology.

• Compare the clinical profiles, available trial evidence, and drawbacks of current and emerging treatment strategies for EoE


NON-CME CORPORATE FORUM The Non-CME Corporate Forum content and views expressed therein do not necessarily reflect the views, policies or position of the American College of Allergy, Asthma & Immunology.

Faculty Mirna Chehade, MD, MPH

Associate Professor of Pediatrics and Medicine Director, Mount Sinai Center for Eosinophilic Disorders Icahn School of Medicine at Mount Sinai New York, New York

Ikuo Hirano, MD

Professor of Medicine (Gastroenterology and Hepatology) Northwestern University Feinberg School of Medicine Chicago, Illinois

Jonathan Spergel, MD

Chief, Allergy Program Children's Hospital of Philadelphia Stuart E. Starr Chair of Pediatrics Professor of Pediatrics Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania

TARGET AUDIENCE This program is intended for allergists/clinical immunologists, gastroenterologists, and other clinicians involved in the identification and management of patients with eosinophilic esophagitis (EoE).

PROGRAM DESCRIPTION During this Call-a-ColleagueTM program, specialists in allergy/immunology and eosinophilic gastrointestinal disease will discuss the disease burden, pathophysiology, diagnosis, and current management of EoE. Faculty will also present clinical trial evidence for emerging treatment options as well as considerations for patients with other atopic conditions. A unique feature of the program will be the Call-a-Colleague sections in which our specialists will elicit additional insight from their multidisciplinary team members, such as a dietitian, a psychologist, and a pediatric gastroenterologist. The clinicians will provide their expertise regarding the mental health burden among patients, the use of an elimination diet to resolve symptoms, and clinical issues pertaining to pediatric patients with EoE.

LEARNING OBJECTIVES After completing this activity, participants will be better prepared to: • Describe the pathophysiologic mechanisms underlying EoE development, with a focus on potential therapeutic targets • Comprehensively assess pediatric and adult patients with suspected EoE to accelerate differential diagnoses and establish appropriate multidisciplinary care • Compare the clinical profiles, available trial evidence, and drawbacks of current and emerging treatment strategies for EoE • Longitudinally manage pediatric and adult patients with EoE based on symptoms, comorbidities, updated clinical guidelines, and therapeutic responses • Communicate with patients, caregivers, and members of the multidisciplinary team to ensure continuity of care and promote shared clinical decision-making

This activity is supported by an independent grant from Sanofi Genzyme and Regeneron Pharmaceuticals.


PROGRAM AGENDA 8:30 PM Welcome & Preactivity Questions 8:40 PM An Overview of EoE: Burden & Pathophysiology Call-a-Colleague: Patient testimonial 8:55 PM Diagnosis and Evaluation of Patients With EoE Call-a-Colleague: Pathology Expert; Margaret H. Collins, MD 9:20 PM Long-term Multidisciplinary Management and Patient Communication Call-a-Colleague: Dietitian; Bethany Doerfler, MS, RD, LDN 9:45 PM Postactivity Questions and Q&A Session

DISCLOSURE OF CONFLICTS OF INTEREST Although we are not offering credit for the program, Integritas Communications (Integritas) adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of this program are required to disclose all financial relationships with any ineligible company within the past 24 months to Integritas. All financial relationships reported are identified as relevant and mitigated by Integritas in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Integritas to assure objectivity and that the activity is free of commercial bias. All relevant financial relationships have been mitigated. The faculty have the following relevant financial relationships with ineligible companies: Mirna Chehade, MD

Consulting Fee: Adare Pharma Solutions, Allakos Inc., AstraZeneca plc., Bristol Myers Squibb, Ellodi Pharmaceuticals, Phathom Pharmaceuticals Regeneron Pharmaceuticals, Inc., Sanofi S.A, Shire plc, Takeda Pharmaceutical Company Limited Contracted Research: Adare Pharma Solutions, Allakos Inc., AstraZeneca plc, Danone S.A., Ellodi Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Shire plc, Takeda Pharmaceutical Company Limited

Ikuo Hirano, MD

Consultant: Adare/Ellodi, Allakos, Amgen, Arena, AstraZeneca, Avir, Celgene/Receptos/BMS, Eli Lilly, EsoCap, Gossamer Bio, Parexel/Calyx, Regeneron, Shire/Takeda. Research funding: Adare/Ellodi, Allakos, AstraZeneca, Celgene/Receptos/BMS, Meritage, Regeneron, Shire/Takeda.

Jonathan Spergel, MD

Consultant: Abbott, Novartis, Regeneron, Sanofi. Research funding: Celgene, Genentech, Novartis, Regeneron, Sanofi.

The planners and managers have the following relevant financial relationships with ineligible companies: Stacey JP Ullman, MHS

Nothing to disclose.

Rose O’Connor, PhD, CHCP Nothing to disclose. Jim Kappler, PhD

Nothing to disclose.

DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Integritas does not recommend the use of any agent outside of the labeled indications.

This activity is supported by an independent grant from Sanofi Genzyme and Regeneron Pharmaceuticals.


The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

FEE INFORMATION & REFUND/CANCELLATION POLICY There is no fee for this activity.

INTEGRITAS COMMUNICATIONS CONTACT INFORMATION For questions about this activity, please contact Integritas Communications at info@exchangecme.com.

This activity is supported by an independent grant from Sanofi Genzyme and Regeneron Pharmaceuticals.


AN OVERVIEW OF EoE Jonathan Spergel, MD, PhD

1

What Is Eosinophilic Esophagitis (EoE)? • Chronic type 2 (T2) inflammatory disease of the esophagus that can cause dysphagia, esophageal stricture, and food impaction in adults, and reflux-like symptoms and feeding problems in children1 • Patients may have aeroallergen sensitization and concurrent atopic diseases including1 – Asthma – Allergic rhinitis – Atopic dermatitis

• Deficient esophageal mucosal barrier2 • Genetic predisposition2 • Immediate esophageal lesions and dysmotility2 1. Hirano I, et al. Ann Allergy Asthma Immunol. 2020;124(5):416-423; 2. Vinit C, et al. Arch Pediatr. 2019;26(3):182-190.

