What’s New in Sprue (near you) Ciarán P. Kelly, MD Professor of Medicine Harvard Medical School & Director, Celiac Center BIDMC, Boston

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 Center Making gluten challenge less challenging The burden of treating celiac disease - a difficult pill to swallow Progress toward new treatments for celiac disease Getting fat gluten free & why it’s good to have celiac disease CeliacNow.org – Celiac disease & the GFD in digestible bytes More Celiacologists come to Boston

The World View of Celiac Disease 1989 Ireland 1/300 Europe 1/1000 North America CD Rare 1/5000 South America Africa Asia CD Rare

TTG serology enables increased celiac disease diagnosis PCPs “discover” TTG blood test (Tissue TransGlutaminase) What happened here? Garud et al. Aliment Pharmacol Ther 2009;29(8):898-905.

Where is celiac disease most common? 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)

Common & Not Limited to Europeans Today’s World View of Celiac Disease Finland: ~2.5% North America & Europe 0.6 to 2.5% Northern India ?3% SouthEast Asia CD Rare Subsaharan Africa CD Rare

An expanded perspective Celiac disease An expanded perspective 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 diagnosis Celiac Disease Foundation Green AJG 2001, Cranney DDS 2007

Celiac disease now more common in the US? Or just more commonly diagnosed? Then: 9,133 healthy young adults at Warren Air Force Base 1950: Blood collected (1948 to 1954) 0.2% with CD (positive TTG) 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) 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 Rubio-Tapia A et al. Gastroenterol 2009;137:88-93. Lohi S et al. Aliment Pharmacol Ther 2007;26:1217-25

Rising incidence of auto-immune & allergic conditions CD in Finland United States Type I Diabetes Bach JF, NEJM 2002, Lohi et al. APT 2007, Rubio-Tapia Gastro 2009

Why is celiac disease more common? “An idle immune system is the devil’s playground” 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

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)?

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

Neither can tolerate it Small bowel biopsies Which person can’t eat gluten? Normal Villous atrophy Neither can tolerate it Slide Atlas of Gastronterology, Misiewicz et al, 1984

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

Non-celiac gluten sensitivity Similar & significant differences for: Abdominal pain, bloating, tiredness & satisfaction with stool consistency NCGS is a real phenomenon Celiac disease cannot be diagnosed by a GFD trial

Gluten & wheat associated disorders Celiac disease Non-celiac Gluten Sensitivity Wheat allergy ~1% of population > 1% < 1% Positive IgA tTG antibody test Abnormal biopsy Symptoms on gluten exposure [after allergy and celiac disease excluded] History (food diary) Skin / RAST

Celiac disease versus NCGS (Non-celiac gluten sensitivity) 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

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

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 Center Making gluten challenge less challenging

aka Gluten free diet holiday: 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 Thank You! BIDMC Celiac center Gluten challenge study Villous height falls on gluten exposure - but 3 g/day = 10 g/day

Gluten challenge: making it easier Improvements: Genetic test before challenge – if negative no challenge Lower dose of gluten (3g versus 10-15g) Option for 2 week dropout (>90% accuracy) 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)

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 Center Making gluten challenge less challenging The burden of treating celiac disease - a difficult pill to swallow

Is There a Role for Non-Dietary Celiac Disease Treatment? Controversial in the past Now widely accepted Better medical & scientific data A more diverse celiac population From expert opinion to opinion of those actually on GFD 42% 35% 23% Satisfaction with GFD Sanders JGLD 2011

Why do we need non-dietary treatments 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 At social events For food prepared outside the home When travelling In restaurants & cafeterias Take-out For the elderly For the illiterate For those with mental or psychological impairment Sanders JGLD 2011

† VAS: 0 = Worst imaginable health 100 = Best imaginable health Perceived overall health is excellent in treated Celiac Disease Overall Health Visual Analog Scale VAS † Best @ 78: CD = Celiac disease Worst @ 55.4 ESRD = Renal disease on hemodialysis 78 72.4 76.7 71.6 69.9 70.5 57.8* 55.4* CD 78 (16.7) (61.3-94.7) GERD 71.6 (21.6) (50-93.2) HTN 72.4 (20.9) (51.5-93.3) IBD 76.7 (19.1) (57.6-95.8) CHF 57.8 (21.2)(36.6-79) IBS 70.5 (18.1)(52.4-88.6) DM 69.9 (23)(46.9-92.9) ESRD 55.4 (17.8) (37.6-73.2) † VAS: 0 = Worst imaginable health 100 = Best imaginable health *Compared with CD, p<0.001 BIDMC Celiac Center 2013 – under review 26

