Celiac Disease: Past, Present and Future

Celiac Disease:

Past, Present and Future

BETH ISRAEL DEACONESS MEDICAL CENTER

HARVARD MEDICAL SCHOOL

Daniel Leffler MD, MS Research Director @ The Celiac Center

Beth Israel Deaconess Medical Center Celiac Disease Program @ Harvard Medical School

Associate Professor of Medicine Harvard Medical School

Celiac Disease in the Past

50 A.D. - Aretaeus the Cappadocian “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 koeliacs"

1888 - Samuel Gee separates celiac disease from non-diet responsive chronic

malabsorption. “On the Coeliac Affection…if the disease is to be cured at all it must be by means of diet”

Celiac Disease in the Present:

Three Breakthrough Discoveries

1950 - Dicke publishes his medical school

thesis: ‘Investigation of the harmful effects of certain cereals on patients with celiac disease’

1970’s –HLA DQ2 associated th celiac disease/dermatitis

herpetiformis

1997 - The role of tissue

transglutaminase in celiac disease identified

Pathophysiology

Step 1: Gluten Entry into the Submucosa

Green, Cellier NEJM 2007

Step 2: Deamidation of Gluten by Tissue Transglutaminase (tTG) Step 3: Immune Activation Only HLA DQ2 and DQ8 are able to bind gluten!

Step 1

Step 2 Step 3

Serologic tests

Dermatitis Herpetiformis: Model for

Celiac Disease Outside the Gut

Zone et al. J. Investigative Dermatology, 2009 Murray, et al. Int. J. Derm, 2003 Antibodies to TG3 or T cells primed to react to TG Antibodies deposit at Dermal-Epidermal junction •Complement activation •Cytokine release •Neutrophil infiltrate Dapsone / sulfapyridine

Celiac Disease is a Multi-System

Autoimmune Disorder

Hadjivassiliou et al. Lancet, Neuro 2010 Dermatitis Herpetiformis Classic Celiac + Manifestations in: Lung, Liver, Kidney, Blood Vessels, Placenta, etc Lane Hamilton Syndrome IgA Nephropathy MPGN Cardiomyopathy, IHD Fertility

+

Changing Prevalence

What happened here?IgA TTG serology > 95% accurate

United States Finland

Lohi et al. APT 2007, Rubio-Tapia Gastro 2009

Mortality Risk in Celiac

Disease

Ludvigsson JAMA. 2009, Grainge AJG 2011, Logan Gastro 1989, Nielsen Scand J Gastro 1985, Cottone DDS 1999, Corrao Lancet 2001, Peters Arch Int Med 2003, West BMJ 2004, Viljamaa DLD 2006, Anderson WJG 2007, Solaymani AJG 2007

S M R

Denmark Finland UK ScotlandN. Ireland Sweden Italy

2.5 2.0 1.5 1.0

Current Epidemiology of Celiac

Disease in the United States

Rubio-Tapia et al. AJG 2012

On Gluten Free Diet ~2 million Seroprevalence of celiac disease ~2 million Diagnosed with celiac disease and on a gluten free diet ~300,000

Current Definitions

• Celiac disease is a chronic small intestinal

immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals.

vs.

• Non-Celiac Gluten Sensitivity (NCGS) relates to one or more of a variety of immunological, morphological or symptomatic manifestations that are precipitated by the ingestion of gluten in people in whom CD has been excluded. Ludvigsson J. Et al.  GUT 2012.

Wahnschaffe U, et al.  CGH 2007.

Initial Studies Suggest an Immune

Mechanism for NCGS

Gluten Exposure in Individuals without Celiac Disease reporting Gluten Responsive GI symptoms

12 Biesiekierski JR, et al. Am J Gastroenterol. 2011;106:508. VAS, visual analog scale.

Mean Change in Symptoms Over 6 Weeks 16g Gluten vs. Placebo *P‐value for  analyses at  Week 1 and  entire study  period P=.047 50 40 30 20 10 0 1 2 3 4 5 6 Week VA S   (0 ‐ 100   mm) Overall Symptoms P=.031 50 40 30 20 10 0 1 2 3 4 5 6 Week VA S   (0 ‐ 100   mm) Bloating P=.001* 50 40 30 20 10 ‐10 1 2 3 4 5 6 Week VA S   (0 ‐ 100   mm) Tiredness 0 P=.02* 50 40 30 20 10 0 1 2 3 4 5 6 Week VA S   (0 ‐ 100   mm) Pain Gluten (n=19) Placebo (n=15)

