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What’s New in Sprue (near you)

Ciarán P. Kelly, MD

Professor of MedicineHarvard Medical School

&Director, Celiac Center

BIDMC, Boston

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What’s New in Sprue

International Celiac NewsHow common is celiac disease? A moving targetWhy are so many people eating Gluten Free (and does it help me)?

News from BIDMC Celiac CenterMaking gluten challenge less challengingThe burden of treating celiac disease - a difficult pill to swallowProgress toward new treatments for celiac diseaseGetting fat gluten free & why it’s good to have celiac diseaseCeliacNow.org – Celiac disease & the GFD in digestible bytesMore Celiacologists come to Boston

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The World View of Celiac Disease1989

North AmericaCD Rare1/5000

South AmericaAfricaAsia

CD Rare

Ireland1/300 Europe 1/1000

TTG serology enables increasedceliac disease diagnosis

New Diagnoses of Celiac Disease at BIDMC

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1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006Year

# o

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What happened here?PCPs “discover”TTG blood test

(Tissue TransGlutaminase)

Garud et al. Aliment Pharmacol Ther 2009;29(8):898-905.

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1980’s - Galway Ireland

The “capital of celiac disease” Estimated 1 in 303 in 1980’s

1990’s – United States

Estimated 0.02% (1/5000)

2000’s – US & Most of the world

Estimated ~1%

Finland 2000 1% (half diagnosed) 2010 2% (quarter diagnosed)

Where is celiac disease most common?5

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Common & Not Limited to Europeans

North America& Europe

0.6 to 2.5%

SubsaharanAfrica

CD Rare

Finland:

~2.5%

Northern India

?3%

SouthEastAsia

CD Rare

Today’s World View of Celiac Disease

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Who? Common in many ethnic

backgrounds

When? Any age after gluten

ingestion Average age at diagnosis

~45 yrs

How? Highly diverse

presentations. Average 11 years of

symptoms prior to diagnosisCeliac Disease Foundation

Green AJG 2001, Cranney DDS 2007

Celiac diseaseAn expanded perspective

Celiac disease now more common in the US? Or just more commonly diagnosed?

Rubio-Tapia A et al. Gastroenterol 2009;137:88-93. Lohi S et al. Aliment Pharmacol Ther 2007;26:1217-25

Then:

9,133 healthy young adults at Warren Air Force Base

1950: Blood collected (1948 to 1954)

0.2% with CD (positive TTG)

Conclusions:

• Celiac disease 4 times more common now than 50 years ago

• 4 fold increased risk of death with undiagnosed CD over 50 year time period

Now:

12,768 gender-matched subjects from 2 recent US cohorts

Circa 2000:Similar years of birth (n = 5558)Similar age at sampling (n = 7210)

0.9% with CD [x 4.5; P < .001].

Mortality hazard ratio = 3.9 (95% CI, 2.0-7.5; P

< .001)

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Rising incidence of auto-immune & allergic conditions

Bach JF, NEJM 2002, Lohi et al. APT 2007, Rubio-Tapia Gastro 2009

CD inFinland

CD inUnited States

Type IDiabetes

Why is celiac disease more common?

Why are many “auto-immune” and allergic conditions increasingly common?

Hygiene theory Our immune system developed to

constantly fight germs and parasites

Modern hygiene leads it to react against harmless environmental antigens and auto-antigens

“An idle immune system is the devil’s playground”

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What’s New in Sprue

International Celiac NewsHow common is celiac disease? A moving targetWhy are so many people eating Gluten Free (and does it help me)?

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Intestinal damage in Celiac disease& healing on the Gluten Free Diet

Healthy VilliFlat Villi

Small bowel biopsies

Slide Atlas of Gastronterology, Misiewicz et al, 1984

Which person can’t eat gluten?

Neither can tolerate it

Normal Villous atrophy

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Non-Celiac Gluten Sensitivity

Theories:

• Imaginary?

• Psycho-somatic?

• Irritable bowel syndrome variant?

• A result of gluten’s:

• Indigestibility

• Ability to activate “innate” immunity

• versus activation of adaptive immunity in celiac disease

INSERT your pet theory HERE

Similar & significant differences for: Abdominal pain, bloating, tiredness & satisfaction with stool consistency

Non-celiac gluten sensitivity

1. NCGS is a real phenomenon2. Celiac disease cannot be diagnosed by a GFD trial

Gluten & wheat associated disorders

Celiac diseaseNon-celiac

Gluten Sensitivity

Wheat allergy

~1%of population

> 1%of population

< 1%of population

• Positive IgA tTG antibody test

• Abnormal biopsy

Symptoms on gluten exposure

[after allergy and celiac disease excluded]

• History (food diary)

• Skin / RAST

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Celiac disease NCGS

Gluten in diet causes: Symptoms Intestinal injury High celiac antibodies Malabsorbtion & Nutritional deficiencies Complications

Osteoporosis, malignancy

Genetic predisposition Associated with other auto-

immune disorders

Requires lifelong, strict GFD

Gluten in diet causes: Symptoms

No known genetic predisposition

No known complications

Strictness & duration of GFD may vary

Celiac disease versus NCGS(Non-celiac gluten sensitivity)

Non-celiac Gluten Sensitivity: The new kid taking over the block?

