Celiac Disease. Disclosures 5/6/2015. Goals/Objectives. Jeff Hunt, DO, FACOI. Speaker for Abbvie. Consultant for Janssen Pharmaceuticals

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1 Celiac Disease Jeff Hunt, DO, FACOI Gastroenterology United of Tulsa OSU Medical Center Disclosures Speaker for Abbvie Consultant for Janssen Pharmaceuticals Research projects with Abbvie Goals/Objectives History of Celiac Pathology of Celiac Disease Clinical features of CD Who and when to test Treatment 1

2 What is celiac disease? A chronic, genetic, auto-immune mediated, small bowel disorder characterized by mucosal inflammation, villous atrophy, and crypt hyperplasia, which occurs upon exposure to dietary gluten, and demonstrates improvement after withdrawal of gluten Alternative names: Celiac sprue, sprue Gluten intolerance Gluten-sensitive enteropathy Spectrum of celiac disease Classic disease 1)Villous atrophy; symptoms of malabsorption such as steatorrhea 2)Weight loss, or other signs of nutrient or vitamin deficiency 3)Resolution of mucosal lesions and symptoms upon withdrawal of gluten from the diet, within a few weeks to months These patient have antibodies to gliadin and tissue transglutaminase Atypical celiac disease Latent celiac disease Classic Spectrum of celiac disease Atypical celiac disease Minor gastrointestinal complaints Anemia, dental enamel defects, osteoporosis, arthritis, increased transaminases, neurological symptoms, or infertility Shows mucosal damage and possess the celiac specific antibody pattern Latent celiac disease 2

3 Classic Spectrum of celiac disease Atypical celiac disease Latent celiac disease Normal jejunal mucosa and minor or no symptoms at one or more time points while on a normal, gluten-containing diet Two variants 1) CD present in past, recovered completely and remained silent when a normal diet was reintroduced 2) Normal mucosa was diagnosed at an earlier occasion while ingesting a normal diet, but celiac disease developed later History Recognized 1st century AD κοιλιακός, (koiliakós, abdominal) Sprue coined in 18 th century Derived from a Dutch word meaning aphthous disease 20 th century Link between cereals and celiac made by Willem Karel Dicke, a Dutch pediatrician During WWII, when cereals were scarce, children s symptoms improved only to return with cereal consumption Van de Kamer showed the water-insoluble portion, gluten moiety of wheat produced intestinal injury 1. Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. History 1954 Paulley: first accurate description of the characteristic intestinal lesions 1986 Howell: observed celiac was associated with HLA- DQ2 haplotypes 1993 Lundin: DQ2 gene products preferentially presents gluten-derived gliadin peptides to intestinal mucosal T cells Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. 3

4 Epidemiology Whites of northern European ancestry Silent celiac disease, a positive serology and villus atrophy with few or no symptoms, is approximately seven times more common than symptomatic celiac disease Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. Epidemiology One of the largest studies in the US: 13,145 subjects who underwent screening (4,508 first-degree relatives of those with celiac disease, 1,275 second-degree relatives, 3,236 symptomatic patients, and 4,126 not-at-risk individuals) Prevalence is 1:22 in first-degree relatives 1:39 in second-degree relatives 1:56 in symptomatic patients In the not-at-risk group, the prevalence was 1:133 or ~1% of the population, ~4 million Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003; 163:286 Epidemiology One of the largest screening investigations of celiac disease was performed in 17,201 school children (6 to 15) from Italy and represented 69 percent of the eligible population The prevalence was 1:184 and the ratio of undiagnosed to diagnosed celiac disease was 7:1; most children had minor but significant symptoms [2] Catassi C, Fabiani E, Ratsch IM, et al. The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl 1996; 412:29 4

5 Pathology Studies of epithelial cell kinetics suggest that villus atrophy is a misnomer and there is evidence for an actual increase in enteropoiesis in the crypts Wright,et al, estimated that intestinal mucosa in patients with celiac produces six times as many cells per hour per crypt as does normal small intestine and that the cell cycle time is halved, reflecting premature shedding [4] Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. Pathogenesis Triggered by an environmental agent (gliadin) in genetically predisposed persons Complex interplay of varying environmental, genetic, and immune factors How these control expression of celiac and change from latent to overt disease remains unknown Pathogenesis ENVIRONMENTAL FACTORS Several wheat proteins are responsible for the grain s toxicity Prolamins (storage form of wheat protein rich in proline and glutamine) are referred to as gliadins Prolamins from wheat, barley, rye and oats have immunologic cross-reactivity and can trigger celiac Oats have the smallest proportion of prolamin and is usually tolerated in those with celiac disease Grains that do not activate disease: rice, corn, sorghum, and millet 5

