What’s New in Eosinophilic GI Disorders & Celiac Disease

John Garber, MD Gastrointestinal Unit

Massachusetts General Hospital Harvard Medical School

Disclosures

• Advisor to NIMA labs

Learning Objectives for Eosinophilic Esophagitis

1. Understand the clinical features of presentation of this emerging allergic disorder

2. Identify populations with increased prevalence requiring heightened index of suspicion

3. Understand the current rational for and approaches to treatment

Case: chronic dysphagia in a 32 year-old man

CC: 32 year-old man with difficulty swallowing HPI: Since college, dysphagia is present 3-4 times/week, usually when eating out at a restaurant. Episodes of food sticking will typically last for 15 minutes to an hour, and generally resolve with drinking water. He admits to being a lifelong “slow eater” and always has water with meals. About 3 months ago, started on omeprazole 40 mg/day and has been taking this since. Symptoms have partially improved with PPI. PMH: seasonal allergies, asthma as a child Medications: omeprazole 40 mg once a day, occasional albuterol

Case: chronic dysphagia in a 32 year-old man Endoscopy: Pathology: FINAL PATHOLOGIC DIAGNOSIS:

A. ESOPHAGUS BIOPSY, DISTAL: Active esophagitis with peak intraepithelial eosinophil count exceeding 40 per HPF. Basal cell hyperplasia. Superficial layering of eosinophils is present. Lamina propria fibrosis. B. ESOPHAGUS BIOPSY, MID: Active esophagitis with peak intraepithelial eosinophil count exceeding 40 per HPF. Basal cell hyperplasia. Superficial layering of eosinophils is present. Lamina propria fibrosis.

Definition and Differential Diagnosis

Eosinophilic esophagitis: a chronic, immune-mediated or antigen-mediated esophageal disease characterized by symptoms related to esophageal dysfunction and eosinophil-predominant inflammation. •Symptoms include feeding problems, vomiting, and abdominal pain in children, and dysphagia and food impaction in adolescents and adults.

•Esophageal mucosal eosinophilia of at least 15 eosinophils per high-power field. Other causes, particularly GERD, must be ruled out.

•Other causes of esophageal eosinophilia (parasitic infection, allergic vasculitis, esophageal leiomyomatosis, and Crohn’s disease of the esophagus) are rare.

Furuta and Katzka NEJM 2015

EoE is a Th2-predominant disease induced primarily by food antigens

• Amino-acid based elemental diet leads to disease remission; reintroduction of food leads to relapse

• IL-13 is significantly increased in esophageal tissues in active EoE

• About 20% of the EoE transcriptome is IL-13-driven

• Th2 cytokines and TSLP direct recruitment of eosinophils, IgE+ mast cells, Th2 lymphocytes, basophils and NK cells

Evidence that EoE is not primarily an IgE-mediated food allergy

• Omalizumab (anti-IgE) has not been effective

• EoE-like disease can be induced in IgE- and B cell-KO mice

• IgE based blood and skin testing does not reliably identify food antigen triggers in EoE

Pathogenesis

Epidemiology of EoE

• ICD-9 code established in 2008

• Estimated prevalence of 10-50 per 100,000 in the U.S.

• Higher in certain subpopulation: 6% of patients undergoing upper endoscopy for any reason; 15% of patients undergoing EGD for dysphagia, 50% of patients who present with a food impaction

• Described in all age groups, but predominantly affects white men,

with onset from school age to midlife

• The prevalence is highest among men 35-39 years old, with a rate of 114.6/100,000 persons.

Noel NEJM 2004 Prasad CGH 2009 Dellon CGH 2014

Clinical presentation of EoE varies by age

<5 years of age Failure to thrive Feeding difficulties Gagging on solid foods

6-14 years of age Vomiting Abdominal pain Dysphagia

>15 years Dysphagia Food impaction Strictures

Mucosal changes in active EoE

Dellon CGH 2013

normal

EoE variations

Histology of EoE

Eosinophils

Basal-zone hyperplasia

Microabscess

EoE leads to progressive strictures and esophageal fibrosis

EoE Normal GERD EoE

Lucendo et al J Allergy Clin Immunol. 2011

Age at diagnosis, duration of EoE symptoms and risk of stricture

Age at diagnosis, duration of EoE symptoms and risk of stricture at MGH

Contrast radiography often reveals strictures and narrowing not apparent on endoscopy

Lee at al CHG 2012

Measurement of esophageal distensibility with Functional Lumen Imaging Probe (EndoFLIP)

Measurement of esophageal distensibility with Functional Lumen Imaging Probe (EndoFLIP)

Measurement of esophageal distensibility with Functional Lumen Imaging Probe (EndoFLIP)

Therap Adv Gastroenterol. 2013 Mar;6(2):97-107

Treatment of EoE

• The goals of treatment are to reduce dysphagia symptoms, prevent food impactions and risk of perforation, and prevent progressive esophageal fibrosis and strictures.