Pros for GFD: More awareness. Easier access. Lower costs?

Cons for GFD: Inconsistencies regarding strictness

New Yorker cartoon by GREGORY

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What’s New in Sprue

International Celiac News How common is celiac disease? A moving target Why are so many people eating Gluten Free (and does it help me)?

News from BIDMC Celiac CenterMaking gluten challenge less challenging

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Already on a Gluten Free Diet but no formal diagnosis

Do I have celiac disease (or NCGS)?

Gluten challenge:Typical regimen:

Full gluten diet for 8 weeks Small intestinal biopsy & celiac antibody tests

Why bother? Certainty re diagnosis

Celiac disease versus non-celiac gluten sensitivity Certainty re need for lifelong, strict GFD Certainty re family risk Certainty re potential for celiac complications & associations Can “cure” celiac disease!

aka Gluten free diet holiday:V

BIDMC Celiac center Gluten challenge study

Villous height falls on gluten exposure - but 3 g/day = 10 g/day

ThankYou!

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Gluten challenge: making it easier

Improvements:1. Genetic test before challenge

– if negative no challenge

2. Lower dose of gluten (3g versus 10-15g)

3. Option for 2 week dropout (>90% accuracy)

4. Late blood work to increase sensitivity further

Next steps? Gluten challenge of biopsy Gluten reaction “biomarkers” in

blood

1.

3.2.

4.

2013 American College of Gastroenterology Guidelines for Gluten Challenge in Celiac disease diagnosis (Am J Gastro in press)

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What’s New in Sprue

International Celiac NewsHow common is celiac disease? A moving targetWhy are so many people eating Gluten Free (and does it help me)?

News from BIDMC Celiac CenterMaking gluten challenge less challengingThe burden of treating celiac disease - a difficult pill to swallow

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Is There a Role for Non-DietaryCeliac Disease Treatment?

Controversial in the pastNow widely accepted

Better medical & scientific data A more diverse celiac population From expert opinion to opinion of those actually on GFD

Sanders JGLD 2011

Satisfaction with GFD

35% 23%42%

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Why do we need non-dietarytreatments for Celiac Disease?

The GFD is highly effective in celiac disease BUT:

> 10% Non-responsive to GFD

1 - 2% Refractory to GFD

~ 30% of adults on GFD for celiac disease have ongoing partial

villous atrophy on biopsy

Strict GFD difficult to maintain

Sanders JGLD 2011

• At social events• For food prepared outside the

homeWhen travelling

In restaurants & cafeterias

Take-out

• For the elderly• For the illiterate• For those with mental or

psychological impairment

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Overall Health

† VAS: 0 = Worst imaginable health 100 = Best imaginable health

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CD HTN GERD ESRD DM CHF IBD IBS

Overall Health State

Mean Overall Health VAS

78.0(16.7) 71.6(21.6) 72.4(20.9) 76.7(19.1) 57.8(21.2) 70.5(18.1) 69.9(23.0) 55.4(17.8) 78

55.4*

76.7

57.8*

69.971.672.4

70.5

*Compared with CD, p<0.001

Visual Analog Scale

VAS †

Best @ 78:CD = Celiac disease

Worst @ 55.4ESRD = Renal disease on hemodialysis

Perceived overall health isexcellent in treated Celiac Disease

BIDMC Celiac Center 2013 – under review

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Treatment Burden

† VAS: 0 = Very Easy 100 = Very Difficult

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CD GERDHTN DMESRD CHF IBD IBS

Perceived Treatment Burden

44.9

23.5* 21.3*

56.4

41.7

38.4 31.

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40.4

*Compared with CD, p<0.001

Renal disease on Hemodialysis = 56.4

Celiac disease = 44.9

Higher than:• Insulin dependant diabetes• Irritable bowel syndrome• Congestive heart failure• Inflammatory bowel disease• Hypertension• GERD

Perceived treatment burden of GFD is very high

VAS †

BIDMC Celiac Center 2013 – under review

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What’s New in Sprue

International Celiac NewsHow common is celiac disease? A moving targetWhy are so many people eating Gluten Free (and does it help me)?

