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1
What’s New in Sprue (near you)
Ciarán P. Kelly, MD
Professor of MedicineHarvard Medical School
&Director, Celiac Center
BIDMC, Boston
2
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
3
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
0
20
40
60
80
100
120
1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006Year
# o
f P
atie
nts
What happened here?PCPs “discover”TTG blood test
(Tissue TransGlutaminase)
Garud et al. Aliment Pharmacol Ther 2009;29(8):898-905.
4
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
6
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
7
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)
9
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”
10
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)?
11
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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
14
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
16
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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
18
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
19
20
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!
21
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)
22
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
23
24
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%
25
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
26
Overall Health
† VAS: 0 = Worst imaginable health 100 = Best imaginable health
02
04
06
08
01
00
Vis
ua
l An
alo
gu
e S
cale
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
27
Treatment Burden
† VAS: 0 = Very Easy 100 = Very Difficult
02
04
06
08
01
00
Vis
ua
l An
alo
gu
e S
cale
CD GERDHTN DMESRD CHF IBD IBS
Perceived Treatment Burden
44.9
23.5* 21.3*
56.4
41.7
38.4 31.
9
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
28
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
29
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?
30
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
0
20
40
60
% S
ub
ject
s w
ith
Glu
ten
To
xici
ty
Gluten-Related Adverse Events
Placebo No challenge Larazotide + Challenge + Challenge
31
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
38
32
25
18
12
6
0
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
32
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
34
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)
35
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
36
What’s New in Sprue (near you)
37
Celiac disease prevalence - a moving target
CeliacNow.org
Level 1 – The basicsLevel 2 – More detailedLevel 3 – In depth information
38
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
39
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!