2

PREVALENCE

3


US EoE Prevalence by Age & Sex 120

Prevalence, Cases Per 100,000

Males Females

100 80 60 40 20

60–64

55–59

50–54

45–49

40–44

35–39

30–34

25–29

20–24

15–19

10–14

<5

0

5–9

• US prevalence range1,2 25.9/100,000 to 56.7/100,000 • In children (<20 years) 50.5/100,000 • In adults (20–64 years) 58.9/100,000

Age Range, Years

Children <18 years of age make up 24% of EoE cases and males make up 65% of all cases1 1. Dellon ES, et al. Clin Gastroenterol Hepatol. 2014;12(4):589–596.e1; 2. Mansoor E, Cooper GS. Dig Dis Sci. 2016;61(10):2928–2934.

4

US EoE Prevalence All Ages

Incidence of EoE, Cases Per 100,000

• Global increase in EoE incidence due to increased awareness of the condition and a true increase in number of new cases 12

Denmark

10

Switzerland Netherlands

8

Slovenia

6

Canada

4

USA

2 0 Initial Time Point

End Time Point

Moawad FJ. Gastrointest Endosc Clin N Am. 2018;28(1):15-25.

5

PATHOPHYSIOLOGY

6


EoE

Disease of Antigen-Driven Th2-Activation • APCs induce Th2 cells to secrete cytokines including IL-4, IL-5, and IL-13 • Eosinophils, mast cells, basophils, innate lymphocyte type 2 cells and T and B lymphocytes are recruited and activated • Activation drives inflammation, leading fibrosis and dysmotility in some untreated cases

Food antigen IL-13 Effects

TGF- Effects Impaired barrier

Hyperplasia

Epithelium

FLG CAPN14

TSLP CRLF2

EDC Genes

Cellular toxicity

CCL26 DSG1 IL-5

MBP

Dendric cell

Lamina propria Basophil and submucosa

Mast cell

Eosinophil

IL-13

TGF-

Th2

Th0

POSTN

Treg

Epithelial-tomesenchymal transition

MBP, EPX ECP, EDN

Muscularis externa

Fibrosis Fibroblast

Smooth muscle

Dysmotility

APC, antigen-presenting cell; CAPN14, calpain 14; CCL26, C-C motif ligand 26; CRLF2, cytokine receptor–like factor 2; DSG-1, desmoglein 1; ECP, eosinophil cationic protein; EDC, epidermal differentiation complex; EDN, eosinophil-derived neurotoxin; EPX, eosinophil peroxidase; FLG, filaggrin; IL, interleukin; MBP, major basic protein; POSTN, periostin; TGF, transforming growth factor; Treg, regulatory T cell; TSLP, thymic stromal lymphopoietin. Oliva S, et al. Expert Rev Clin Immunol. 2020;16(4):421-428; Vinit C, et al. Arch Pediatr. 2019;26(3):182-190; Graphic adapted from Davis BP, Rothenberg ME. Annu Rev Pathol. 2016;11:365-393.

7

EoE

Disease of Barrier Dysfunction Loss of Barrier Function1

Dysregulated Esophageal Epithelium2

• Decreased tight junctions in esophageal biopsies

TSLP

– Decreased expression of occluding and claudin 1

Barrier function

SPINK7 desmoglein-1

Proliferation

IL-33

– IL-13 decreases DSG-1

• Epithelial changes include

• High expression of TLR-2 and TLR-3

IL-5

IL-3

– Destruction of desmosomal complexes

Fibrosis

POSTN

– Reduced epithelial resistance

IL-9

Dendritic cell

Th2

– Basal zone hyperplasia – Dilated intercellular space

TSLP

TGFß

CCL26

Basophil

Mastocytosis

Eosinophil Mast cell

Allergic Insult + GERD Genetic Risk Factor

– Increased paracellular permeability

Eosinophilia

GERD, gastroesophageal reflux disease; SPINK7, serine peptidase inhibitor, kazal type 7; TLR, toll-like receptor. 1. Ruffner MA, et al. Allergy. 2019;74(12):2449-2460; 2. Oliva S, et al. Expert Rev Clin Immunol. 2020; 16(4):421-428; Graphic adapted from Merves J, et al. Ann Allergy Asthma Immunol. 2014;112(5):397-403.

8

Inflammatory Pathway of EoE Healthy Esophagus

Atopy Environmental exposure Genetic susceptibility Epithelium

Eosinophilic Esophagus Food exposure TSLP

Lumen

IL-33

Dilated intracellular spaces

T-cell recruitment IL-4

Basal Membrane

IL-13

Lamina Propria

Immune cell infiltrate

T-helper type 2 cells

Granulocyte recruitment

Basal cell hyperplasia

Eotaxin-3

IL-5

Basophil

Eosinophil Mast cell TNF, tumor necrosis factor. Muir A, Falk GW. JAMA. 2021;326(13):1310-1318.

9

TGF TNF

Fibroblast activation

Collagen deposition


Esophageal Tissue

Increased Expression of Th2 Ligands, CCL26 and IL-33 Ai H&E

Bi H&E

Ci H&E

ii Chymase

ii Chymase

ii Chymase

iii IL-33

iii IL-33

iii IL-33

Judd LM, et al. Am J Physiol Gastrointest Liver Physiol. 2016;310(1):G13-G25.