• There are currently no FDA-approved treatments for EoE

• Currently, the main approaches to treatment are immune suppression or dietary modification.

• Endoscopic dilation remains an important aspect of therapy.

Corticosteroids in the treatment of EoE

Fluticasone: Children: 50% complete response, 95% partial response (symptoms and histology) Adults: 62% histologic response, but no significant improvement in symptoms Budesonide: Adults: 72% remission (<5 eos/HPF), ~75% symptom improvement after 15 days. Typical initial duration of 8 weeks

Dellon et al. AJG 2013

Corticosteroids in the treatment of EoE

EoE will recur in the majority of patients after stopping steroid therapy. 91% of patients had recurrent symptoms at a mean of 8.8 months after treatment was completed; 69% repeated steroid treatment at least once.

Helou et al (2008)

Dellon et al. AJG 2013

Elimination diets in adults with EoE

Components of a 6-food elimination diet: * Wheat * Dairy * Eggs * Soy * Peanut and tree nuts * Fish and shellfish

Elimination diets in adults with EoE

Gonsalves et al. reported 50 adult subjects with EoE treated with 6 food elimination diet (milk, soy, egg, wheat, peanuts/tree nuts, and shellfish/fish) for 6 weeks.

Mean peak eosinophil count 34 8/HPF (proximal) Mean peak eosinophil count 44 13/HPF (distal) 70% had peak counts of <10 eos/hpf after SFED Symptom scores decreased in 94%

Gonsalves et al Gastro 2012

Eosinophil counts Symptom scores Eosinophil counts with reintroduction

Elimination diets in adults with EoE

Skin prick testing (SPT) accurately predicted only 13% of causal agents, and 67% of patients who had a food trigger identified by the reintroduction process had a negative SPT to all foods. The most common food triggers were wheat (60%) and milk (50%), followed by soy (10%), nuts (10%), and egg (5%).

Gonsalves et al Gastro 2012

Eosinophil counts Symptom scores Eosinophil counts with reintroduction

Elimination diets in adults with EoE

Components of a 6-food elimination diet: * Wheat * Dairy * Eggs * Soy * Peanut and tree nuts * Fish and shellfish

Implicated in 50-60% of all cases

General approach to EoE diagnosis and treatment

Takeaway points in EoE

• Consider EoE in any patient with chronic dysphagia or history of food impaction

• Can present at any age 0-99

• Have a high suspicion in men in their 3rd and 4th decades of life, especially if other atopic history (asthma, eczema, food allergies)

• EGD or barium esophagram are reasonable first steps

• Diagnosis and treatment are critical to reduce the risk of progressive fibrosis and esophageal stricture.

Celiac Disease

Learning Objectives for Celiac Disease

1. Understand the definitions of gluten, celiac disease and non-celiac gluten-sensitivity

2. Review the typical and atypical presentations of celiac disease involving both intestinal and extra-intestinal sites

3. Review the requirements and pitfall in the serologic and histologic diagnosis of celiac disease

4. Understand the current approach to therapy and preview promising non-dietary therapies currently in development

History

Aretaeus of Cappadocia (c. 100 A.D.) “If the stomach be irretentive of the food and if it pass through undigested and crude, and nothing ascends into the body, we call such persons coeliacs.”

History

Dr. Mathew Baillie (1800s) “Some patients have appeared to derive considerable advantage from living almost entirely upon rice.”

Samuel Gee (1888): “On the Coeliac Affection”: “if the patient can be cured at all, it must be by means of diet.”

History

Willem-Karel Dicke (1944) “In recent literature it is stated that the diet of Haas and Fanconi gives the best results in the treatment of patients suffering from coeliac disease. At present these items are not available. Therefore, I give a simple diet, which is helping these children at this time of rationing. The diet should not contain any bread or rusks. A hot meal twice a day is also well tolerated. The third meal can be sweet or sour porridge (without any wheat flour).”

The Modern Definition of Celiac Disease

Celiac disease is a chronic, small intestinal, immune-mediated enteropathy that is precipitated by dietary gluten in genetically predisposed individuals.