News from BIDMC Celiac CenterMaking gluten challenge less challengingThe burden of treating celiac disease - a difficult pill to swallowProgress toward new treatments for celiac disease

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Gluten is Everywhere

BreadingBroth/Bouillon

Candy Coating/Drink mixes Communion wafers

Croutons

DressingFlour or cereal products

GraviesImitation bacon Imitation seafood

Lipstick and lip balm

MarinadesPankoPastas

Play-DohProcessed luncheon meats

SaucesDry pet food

SeasoningsSelf-basting poultry

Soup bases Thickeners (Roux)

Toothpaste Dental pumiceMedications

“Wheat-free” ≠ “Gluten-free.”

© 2008 Delete the Wheat

Help on it’s way?

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Larazotide acetate reduces symptomsduring gluten challenge

86 study subjects

Leffler et al Am J Gastro. 2012;107:1554-62.

Changes in symptom score during gluten challenge

Placebo

Larazotide

No gluten challenge Disease Control Negative Control Active Treatment

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Gluten-Related Adverse Events

Placebo No challenge Larazotide + Challenge + Challenge

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0.03

0.008

0.01 0.02

0.005

0.009

Placebo

Larazotide acetete: 8 mg three times daily 1 mg three times daily 4 mg three times daily

Day 0 Day 7 Day 21 Day 35 Day 49 Day 56 LDBTPV

Gluten challenge

Day 0 7 21 35 49 56 Last visit

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IgA-tTG (IgA-tissue Transglutaminase) fold change from baseline (mean)

Larazotide acetate prevents IgA tTG Increases during gluten challenge

Kelly et al Aliment Pharmacol Ther. 2013 Jan;37(2):252-262.

184 study subjects

Next study completed enrollment• >200 subjects• Continued symptoms & high tTG• Despite GFD

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What’s New in Sprue

International Celiac NewsHow common is celiac disease? A moving targetWhy are so many people eating Gluten Free (and does it help me)?

News from BIDMC Celiac CenterMaking gluten challenge less challengingThe burden of treating celiac disease - a difficult pill to swallowProgress toward new treatments for celiac diseaseGetting fatter gluten free & why it’s good to have celiac disease

33Aliment Pharmacol Ther. 2012 Mar;35(6):723-9.

<18.5 18.5-24.9

25-29.9

>300.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%At Diag-nosis

In 679 celiac patients:

At diagnosis: 32% overweight or obese (compared to 59% in regional population)

On GFD:• Mean BMI increased from 24.0 to 24.6• 22% with normal or high BMI at

diagnosis increased BMI by >2 points• 15.8% became overweight• 22% overweight at diagnosis gained

additional weight

Attention to weight maintenance essential on GFD

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Diabetes Mellitus Type 2

is far less common in Celiac disease

All BMI <18.5 18.5-24.9

25-29.9 >300.0%

5.0%

10.0%

15.0%

20.0%

25.0%

Celiac

Control Group

General Population

BMI (Body Mass Index)

Pravelence of diabetes type 2Celiac - 3.1%Control – 9.6% (x3 celiac rate)Population - 9.8% (x3 celiac rate)

P < 0.0001

(n = 840)

(n = 840)

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What’s New in Sprue

International Celiac NewsHow common is celiac disease? A moving targetWhy are so many people eating Gluten Free (and does it help me)?

News from BIDMC Celiac CenterMaking gluten challenge less challengingThe burden of treating celiac disease - a difficult pill to swallowProgress toward new treatments for celiac diseaseGetting fat gluten free & why it’s good to have celiac diseaseCeliacNow.org – Celiac disease & the GFD in digestible bytesMore Celiacologists come to Boston

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What’s New in Sprue (near you)

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Celiac disease prevalence - a moving target

CeliacNow.org

Level 1 – The basicsLevel 2 – More detailedLevel 3 – In depth information

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Boston Children’s Hospital – Director: Alan Leichtner, MDBIDMC – Director: Ciaran Kelly, MD& the new kids on the block:MGH – Director: Alessio Fasano, MD

Celiac Research Groups in Boston

All Major Teaching Hospitals of Harvard Medical School

Collaborate in:Research – Education –Fund raising –

Combined Groups: ~ 40 Celiac Researchers (MD, PhD, RD et al) > 25 Celiac disease research publications in 2012 Current expenses ~$3 million per annum

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What did he say?

International Celiac NewsCeliac disease is more common than everNon Celiac Gluten Sensitivity - a recognized medical entity

News from BIDMC Celiac CenterGluten challenge (aka “GFD holiday”) less challengingGFD considered burdensome by patientsNew treatments for celiac disease – progress, but slowGFD can make you look fat but at least you may avoid diabetesCeliacNow.org for all your Gluten Free bytesBoston abounds in Celiac Researchers – let’s keep us busy!