10

RISK FACTORS

11

Environmental & Genetic Risk Factors EoE Frequency

Multiple genes likely contribute to the development of EoE:1 • TSLP

• • • • • •

CAPN14 EMSY LRRC32 STAT6 ANKRD27 Results from twin studies indicate environmental factors and epigenetic mechanisms are likely to play a significant role as well

81% 80%

Risk of EoE, %

– SNPs in TSLP receptor gene are significantly associated with EoE in males only2 – May be reason majority of EoE patients are male2

90%

70% 60% 50% 41% 40% 30%

22%

20% 10%

2.40%

0% MZ Twins

DZ Twins

Siblings

0.00055 Common General family Population environment

ANKRD27, ankyrin repeat domain 27; CAPN14, calpain 14; DZ, dizygotic; EMSY, EMSY transcriptional repressor, BRCA2 interacting; LRRC32, leucine rich repeating containing 32; MZ, monozygotic; SNP, single nucleotide polymorphism; STAT6, signal transducer and activator of transcription 6. 1. O’Shea KM, et al. Gastroenterology, 2018;154(2):333–345; 2. Sherrill JD, et al. J Allergy Clin Immunol. 2010;126(1):160-165.e3; 3. Alexander ES, et al. J Allergy Clin Immunol. 2014;134(5):1084-1092e1.

12


Let’s Hear From Nicole Patient With EoE 2 of her 3 children also have EoE Family members with EoE: Mom, Nicole, 40 yo Daughter, Cindy, 8 yo Son, Ethan, 5 yo

Family members without EoE or any atopic conditions: Dad, Matthew, 43 yo Son, Kevin, 10 yo

yo, years old.

13

EoE DUE TO AEROALLERGENS

14

Seasonal Variation of EoE 150

125

100

Eos/HPF

• Symptoms of allergy and EE peaked during pollen season • Children with EoE and allergic rhinitis have exacerbations in their EE depending on the specific aeroallergens to which they are sensitized • Suggests a link between EoE and environmental aeroallergens

75

50

25

0

In-Season EE, esophageal eosinophilia; HPF, high power field. Ram G, et al. Ann Allergy Asthma Immunol. 2015;115(3):224-228.e1.

15

Out-of-Season


Consequences of Underrecognized EoE • Regardless of how T2 inflammatory signaling becomes activated, the underlying pathways can become self-perpetuating leading to1-3

Normal

– Ongoing inflammation in the esophagus – Progression of disease – Potentially fibrostenosis4

EoE EoE Inflammation Inflammation + Fibrosis

EoE Fibrosis

EGD Histology

Children Medical/Diet Therapy

Adult Esophageal dilation

EGD, esophagogastroduodenoscopy. 1. Inage E, et al. Am J Physiol Gastrointest Liver Physiol. 2018;315(5):G879-G886; 2. Ruffner, MA, et al. Expert Rev Clin Immunol. 2019;15(1):83-95; 3. Oliva S, et al. Expert Rev Clin Immunol. 2020;16(4):421-428; 4. Dellon ES, Hirano I. Gastroenterology. 2018;154(2), 319–332.e3.

16

Delayed Diagnosis Leads to Increased Risk for Strictures • Esophageal strictures developed in1 – – – – – –

17% of patients with a delay in EoE diagnosis of 0–2 years 31% with a delay of 2–5 years 38% with a delay of 8–11 years 64% with a delay of 14–17 years 71% with a delay of more than 20 years Duration of untreated disease appears to be the single best predictor of stricture risk Failure to promptly identify affected patients can have serious consequences; a growing pool of evidence shows that strictures are more likely to develop when EoE cases are not quickly identified2,3

1. Dellon ES, Hirano I. Gastroenterol. 2018;154(2), 319–332.e3; 2. Schoepfer AM, et al. Gastroenterology. 2013;145(6):1230-1236; 3. Lipka S, et al. J Clin Gastroenterol. 2016;50(2):134-140.

17

DIAGNOSIS AND EVALUATION OF PATIENTS WITH EoE Mirna Chehade, MD, MPH

18


Symptoms of EoE Children vs Adults

Infants and toddlers1

School-age children1

– Gastroesophageal reflux – Vomiting – Growth & feeding concerns – Irritability

Adults/ adolescents1

– Gastroesophageal reflux – Abdominal pain – Heartburn – Vomiting – Dysphagia

– – – – – –

Dysphagia Food impaction Heartburn Chest pain Nausea Decreased appetite – Vomiting

Patients may not appear to have feeding/eating difficulties; only 20% present with FTT (mostly in younger patients). The majority are either normal weight or, at times, obese2 Symptoms may be subtle due to behavioral feeding modifications3 FTT, failure to thrive. 1. Muir AB, et al. Clin Exper Gastroenterol. 2019;12:391–399; 2. Dellon ES, et al. Clin Gastroenterol Hepatol. 2014;12(4):589–96.e1; 3. Dellon ES, Hirano I. Gastroenterol. 2018;154(2), 319–332.e3.

19

Patients, %

Symptoms of EoE Change as Age Increasesa 100 90 80 70 60 50 40 30 20 10 0

Children

Adults Children Adults Children

Dysphagia

0-2 Years

3-10 Years

11-17 Years

18-35 Years

36-50 Years

51+ Years

Adults

Food Impaction

Children

Adults

Heartburn

Dysphagia and heartburn are greater among adults than children 0-17y; Food impaction is greater among teens and adults than young children 0-10y. aP<0.001.

N=793 patients with EoE (n=476 adults, n=317 children) retrospective, multicenter, cross-sectional analysis from clinical registries and 5 tertiary centers in the US. Moawad FJ, al. Clin Gastroenterol Hepatol. 2016;14(1):23-30.

20

Pediatric Patients, %

Symptoms of EoE Change as Pediatric Patients Get Oldera 100

0-2 Years

90

3-10 Years

80

11-17 Years

70 60 50 40 30 20 10 0 Growth Failure

Emesis

Food Refusal

Dysphagia

Food Impaction

Heartburn

Growth failure, emesis, and food refusal decreased with age, while dysphagia, food impaction, and heartburn increased. aP<0.005.

N=793 patients with EoE (n=476 adults, n=317 children) retrospective, multicenter, cross-sectional analysis from clinical registries and 5 tertiary centers in the US. Moawad FJ, al. Clin Gastroenterol Hepatol. 2016;14(1):23-30.