Ludvigsson et al: The Oslo definitions for coeliac disease and related terms. Gut 2013

What is gluten?

What is gluten?

Pathophysiology

Green and Cellier NEJM 2007

Discovery of tissue transglutaminase (TTG)

• Anti-gliadin antibodies first characterized in 1980s

• EMA assay 1985 – unknown antigen in the endomysium surrounding smooth muscle

• TTG identified as the autoantigen in the EMA assay (1997)

• The function of TTG in deamidating gluten peptides described – enhanced presentation by HLA-DQ2 (1998)

Di Sabatino et al. Autoimmunity Rev 2012

Deamidation enhances presentation on HLA-DQ2-encoded MHC; transamidation generates neo-

epitopes and anti-TTG autoantibodies

Endoscopic Appearance

Normal healthy duodenum Active celiac

http://daveproject.org/

Histopathology

Normal duodenum Celiac duodenum

Sleisenger and Fordtran 2006 Marsh Classification

The family of human transglutaminases

TG1 Keratinocyte transglutaminase skin ichthyosis

TG2 Tissue transglutaminase gut, kidney, lung, hematopoietic, smooth muscle, endothelium

Celiac, nephropathy, cirrhosis

TG3 Epidermal transglutaminase skin Dermatitis herpetiformis

TG4 Prostatic secretory transglutaminase prostate Prostate cancer

TG5 Transglutaminase X skin Dermatitis herpetiformis

TG6 Neuronal transglutaminase CNS Gluten ataxia

Blood coagulation Factor XIIIa

Transglutaminase Factor XIIIa plasma coagulopathy

Class Synonym Tissue Clinical association

Dermatitis herpetiformis: a model for extra-intestinal manifestations of celiac disease

• Gluten is the dietary trigger of DH • Urticarial, vesicular, or bullous lesions, usually localized

to the scalp, shoulders, elbows, knees, buttocks • IgA deposits in the upper dermis • Responds gradually to gluten free diet

Dermatitis herpetiformis: a model for extra-intestinal manifestations of celiac disease

Anti-TG2 IgA Anti-TG3/TG5 IgA

INF-γ, TNF-α, IL-2, IL-6, TGF-β Complement activation Inflammatory infiltrate

intestine Dermal-epidermal junction

Gluten ataxia

Anti-TG2 IgA Anti-TG6 IgA

INF-γ, TNF-α, IL-2, IL-6, TGF-β Complement activation Inflammatory infiltrate

intestine

Cerebellum vasculature

Celiac prevalence approaches 1% and appears to be increasing

• Current estimate 1 in 133 of average healthy U.S.

– 1 in 56 with related symptoms – 1 in 22 in those with a first degree relative – 1 in 236 African, Hispanic, Asian

• Projected number of celiac in US: 1.5-2

million • Actual number diagnosed ~50,000 • For each case of CD, ~ 50

undiagnosed • Population prevalence of celiac

disease appears to be increasing (+TTG 0.2% in 1950 vs. 0.9% in 2000s)

Fasano Arch Internal Med 2003 Abadie Ann Rev Immunol 2009 Rubio-Tapia A Gastro 2009

Prompt diagnosis is the exception

• On average patients have

symptoms for a 4-10 years before diagnosis

• The majority of new diagnoses now present with non-classic symptoms to diverse medical specialties

• Ecchymosis • Edema • Dermatitis • Amenorrhea, infertility • Secondary hyperparathyroidism • Obesity • Constipation • Anemia • Bleeding disorders • Abnormal LFTs • Musculoskeletal abnormalities • Neuropathy • Ataxia • Osteopenia • Pathologic fractures

Green et al AJG 2001, 2006

The Diagnosis of Celiac Disease

Required: 1. Distal duodenal biopsy

specimens demonstrating characteristic histologic changes

2. Positive CD-specific serologies (anti-TTG IgA or EMA)

Supportive: 1. Genetic testing (HLADQ2/8

necessary but not sufficient) 2. Stool testing for steatorrhea 3. Radiology/barium studies

(rarely) 4. Response to GFD or gluten

challenge

Diagnosis Still Requires Small Intestine Biopsy

Leffler and Schuppan AJG 2010

5 mini-cases illustrating use of serology and biopsy in suspected celiac disease

Case 1: 21 year-old man with mild IBS symptoms, more frequent loose stools over the past year along with some fatigue. He is not anemic and his weight is stable. His mother has celiac disease, and he wonders about the possibility. What is your next step? A referral to dietician to start gluten-free diet B check TTG IgA C check HLA-DQ2/DQ8 D referral for upper endoscopy