Biesiekieski; Gastro 2013

No Effect of Gluten on

Symptoms

Role of alpha amylase/

trypsin inhibitors (ATIs)

Junker Y, et al. J EX Med, 2013

Current Paradigm

Celiac Disease

• Innate and adaptive immune activation • Auto-antibodies • Destructive mucosal inflammation IBS • Visceral Hyperalgesia •↑↓ Altered permeability • 1◦Motility disturbance • ? Low grade inflammation NCGS ? Gluten related alterations in: • Intestinal permeability • Motility • Inflammation •Innate  immune  activation •Anti‐gliadin  antibodies  Altered intestinal  microflora

• Less than 300 cases published from

referral centers (10% nonresponsive CD)

• Females (2:1), >50 years old

• Population-based cohorts

• 5 (0.7%) of 713 CD patients from Derby (UK) • 3 (1.4%) of 204 CD patients from Olmsted County • 8 (1.7%) of 480 CD patients from Boston • Incidence 0.06 (95% CI: 0.0-0.12) per 100,000

persons years

Rubio-Tapia A et al, Gut 2010 West J. Gastroenterology 2009;136:32 Roshan B, Leffler DA et al AJG 2011

Refractory Celiac Disease

Celiac Disease / Type 1 Refractory Sprue Type 2 Refractory sprue CD3 CD8

Abnormal IELs (CD3



+ CD8-) in

refractory sprue

Cellier et al, Lancet 2000

Prognosis by Refractory Celiac

Disease Classification

Al-toma et al, Gut 2007

Type 1 RCD

Type 2 RCD

De Novo EATL Secondary EATL

Let Thy Food Be Thy Medicine

• Strict gluten free diet is the only

accepted treatment for celiac disease

• The GFD is one of the more

challenging treatments we assign patients

• Involves avoidance of all wheat, rye

and barley products

• Less than 50 mg of gluten (1/30th of a

slice of bread) can cause significant, sustained mucosal inflammation

• Untreated celiac disease increases risk

of malignancy, infection, and results in a 2-3 fold increase in mortality

GFD

Hippocrates, 400 AD

Patient Satisfaction with

the GFD is Low

• Controversial in the past

• Better scientific data and a more diverse

celiac population

→

general acceptance

Sanders JGLD 2011

Treatment Burden is Second Only

to Hemodialysis

*VAS: 0=Very Easy 100=Very Difficult VAS*

Many Barriers to Staying Gluten Free

Impact

Hidden gluten/cross contamination Health concerns Cost Label reading Access to gluten-free foods Nutritional Content Social and professional life Psychological well-being

Leffler, AP&T 2007, Leffler et al. CGH 2009, Zarkadas J Hum Nutr Dietet 2006

•Medications •Supplements •Processed meats •Frozen Vegetables •Soy Sauce •Seasonings •Drink mixes Other included: Peptic ulcer disease (2), Crohn’s disease (1), Duodenal adenoCA (1), Food allergy (1), Gastroparesis (1)

Leffler et al. CGH 2006

“Non-Responsive” Celiac Disease

Persistent or recurrent signs/symptoms occur in ~10-30% of patients

Histologic Recovery is Age Related

Current Recommendations for

Celiac Monitoring

• Currently: No standard practice

regarding need for and timing of clinical,

serologic and histologic follow up

• Commonly recommended:

– Clinical and serologic follow up Q3-6 months until normal than Q1-2 years – Histologic follow up: variable from repeat

biopsy at 4-6 months to never if clinical and serologic response

– DXA at least once

Available Biomarkers

• Excellent for diagnosis

– tTG/DGP are >90% accurate – Biopsy confirmatory

– Response to therapy supportive and typical

• Imperfect for monitoring

– Drop in serologic titers after diagnosis is helpful – Repeat histology can be reassuring