21


Making the Diagnosis

Diagnostic Algorithm for EoE Clinical Symptoms Suggestive of EoE

Including • Symptoms in children and adults • History of atopic comorbidities • Family history of EoE or dysphagia • History of esophageal stricture or stricture dilation

Esophageal Eosinophilia ≥15 EOS/HPF (60 eos/mm2)

EGD with biopsy Rule out other causes of esophageal eosinophilia

Eosinophilic Esophagitis EOS, eosinophils. Based on Spergel JM, et al. Ann Allergy Asthma Immunol 2018;121(3):281-284; Dellon ES, et al Gastroenterology. 2018;155(4):1022-1033.

22

Differential Diagnosis for EoE1,2 • GERD (gastroesophageal reflux disease) • Eosinophilic gastroenteritis • Eosinophilic gastrointestinal disease • Achalasia • Hypereosinophilic syndrome • Infectious esophagitis

• Pill-induced esophagitis • Celiac disease • Crohn’s disease • Connective tissue disorders • Infections • Graft-vs-host disease • Vasculitis

Diagnosis of EoE includes exclusion of other eosinophilic diseases of the esophagus and of other more general immune-mediated diseases1 1. Muñoz-Mendoza D, et al. Clin Rev Allergy Immunol. 2018;55(1): 7-18; 2. Muir A, Falk GW. JAMA. 2021;326(13):1310-1318.

23

Rationale for Removing PPI Trial From Diagnostic Criteria • Similarities between EoE and Proton Pump Inhibitor-Responsive Esophageal Eosinophilia (PPI-REE) – PPIs are better classified as a treatment for EE due to EoE than as a diagnostic criterion

• EoE and GERD are not necessarily mutually exclusive • Lack of a criterion standard for GERD diagnosis – Without a definitive method for defining GERD, no single test can exclude that presence of GERD

• Novel mechanisms of action of PPIs to explain response of eosinophilia • Observation that PPI-REE could also respond to classic EoE treatments • Concern about using a treatment response to define a disease PPI-REE, proton pump inhibitor-responsive esophageal eosinophilia. Dellon ES, et al. Gastroenterology. 2018;155(4):1022-1033.

24


Making the Diagnosis Endoscopy

• Diagnosis of EoE requires endoscopy with biopsies • Endoscopic findings consist of – Edema – Linear furrows – appearing as vertical lines within the mucosa – Rings – appearing as concentric rings of esophageal narrowing – White exudates – small whitish plaques – Strictures – narrowing of the esophageal passage

• 10%-25% of patients with EoE have a normal-appearing esophagus

Normal

Linear Furrows

Rings

White plaques

Muir A, Falk GW. JAMA. 2021;326(13):1310-1318; Dellon ES. Gastroenterol Clin North Am. 2013;42(1):133-153; Hirano I, et al. Gut. 2013;62(4):489-495.

25

Making the Diagnosis Pathology

• Histopathological study is the gold standard for diagnosis • Obtain a minimum of 6 biopsies – Proximal and distal esophagus

• ≥15 eosinophils per HPF in the maximally affected high-power field is necessary for diagnosis

Dellon ES, et al. Gastroenterology. 2018;155(4):1022-1033; Muir A, Falk GW. JAMA. 2021;326(13):1310-1318; Photo courtesy of Dr. Margaret Collins.

26

Comprehensive Evaluation of Patients With EoE  Assess for symptoms of esophageal dysfunction based on clinical diagnostic criteria  Look for atopic comorbidities  Evaluate for nonatopic comorbidities

27


Frequency of Atopic Comorbidities in Patients With EoE1,a 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Children <11 yo

Children 11-17yo

61% 61% 59%

Adults

76% 63%

61%

54%

48% 49% 36%

35%

Allergic rhinitis

Asthma

28%

Atopic dermatitis

And it is common to have more than 1 atopic disease2,b • 78% reported at least 1 • 48% reported having >1 • 22% reported having 3 (Allergic rhinitis, asthma and atopic dermatitis

Food Allergy

History of food allergy or atopic dermatitis is associated with a significantly shorter time between symptom onset and diagnosis.1 Assess for EoE when patients present with symptoms of esophageal dysfunction + any of these atopic comorbidities aN=705 patients 6 months to 65 years of age with EoE from multisite single-visit registry; bN=449 patients with EoE at Cleveland Clinic electronic medical record analysis over 10-year period. 1. Chehade M, et al. J Allergy Clin Immunol Pract. 2018;6(5):1534-1544; 2. Mohammad AA, et al. J Am Acad Dermatol. 2017;76(3):559-560.

28

Psychiatric Comorbidities – Of these, 40% were diagnosed with a psychiatric illness after the diagnosis of EoE – They were more likely to be older, female, and white, and have longer duration of symptoms

• Another study of children with EoE reported problems socially (64%), with sleep (33%), and school difficulties (26%)2

Psychiatric Diagnosis, %

• 28% of patients with EoE had a psychiatric comorbidity1,a 30

Adults and Children with EoE vs US Population1,3,4

Anxiety Depression

25 20 15 10 5 0 Adults with EoE

US Adults

Children with US Children EoE (3-17 yrs)

aN=883.

1. Reed CC, et al. Am Journal Gastroenterol. 2020;115(6), 853–858; 2. Harris RF, et al. J Pediatr Gastroenterol Nutr. 2013;57(4):500-505. 3. CDC. https://www.cdc.gov/childrensmentalhealth/data.html. Accessed October 22, 2021; 4. NAMI. You are not alone. 2020. Nami.org; Accessed October 22, 2021.