5 mini-cases illustrating use of serology and biopsy in suspected celiac disease

Case 2: 48 year-old woman recently found to have significant osteoporosis on DXA scan. TTG IgA was checked and found to be 31.2 U/ml (normal is 0-15). What is your next step? A referral to dietician to start gluten-free diet B check celiac genetic tests (HLA-DQ2, DQ8) C referral for EGD with biopsies to confirm the diagnosis

5 mini-cases illustrating use of serology and biopsy in suspected celiac disease

Case 3: 48 year-old woman recently found to have significant osteoporosis on DXA scan. TTG IgA was checked and found to be >300 U/ml (normal is 0-15). What is your next step? A referral to dietician to start gluten-free diet B check celiac genetic tests (HLA-DQ2, DQ8) C referral for EGD with biopsies to confirm the diagnosis

5 mini-cases illustrating use of serology and biopsy in suspected celiac disease

Case 4: 21 year-old woman with longstanding bloating and constipation; found to have modestly elevated TTG IgA (54.5 IU/ml). She was told she has celiac disease and she started a gluten-free diet 3 months ago. What is your next step? A repeat TTG IgA to see if titers have decreased B referral for endoscopy to confirm the diagnosis of celiac disease C recommend resuming full-gluten diet for at least 2 weeks before EGD with biopsies

5 mini-cases illustrating use of serology and biopsy in suspected celiac disease

Case 5: 21 year-old man with 1 year of intermittent diarrhea, bloating and upper abdominal pain. An EGD was done, and duodenal biopsies revealed mild villus blunting and increased intraepithelial lymphocytes (IELs). TTG IgA was subsequently checked and was negative at 1.5 U/ml (normal is 0-15). What is your next step? A referral to dietician to start gluten-free diet B look for other causes of villus blunting (e.g., Giardia) C start IBS treatments (probiotics, fiber, TCA)

Villous Atrophy with Negative Celiac Serologies?

Histological mimics of CD include: -Giardia -CVID -Peptic injury -Autoimmune enteritis -Radiation -Whipple’s disease -Collagenous and tropical sprue -Eosinophilic enteritis -HIV enteropathy -Lymphoma -Crohn’s -Other food allergies

Treatment • Only accepted treatment is

strict, lifelong adherence to a gluten-free diet (wheat, rye, barley and initially oats)

• Treatment of nutritional deficiency states (iron, folate, vitamin B12, zinc, copper)

• Determination of bone mineral density to assess for osteoporosis

Presutti et al AFP 2007

A gluten-free diet is one of the most difficult treatments we recommend to our patients

• GFD can cost as much as 3x vs. regular diet • Limitations in access to GF foods • Impacts social and professional life • Gluten-free foods usually not fortified (thiamine, folate, iron,

B2, niacin) • Relatively higher fat, sugar, protein content can lead to

excessive weight gain • Lower fiber – constipation in patients with large IBS overlap

New approaches to the treatment of celiac disease

Topical steroid Budesonide Small molecule Available

Immune modulation anti-CCR9 blockade; humanized IL-15 specific antibody

Monoclonal antibody; parasite

Phase 1-2

Intestinal barrier enhancement Zonulin antagonist (Larazotide)

Peptide Phase 2b

Glutenase ALV003 Peptide Phase 2

Immunotherapy Nexvax2; COUR-NP-GLI Peptide; nanoparticle Discovery-Phase 1b

Gluten sequestration BL-7010 Non-absorbable polymer with high affinity for gliadins

Phase 1/2

Transglutaminase inhibition

Dihydroisoxazoles, ZED-101

Small molecule

Phase 1

HLA-DQ2 blockade Dimeric/cyclic gluten peptide analogues

Peptide discovery

Gluten tolerization Genetically modified Lactococcus lactis

Bacteria discovery

Approach Example Class Status

Takeaway points in celiac disease

• Atypical or non-classical presentation is now the most common presentation

• Consider the diagnosis in the setting of typical GI symptoms and family history, as well as osteoporosis, arthritis, infertility, fatigue, constipation, thyroid, skin and neurologic disease

• TTG IgA is the best initial test if celiac is suspected – negative predictive value is 99%; positive predictive value ~75%

• To make the diagnosis, one must have a positive serology (TTG or EMA) and positive biopsy – consuming a full-gluten diet will increase the chances of detection