† VAS: 0 = Very Easy 100 = Very Difficult Perceived treatment burden of GFD is very high Treatment Burden VAS † 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 56.4 44.9 41.7 38.4 40.4 CD 44.9(30.9) Gerd 21.3(25.3) Htn 23.5(25.7) IBD 31.9(27.7) Chf 38.4(31) Ibs 40.4(24.4) Dm 41.7(30.4) Esrd 56.4(31.9) 31.9 23.5* 21.3* † VAS: 0 = Very Easy 100 = Very Difficult *Compared with CD, p<0.001 BIDMC Celiac Center 2013 – under review 27

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 Center Making gluten challenge less challenging The burden of treating celiac disease - a difficult pill to swallow Progress toward new treatments for celiac disease

Help on it’s way? Gluten is Everywhere “Wheat-free” ≠ “Gluten-free.” Dressing Flour or cereal products Gravies Imitation bacon Imitation seafood Lipstick and lip balm Breading Broth/Bouillon Candy Coating/Drink mixes Communion wafers Croutons Marinades Panko Pastas Play-Doh Processed luncheon meats Sauces Dry pet food Seasonings Self-basting poultry Soup bases Thickeners (Roux) Toothpaste Dental pumice Medications Help on it’s way? © 2008 Delete the Wheat

Larazotide acetate reduces symptoms during gluten challenge 86 study subjects Gluten-Related Adverse Events Placebo No challenge Larazotide + Challenge + Challenge Changes in symptom score during gluten challenge Placebo Larazotide No gluten challenge Leffler et al Am J Gastro. 2012;107:1554-62.

Larazotide acetate prevents IgA tTG Increases during gluten challenge Next study completed enrollment >200 subjects Continued symptoms & high tTG Despite GFD IgA-tTG (IgA-tissue Transglutaminase) fold change from baseline (mean) 38 32 25 18 12 6 Gluten challenge Placebo Larazotide acetete: 8 mg three times daily 1 mg three times daily 4 mg three times daily 0.03 0.01 0.02 0.009 0.008 0.005 Day 0 7 21 35 49 56 Last visit Day 0 Day 7 Day 21 Day 35 Day 49 Day 56 LDBTPV 184 study subjects Kelly et al Aliment Pharmacol Ther. 2013 Jan;37(2):252-262.

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 Center Making gluten challenge less challenging The burden of treating celiac disease - a difficult pill to swallow Progress toward new treatments for celiac disease Getting fatter gluten free & why it’s good to have celiac disease

Mean BMI increased from 24.0 to 24.6 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 Aliment Pharmacol Ther. 2012 Mar;35(6):723-9.

Diabetes Mellitus Type 2 is far less common in Celiac disease Pravelence of diabetes type 2 Celiac - 3.1% Control – 9.6% (x3 celiac rate) Population - 9.8% (x3 celiac rate) P < 0.0001 (n = 840) (n = 840) BMI (Body Mass Index)

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 Center Making gluten challenge less challenging The burden of treating celiac disease - a difficult pill to swallow Progress toward new treatments for celiac disease Getting fat gluten free & why it’s good to have celiac disease CeliacNow.org – Celiac disease & the GFD in digestible bytes More Celiacologists come to Boston

What’s New in Sprue (near you)

Celiac disease prevalence - a moving target CeliacNow.org Level 1 – The basics Level 2 – More detailed Level 3 – In depth information

Celiac Research Groups in Boston Boston Children’s Hospital – Director: Alan Leichtner, MD BIDMC – Director: Ciaran Kelly, MD & the new kids on the block: MGH – Director: Alessio Fasano, MD 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

What did he say? International Celiac News Celiac disease is more common than ever Non Celiac Gluten Sensitivity - a recognized medical entity News from BIDMC Celiac Center Gluten challenge (aka “GFD holiday”) less challenging GFD considered burdensome by patients New treatments for celiac disease – progress, but slow GFD can make you look fat but at least you may avoid diabetes CeliacNow.org for all your Gluten Free bytes Boston abounds in Celiac Researchers – let’s keep us busy!