29

Nonatopic Comorbidities

in Children, Teens and Adults with EoE Total, %

Children, % (<11 yo)

Teens, % (11-17 yo)

Adults, % ( ≥18 yo)

GERD

54.2

55.7

49.7

56.1

Condition GI Infectious/ Immunologic

IBSa

6.5

3.2

3.7

Celiac disease

2.0

2.3

2.6

0.6

Pneumonia

24.5

22.0

27.5

26.3

Developmental Delaya

11.2

18.0

7.9

1.2

Depression/anxietya

15.5

9.3

19.0

24.0

Autism/behavioral disordera

6.2

7.8

8.5

0.6

Systemic Problems

FTTa

21.3

31.9

18.0

3.5

Surgical History

Tympanostomy tube placementa

19.6

24.3

20.1

9.4

Neurological/ Developmental Disorders

aP≤0.0003

for age comparisons; N=705 patients 6 months to 65 years of age with EoE from multisite single-visit registry. Chehade M, et al. J Allergy Clin Immunol Pract. 2018;6(5):1534-1544.

30

16.4


LONG-TERM MULTIDISCIPLINARY MANAGEMENT AND PATIENT COMMUNICATION Ikuo Hirano, MD

31

NONPHARMACOLOGIC AND PHARMACOLOGIC TREATMENT OPTIONS What Do the Guidelines Say?

32

AGA/JTF Clinical Guidelines Dietary Therapy Strength of Recommendation

Quality of Evidence

In patients with EoE, the AGA/JTF suggests using elemental diet over no treatment

Conditional

Moderate

In patients with EoE, the AGA/JTF suggests using an empiric, 6-food elimination diet over no treatment

Conditional

Low

In patients with EoE, the AGA/JTF suggests using an allergy testing-based elimination diet over no treatment

Conditional

Very low quality

Recommendation

AGA, American Gastroenterological Association JTF, Joint Task Force on Allergy-Immunology Practice Parameters. Hirano I, et al. Gastroenterology. 2020;158(6):1776-1786.

33


Dietary Therapy for EoE Management • In patients with EoE, about

Most Common Food Allergies in Patients With EoE

66%

60

Patients, %

– 30%-50% have 1 food allergy – 30% have 2 food allergies – 30% have 3 food allergies

70

50 40 27%

30

24%

20

12%

10

4%

2%

Peanut/ tree nuts

Fish/ shellfish

0 Milk

Wheat

Egg

Soy/ legumes

Goal: Avoid and identify potential food allergen triggers N=702 US pediatric and adult patients with EoE across 11 studies examining most common food allergens. Spergel J, Aceves SS. J Allergy Clin Immunol. 2018;142(1):1-8.

34

Food Elimination Diets 6-FED • Eliminates foods consisting of wheat/gluten, milk, soy, egg, nuts, and fish/seafood • Dairy and wheat are the most commonly implicated food groups • Requires multiple endoscopies to identify culprit food group(s) • Requires well-motivated patient

4-FED • Eliminates dairy, glutencontaining cereals, egg, and legumes 2-FED • Eliminates dairy and glutencontaining cereals

4-FED, four-food elimination diet; 6-FED, six-food elimination diet; 2-FED, two-food elimination diet. Muir A, Falk GW. JAMA. 2021;326(13):1310-1318; Molina-Infante J, Lucendo AJ. J Allergy Clin Immunol. 2018;142(1):41-47.

35

Elemental Diet • Consists of diet exclusively made up of amino acid-based formula • No adverse effects • Cost may be a consideration • Palatability is poor • After elemental diet, reintroduction of food groups may increase IgE-mediated allergies

Muir A, Falk GW. JAMA. 2021;326(13):1310-1318.

36


Histologic Remission Rate, %

Efficacy of Dietary Therapies for EoE in Children and Adults 100

Adult

90

Children

80 70 60 50 40 30 20 10 0 Elemental Diet

6-FED

4-FED

2-FED

Allergy TestingGuided

Dairy a

aIndirect

data from prospective studies on 4- and 2-food elimination diets. Molina-Infante J, Lucendo AJ. J Allergy Clin Immunol. 2018;142(1):41-47.

37

Dietary Therapy Overview • Food elimination diet is effective in 67% of patients1 • Continued food avoidance can serve as a long-term disease control option • Nonpharmacologic • Inexpensive

• Repeated endoscopy needed to assess response to changes in food antigen exposure • Relapse upon diet discontinuation common • Long-term recurrence while maintaining avoidance diet is poorly understood2 • Risk of nutritional deprivation • Adherence is difficult with significant impacts on quality of life possible

1. Arias A, et al. Gastroenterology. 2014;146:1639-1648. 2. Wilson JM, et al. J Asthma Allergy. 2020;13:679-688.

38

CURRENT PHARMACOLOGIC TREATMENT OPTIONS

39


Current Pharmacologic Therapy AGA/JTF Clinical Guidelines

Current Pharmacologic Treatment Options • PPI • Swallowed topical glucocorticosteroids

Strength of Quality of Recommendation Evidence

Recommendation In patients with symptomatic EE, the AGA/JTF suggests using PPI over no treatment In patients with EoE, the AGA/JTF recommends topical glucocorticosteroids over no treatment In patients with EoE, the AGA/JTF suggests topical rather than oral glucocorticosteroids

Conditional

Very low quality

Strong

Moderate

Conditional

Moderate

Currently, there are no FDA-approved treatments for EoE. AGA, American Gastroenterology Association; FDA, Food and Drug Administration; JTF, Joint Task Force on Allergy-Immunology Practice Parameters. Hirano I, et al. Gastroenterology. 2020;158(6):1776-1786.

40

Proton Pump Inhibitors

In Patients With Esophageal Eosinophilia Histologic Response 22 Studies

Overall (I2=81%, P<0.001) 0.526 (95% CI, 0.450, 0.601)

0

0.2

0.4

Proportion

0.6

0.8

58.3% of patients treated with PPIs failed to achieve histopathologic remission (<15 eos/hpf) vs 86.7% treated with placebo CI, confidence interval. N=1051 participants in 23 observational studies from 2009 – 2017; certainty in the effect estimate was graded very low for inconsistencies. Rank MA, et al. Ann Allergy Asthma Immunol. 2020;124(5):424-440.