– Symptomatic improvement BUT

– Serology and symptoms are not predictive of mucosal healing

– Histologic changes can be patchy and misleading and have differing responsiveness

iFABP

Adriaanse, Leffler et al. in press, Adriaanse et al. Aliment Pharmacol Ther. 2013 Vh:Cd p>0.001 Vh: C d Vh:Cd 2.2 Vh:Cd 1.8 Vh:Cd 1.1

Schuppan, Gastro 2009

Celiac Disease in the Future

Larazotide (Alba)

 Tight junctions are inter-cellular “gates” that open and close in response to internal and external stimuli

 Tight junction abnormalities trigger increased permeability and inflammation

 Modifying disease state epithelial permeability through the regulation of tight junctions – A potential paradigm shift in the treatment of immune mediated and inflammatory diseases Apical surface Intestinal epithelial cells Basal surface Tight Junction Paracellular Transport

Gluten-Related Adverse Events

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Disease Control Negative Control Active Treatment

T o ta l G S R S Sc o re Ch an g e fr o m Day 0 to Day 14 p = 0.032 p = 0.013

No differences in primary endpoint of LA:MA

Prevention of immunologic changes in PBMc (B cells)

Daily diary: Reduction in frequency of bowel movements, abdominal discomfort & pain

Safety comparable to placebo Symptoms Score (GSRS)

Phase 2a Larazotide Acetate: Prevention of Signs & Symptoms of Gluten Exposure During Two Week Gluten Challenge

p = 0.001 p = 0.008

Daniel A Leffler, C P Kelly, H Z Abdallah, et al., A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease during Gluten Challenge, The American Journal of Gastroenterologydoi:10.1038/ajg.2012.211

ALV-003 (Alvine)

Digestively Resistant Gluten

Fragments Gluten Peptide

Processed in the Mucosa

T-Cell Activation Causes Inflammatory Response Celiac Specific Antigen Presentation Celiac Patient Immune Reaction Causes Inflammation Normal No Immune Reaction Intestinal Mucosa GLUTEN INGESTED GLUTEN INGESTED 11 22 REACTIONREACTION

TRIGGERS IMMUNE RESPONSE AMD INFLAMMATION IN SMALL INTESTINE TRIGGERS IMMUNE RESPONSE AMD INFLAMMATION IN SMALL INTESTINE

33

Phase 2a ALV-003: Prevention of Gluten Induced Mucosal Injury Exposure During 6 Week Gluten Challenge

Lahdeaho ML, Kaukinen K, et al., Gastro 2014

Nexvax (ImmunosanT)

• Treatment shifts T cells from pro-inflammatory to tolerant response to gluten

• Induces tolerance in a celiac mouse model • Phase 2a trials underway

• Nexvax administration → symptoms mimicking oral gluten exposure

Peptide library:

18,117 12mers

2,92220mers 3 16AA Proteins

Dominant peptides

Non-Dietary (

non-behavioral

) Therapies

:

Transformative for Celiac Disease?

Case Study: Erectile Dysfunction Though 1980 ED was considered an uncommon psychological disorder “all sexual dysfunctions are caused by a single factor: anxiety”

In the 1980s the first surgical/injectable ED treatments were approved →

1. “80% of ED cases stem from physical problems” 2. “The emergence of the urologist as the primary

coordinator of care for the patient with sexual dysfunction”

Masters and Johhnson 1979, Wentzel E Med Anthro 2008, Cherry D CDC Statistics 2001

Good Therapies

→

More Care and More Research

Introduction of Injectable Therapies 800 700 600 500 400 300 200 100 Public a tions pe r y e a r

Conclusions

• In the past:

– Celiac diagnosis/treatment limited to patients with classic symptoms and monitoring was non-existent • In the present:

– Diagnostic tools are excellent and diagnosis is improving

– Histological recovery is slow/partial, recurrent symptoms are common and long term risks elevated

– GFD is recognized as an imperfect therapy

– Treatment and monitoring strategies are lacking which perpetuates reluctance to diagnose and follow • In the future:

– Novel therapeutics will significantly alter all aspects of celiac disease care, increasing diagnosis, encouraging monitoring and improving outcomes