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Celiac Disease:Past, Present and Future

BETH ISRAEL DEACONESSMEDICAL CENTER

HARVARD MEDICAL SCHOOL

Daniel Leffler MD, MSResearch Director @ The Celiac CenterBeth Israel Deaconess Medical Center

Celiac Disease Program @ Harvard Medical SchoolAssociate 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

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PathophysiologyStep 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

+

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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

SMR

DenmarkFinland N. Ireland SwedenUK ItalyScotland

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

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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

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

Mean Change in Symptoms Over 6 Weeks16g Gluten vs. Placebo

*P‐value for analyses at Week 1 and entire study period

P=.047

50

40

30

20

10

01 2 3 4 5 6

Week

VAS (0‐100 mm)

Overall Symptoms

P=.03150

40

30

20

10

01 2 3 4 5 6

Week

VAS (0‐100 mm)

Bloating

P=.001*

50

40

30

20

10

‐101 2 3 4 5 6

Week

VAS (0‐100 mm)

Tiredness

0

P=.02*

50

40

30

20

10

01 2 3 4 5 6

Week

VAS (0‐100 mm)

Pain

Gluten(n=19)Placebo(n=15)

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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

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• 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 RefractorySprue

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

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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*

Shah S, Leffler DA, AJG 2014

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Many Barriers to Staying Gluten Free

Impact

Hidden gluten/cross contamination Health

concerns

Cost

Label readingAccess 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 DiseasePersistent or recurrent signs/symptoms occur in

~10-30% of patients

Histologic Recovery is Age Related

Lebwohl et al. APT 2014

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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 improvementBUT– 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:Cdp>0.001

Vh

:CdVh:Cd

2.2

Vh:Cd1.8

Vh:Cd1.1

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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 surfaceIntestinal 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

Tota

l GS

RS

Sc

ore

Ch

an

ge

fro

m D

ay

0 t

o D

ay

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 Gastroenterology doi:10.1038/ajg.2012.211

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ALV-003 (Alvine)

DigestivelyResistant GlutenFragments Gluten Peptide

Processed in the Mucosa

T-Cell ActivationCauses Inflammatory Response

Celiac Specific

Antigen Presentation

Celiac Patient

Immune ReactionCausesInflammation

Normal

No ImmuneReaction

IntestinalMucosa

GLUTENINGESTEDGLUTENINGESTED

11 REACTIONREACTION22

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

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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

2,922 20mers 3 16AA Proteins

Dominant peptides

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Non-Dietary (non-behavioral) Therapies:Transformative for Celiac Disease?

Case Study: Erectile DysfunctionThough 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

Pu

blicatio

ns p

er year

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