41

Topical Corticosteroids • Medication options include – Fluticasone, 440-880 µg, twice daily – Budesonide, 1-2 mg, twice daily

• Adverse effects – Esophageal candida (12%-16%) – Oral thrush (2%-3%)

• Considerations – Off-label use of asthma medications results in need to repurpose as a slurry for budesonide and swallow instead of inhale for fluticasone – Cost may be considerable because it is not always covered by insurance Muir A, Falk GW. JAMA. 2021;326(13):1310-1318.

42


Topical Corticosteroids in Pediatric Patients Histologic Response

Symptomatic Response

5 Studies

4 Studies

RR, M-H, Fixed, 95% CI

RR, M-H, Fixed, 95% CI

0.01

0.1

1

10

Favors Control

100

Favors Experimental

0.01

0.1

1

Favors Control

Glucocorticoid treatment: 49% Placebo: 4%

10

100

Favors Experimental

Glucocorticoid treatment: 34% Placebo: 22%

M-H, Cochran-Mantel-Haenszel method; RR, risk ratio. N=5 RCTs (randomized controlled trials) comparing corticosteroid forms with a placebo or with dietary interventions in patients up to 18 years of age with a diagnosis of EoE; studies were excluded for unclear methodology, poorly reported or unreported outcomes, and RCTs that included patients with gastrointestinal comorbidities. Munoz-Osores E, et al. Pediatrics. 2020; 146(5):e20200874.

43

Clinical Decision Support Tool Pharmacologic Therapy Eosinophilic Esophagitis Medical Therapy

Nonresponse

• Proton pump inhibitor • Topical corticosteroids

Nonresponse

Diet Therapy • Elemental formula • Empiric elimination • Allergy testing directed

Clinically relevant esophageal stricture

Response

Esophageal Dilation

Response

Maintenance Therapy

For a link to this tool and other clinical resource, please visit our Clinical Resource Center at: www.ExchangeCME/EoEResources. Hirano I, et al. Gastroenterology. 2020;158(6):1776-1786.

44

Esophageal Dilation Benefits and Limitations

• Therapeutic option for treating esophageal strictures, rings, and narrow-caliber esophagus • Systematic reviews and meta-analyses have shown – Dilation was associated with clinical improvement in 95% of patients with EoE, with a median duration of improvement of 12 months – Dilation is safe • Early concerns about perforation rates unfounded (perforation rates 0.033%) • Bleeding rate 0.028% • Hospitalization rate 0.69%

– Most frequent adverse event was chest discomfort (23.6%)

• Dilation does not improve esophageal eosinophilic inflammation and ongoing mucosal damage Muir A, Falk GW. JAMA. 2021;326(13):1310-1318.

45


EMERGING TREATMENT OPTIONS

46

Inflammatory Pathway of EoE Healthy Esophagus

Atopy Environmental exposure Genetic susceptibility

Eosinophilic Esophagus Food exposure TSLP

Epithelium

Dupilumab Cendakimab

Lumen

Inhibit inflammatory cytokine pathways

IL-33

Dilated intracellular spaces

T-cell recruitment

Immune cell infiltrate

IL-4

Basal Membrane

IL-13

Lamina Propria

Benralizumab Mepolizumab

T-helper type 2 cells

Inhibit inflammatory cytokine pathways

Granulocyte recruitment

Basal cell hyperplasia Eotaxin-3

Reduce epithelial cell inflammatory chemokine expression

IL-5

Lirentelimab Depletes eosinophils Inhibits mast cells

Basophil

Eosinophil

Proton pump inhibitors

Fibroblast activation

TGF TNF

Mast cell

Collagen deposition

Muir A, Falk GW. JAMA. 2021;326(13):1310-1318.

47

Budesonide Oral Suspension ORBIT 1 Phase 3 Trial Results

Histologic Response 53.1

Dysphagia Symptom Response 60

P<0.001

50

Patients, %

Patients, %

60 40 30 20 10

1

0 BOS 2.0 mg BID (n=213)

Placebo (n=105)

52.6

P=0.024

50 39.1

40 30 20 10 0 BOS 2.0 mg BID (n=213)

Placebo (n=105)

BOS was well tolerated; most adverse events were mild/moderate in severity; BOS has been granted a priority review in EoE by the US FDA BID, twice daily; BOS, budesonide; DSQ, dysphagia symptom questionnaire. N= 322 patients aged 11-55 years with histologic evidence of EoE randomly assigned 2:1 to receive BOS 2.0 mg, BID or placebo for 12 weeks. Histologic response defined as ≤6 eos/hpf at week 12 of therapy. Dysphagia symptom response defined as ≥30% reduction in DSQ score at week 12 of therapy. Hirano I, et al. Clin Gastroenterol Hepatol. 2021. [Epub ahead of print.]

48


Budesonide Oral Suspension ORBIT 1 Phase 3 Trial Results

EREFS

EoE HSS

BOS 2.0 mg BID (n=202)

Change in Total Score Ratios, %

Change in Total Score, %

0 -1 -2 -2.2

-3

△ -1.8

-4

-4

-5

Bos 2.0 mg BID (n=201)

Placebo (n=93)

P<0.001

0 -0.05 -0.1 -0.15 -0.2 -0.25

Placebo (n=92)

BOS 2.0 mg BID (n=201)

Placebo (N=92) 0

-0.03

△ -0.20

△-0.19 -0.22 P<0.001

-0.2

Grade Score

Stage Score

P<0.001

In patients with EoE, BOS was superior to placebo in improving endoscopic outcomes over 12 weeks EREFS, Endoscopic reference score; HSS, histological scoring system N= 322 patients aged 11-55 years with histologic evidence of EoE randomly assigned 2:1 to receive BOS 2.0 mg, BID or placebo for 12 weeks. Histologic response defined as ≤6 eos/hpf at week 12 of therapy. Dysphagia symptom response defined as ≥30% reduction in DSQ score at week 12 of therapy. Hirano I, et al. Clin Gastroenterol Hepatol. 2021. [Epub ahead of print.]

49

Dupilumab

Anti-IL-4Rα Therapy IL-4

IL-4

Dupilumab

IL-13

OR

Dupilumab

IL-4Rα

γc

IL-4Rα

IL-13Rα1

IL-4 mediates IgE production, Th2-cell differentiation, B-cell growth, and eosinophil recruitment

• As of October 2021, dupilumab is FDA approved2 – For patients ≥6 years of age with moderateto-severe atopic dermatitis – For patients ≥6 years of age as an add-on maintenance treatment in patients with moderate-to-severe asthma with an eosinophilic phenotype or with oral corticosteroid-dependent asthma – For adults as an add-on maintenance treatment with inadequately controlled chronic rhinosinusitis with nasal polyposis

IL-4Rα, interleukin-4 receptor α; IL-7Rα, interleukin-7 receptor α; TSLPR, TSLP receptor. 1. Adapted from Gandhi NA, et al. Nat Rev Drug Discov. 2016;15(1):35-50 and Lambrecht BN, Hammad H. Nat Immunol. 2015;16(1):45-56; 2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761055s031lbl.pdf.

50

Dupilumab Phase 3 LIBERTY EoE TREET Parts A & C Results

70 60 50 40 30 20 10 0

59.5

Dysphagia Symptom Response 55.9

5.1 Dupilumab Placebo Week Dupilumab Week 24 (n=42) 24 (n=39) Week 52 (n=40)

Absolute Change From Part A Baseline

Patients, %

Histologic Response

Dupilumab Week 24 (n=42)

Placebo Week 24 (n=39)

Dupilumab Week 52 (n=40)

0 -5 -10

-9.6

-15 -20 -25

-21.92

-23.44

Significant and sustained improvements observed in histologic, symptomatic, and endoscopic measures at 24 and 52 weeks; dupilumab was generally well tolerated. P<0.001 for 24-week results in both graphs; N=81 adult and adolescent patients with EoE were randomized 1:1 to receive dupilumab 300 mg once weekly or placebo for 24 weeks; N=40 patients treated with dupilumab continued to 52 weeks at same dosage. Histologic response defined as ≤6 eos/hpf at 24 and 52 weeks; dysphagia symptom response = absolute change from baseline in DSQ score by week 24 and 52. Dellon ES. A phase 3, randomized, 3-part study to investigate the efficacy and safety of dupilumab in adult and adolescent patients with eosinophilic esophagitis: results from part A. Abstract LB3. American College of Gastroenterology Conference. October 26, 2020; Dellon ES, et al. Dupilumab efficacy and safety up to 52 weeks in adult and adolescent patients with EoE: results from part A and C of a randomized, placebo-controlled, 3-part, phase 3 LIBERTY EoE TREET study.

51


Dupilumab Phase 3 LIBERTY EoE TREET Parts A & C Results

EREFSa

EoE HSS Week 24a Dupilumab Week 52 (n=40)

0 -0.3

-1 -2 -3 -4

-3.2 -4.1

-5

Dupilumab (n=42)

Change in Total Score Ratios, %

Change in Total Score, %

Dupilumab Placebo Week 24 Week 24 (n=42) (n=39)

0

Placebo (n=39)

Dupilumab (n=42)

-0.001

Placebo (n=39) -0.012

-0.2 -0.4

△ -0.759

△ -0.741

-0.6 -0.8

-0.761

-0.753

Grade Score

Stage Score

Total EREFS was reduced from Part A baseline at 52 weeks and EoE HSS had a significantly greater change at 24 weeks. aP<0.001

for 24-week results; N=81 adult and adolescent patients with EoE were randomized 1:1 to receive dupilumab 300 mg once weekly or placebo for 24 weeks; N=40 patients treated with dupilumab continued to 52 weeks at same dosage. Dellon ES. A phase 3, randomized, 3-part study to investigate the efficacy and safety of dupilumab in adult and adolescent patients with eosinophilic esophagitis: results from part A. American College of Gastroenterology Conference. October 26, 2020; Abstract LB3. Dellon ES, et al. Dupilumab efficacy and safety up to 52 weeks in adult and adolescent patients with eosinophilic esophagitis: results from part A and C of a randomized, placebo-controlled, 3-part, phase 3 LIBERTY EoE TREET study. United European Gastroenterology Week Virtual 2021 congress. October 3-5, 2021. Abstract LB10.

52

Other Emerging Monoclonal Antibodies For EoE

Drug

Target

Phase of EoE Trials

Benralizumab1,2

Anti-IL-5

3

Add-on maintenance therapy for patients ≥12 years of age with severe asthma with an eosinophilic phenotype

Mepolizumab2,3

Anti-IL-5

2/3

Add-on maintenance treatment patients ≥6 years of age with severe asthma with an eosinophilic phenotype; Addon maintenance treatment patients ≥18 years of age with CRSwNP; eosinophilic granulomatosis with polyangiitis; patients ≥12 years of age with HES for ≥6 months without an identifiable nonhematologic secondary cause.

Anti-Siglec-8 Ig1

2/3

Anti-IL-13

3

Lirentelimab4 Cendakimab5

Currently FDA approved for

aAll

are administered via subcutaneous injection. CRWwNP, chronic rhinosinusitis with nasal polyps; EGPA, eosinophilic granulomatosis with polyangiitis; HES, hypereosinophilic syndrome; SC, subcutaneous. 1. https://clinicaltrials.gov/ct2/show/NCT04543409; 2. Drugs@FDA www.accessdata.fda.gov/drugsatfda/; 3. https://clinicaltrials.gov/ct2/show/NCT03656380; 4. https://clinicaltrials.gov/ct2/show/NCT04322708; 5. Hirano I, et al. Gastroenterology. 2019;156(3):592-603e10.

53

LET’S BRING BACK Dr. SPERGEL Management Perspectives From the Allergist

54


What Is the Role of the Allergist in EoE Management? • Manage concomitant atopic conditions – – – –

Asthma Allergic Rhinitis Atopic Dermatitis IgE Food Allergy

• Treat concomitant atopic conditions – SCIT for aero-allergen induced EoE?

• Assessing treatment response over time • Help with food removal/introduction • Assess risk of OIT and EoE OIT, oral immunotherapy; SCIT, subcutaneous immunotherapy.

55

EoE and Subcutaneous Immunotherapy • 3 case reports of being treated with SCIT with normalization of biopsies – Dust mite: 4 yo – Grass/birch: 10 yo – Dust mite, cockroach, weed, and trees: 30 yo

• 9 cases of adults being treated with SCIT – 20% responded with histologic improvement – 40% responded with symptom improvement

Robey BS, et al. Ann Allergy Asthma Immunol. 2019;122(5):532-533e; Ramirez RM, Jacobs RL. J Allergy Clin Immunol. 2013;132(2):503-504; Wells R, et al. BMJ Case Reports. 2018;bcr2017223465; Castilano A, Zacharias D. Ann Allergy Asthma Immunol. 2013;111(5):A62.

56

Key Messages • EoE is a chronic T2 inflammatory disease of the esophagus that can cause dysphagia, esophageal stricture, and food impaction in adults, and reflux-like symptoms and feeding problems in children – Patients may have aeroallergen sensitization and concurrent atopic diseases including asthma, allergic rhinitis, and atopic dermatitis

• Children make up 24% of EoE cases and males make up 65% of all cases • Disease burden is great among patients and diagnosis can be difficult since many patients adopt coping strategies that circumvents symptom detection or lead to underestimation of symptoms • Diagnosis requires an endoscopy with biopsy of the esophagus – ≥15 eosinophils per HPF are necessary for diagnosis

57


Key Messages • Nonpharmacologic treatment options include dietary therapy such as an elimination diet, elemental diet, and testing-directed elimination diet • Currently, there are no FDA-approved treatments for EoE, although swallowed topical glucocorticosteroids and proton pump inhibitors are used off-label • Among the topical glucocorticosteroids, budesonide, has shown positive histologic, symptomatic, and endoscopic outcomes in phase 3 trials • Several monoclonal antibodies are emerging as potential treatments; they inhibit the IL-4, IL-5, IL-13, and Siglec-8 Ig1 receptors – A few are already FDA approved for other comorbid conditions: benralizumab, dupilumab, and mepolizumab

58


GUIDELINES Updated international consensus diagnostic criteria for eosinophilic esophagitis: proceedings of the AGREE conference. Dellon ES, et al. Gastroenterol. 2018;155(4):1022-1033.e10 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174113/

AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis. Hirano I, et al. Gastroenterology. 2020;158(6):1776-1786. 4 https://pubmed.ncbi.nlm.nih.gov/32359562/

Technical review on the management of eosinophilic esophagitis: a report from the AGA institute and the joint task force on allergy-immunology practice parameters. Rank MA, et al. Ann Allergy Asthma Immunol 2020;124(5):424-440.e17 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171057/

PATIENT RESOURCES American Partnership for Eosinophilic Disorders (Apfed). 4 https://apfed.org/

Campaign Urging Research for Eosinophilic Disease (CURED) 4 http://curedfoundation.org/

National Organization for Rare Disorders. 4 https://rarediseases.org/rare-diseases/eosinophilic-esophagitis/

SUGGESTED READING Phenotypic characterization of eosinophilic esophagitis in a large multicenter patient population from the Consortium for Food Allergy Research. Chehade M, et al. J Allergy Clin Immunol Pract. 2018;6(5):1534-1544.e5 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132253/

Mechanisms of disease of eosinophilic esophagitis. Davis BP, Rothenberg ME. Annu Rev Pathol. 2016;11:365-393. 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918086/

A phase 3, randomized, 3-part study to investigate the efficacy and safety of dupilumab in adult and adolescent patients with eosinophilic esophagitis: results from part A. Dellon ES. American College Gastroenterology Conference. October 26, 2020. Abstract LB3. 4 https://www.eventscribe.com/2020/ACG/fsPopup.asp?efp=RElCSUFHUk02NDI2&PresentationID=783291&rnd=0.6661928&mode =presinfo

Budesonide oral suspension improves outcomes in patients with eosinophilic esophagitis: results from a phase 3 trial. Hirano I, et al. Clin Gastroenterol Hepatol. 2021. doi: 10.1016/j.cgh.2021.04.022. [Epub ahead of print.] 4 https://www.cghjournal.org/article/S1542-3565(21)00456-0/fulltext

CLINICAL RESOURCE CENTER: www.ExchangeCME.com/EoEResources


Effects of race and sex on features of eosinophilic esophagitis. Moawad FJ, et al. Clin Gastroenterol Hepatol. 2016;14(1):23-30. 4 https://pubmed.ncbi.nlm.nih.gov/26343181/

Dietary therapy for eosinophilic esophagitis. Molina-Infant J, Lucendo AJ. J Allergy Clin Immunol. 2018;142(1):41-47. 4 https://www.jacionline.org/article/S0091-6749(18)30320-8/fulltext

Eosinophilic esophagitis: a review. Muir A, Falk GW. JAMA. 2021.326(13):1310-1318. 4 https://pubmed.ncbi.nlm.nih.gov/34609446/

Pathophysiology of eosinophilic esophagitis. O’Shea KM, et al. Gastroenterology. 2018;154(2):333-345. 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787048/

Medical algorithm: diagnosis and treatment of EoE in children. Spergel JM, et al. Allergy. 2020;75(6):1522-1524. 4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040021/

CLINICAL RESOURCE CENTER: www.ExchangeCME.com/EoEResources


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