6 Potential Causes/Protectors Rotavirus Adenovirus Surgery Pregnancy Infection Emotional stress Smoking? (adult onset) Breastfeeding GENETIC FACTORS Pathogenesis Concordance for CD in first-degree relatives ranges between 8% and 18% and reaches 70% in monozygotic twins [1] Close association with HLA-DQ2 and HLA-DQ8 genes HLA-DQ2 is present in more than 90% of persons with celiac disease compared with approximately 35% of general population However, only a minority of persons who express DQ2 actually develop CD, indicating that genes other than those encoding the DQ2 are involved in the development of CD Still much unknown Some of which are also associated with type 1 diabetes (15q26) [5] Houlston RS, Tomlinson IP, Ford D, et al. Linkage analysis of candidate regions for coeliac disease genes. Hum Mol Genet 1997; 6:1335. Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. IMMUNE FACTORS Pathogenesis Both humoral- and cell-mediated immune responses IgA and IgG serum antibodies to purified gliadin, all major fractions of gliadin, detected in the serum of patients with untreated CD IgA antibodies to endomysium, a connective tissue structure surrounding smooth muscle, are virtually pathognomonic for CD and are found only rarely in the absence of disease Now known that the target auto-antigen contained within the endomysium is the enzyme Tissue Transglutaminase-2 (TTG) 6

7 Clinical Features SUBCLINICAL DISEASE Mild and non-specific symptoms such as fatigue, iron deficiency, or otherwise unexplained elevations in serum aminotransferases, or no symptoms at all Establishing the diagnosis of subclinical disease is important 1) Danger of malignancy 2) Presence of nutritional deficiencies 3) Association with autoimmune disorders Clinical Features GASTROINTESTINAL FEATURES Classic signs: flatulence, diarrhea with bulky, foul-smelling, floating stools due to steatorrhea Malabsorption leading to growth failure, weight loss, anemia, neurologic disorders from deficiencies of B vitamins, and osteopenia from low vitamin D and calcium NON-GI FEATURES Neuropsychiatric Clinical Features Headache, peripheral neuropathy, ataxia, depression, dysthymia, anxiety, and epilepsy Peripheral neuropathy have been described in up to 50 percent of patients with celiac disease and may precede the diagnosis [1] Neuropathy may be associated with lymphoma and deficiencies of vitamins B1 (thiamine), B3 (niacin), B6 (pyridoxine), B12 (cobalamine), and E Gluten-free diet has been shown to have a favorable effect on headaches and dysthymia. Does not improve peripheral neuropathies Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. 7

8 Non-GI Clinical Features Metabolic bone disease Common and can occur in the absence of gastrointestinal symptoms Higher likelihood of secondary hyperparathyroidism that is probably due to Vitamin D deficiency Axial skeletal bone density can normalize on gluten-free diet, while loss of bone density in the appendicular skeleton may persist Hyposplenism Several case reports of hyposplenism (pathogenesis unknown) Prophylactic vaccinations for encapsulated organisms (Streptococcus, Neisseria, Hemophilus) are recommended Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. Howell-Jolly Bodies Non-GI Clinical Features Kidney disease Glomerular IgA deposition is common and may occur in as many as 1/3 of patients. Majority have no clinical manifestations of renal disease Idiopathic pulmonary hemosiderosis Coexistance of CD and idiopathic pulmonary hemosiderosis (Lane-Hamilton syndrome) reported in a few cases Gluten free diet has been associated with remission of pulmonary symptoms in several patients 8

9 Non-GI Clinical Features OB/GYN Delayed menarch Earlier menapause Infertility 9-fold increase in miscarriage rates Lower birth weights Premature births Eliakim and Sherer, Gynecol Obstet Invest, 51:3,2001 Soni and Badawy, J Reprod Med, 55:3, 2010 Ozgor, B, Scand J Gastroenterology, 45:395, 2010 Iron/folate deficiency Lab Anomalies CD may be a surprisingly frequent cause of iron deficiency anemia (with all EGDS bx duodenum!) 93 patients presenting with iron deficiency anemia found 12 percent of small bowel biopsy findings compatible with celiac(some had esophagitis and gastritis) Another report showed 6% of 85 patients with iron deficiency anemia had CD [3] Coagulopathy due to impaired absorption of vitamin K Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. Associated Conditions DERMATITIS HERPETIFORMIS Multiple intensely pruritic papules and vesicles that occur in grouped arrangements, usually involving the elbows, dorsal forearms, knees, scalp, back, and buttocks 9

10 Associated Conditions Histologic dx by demonstrating granular IgA deposits along the dermal-epidermal basement membrane Dermatitis herpetiformis responds to gluten withdrawal Dapsone if no response to GF diet DIABETES MELLITIS Associated Conditions CD is closely associated with Type I DM 2.6%-7.8% of adults with type I DM had IgA autoantibodies to endomysium or tissue transglutaminase Most were proven to have CD on small bowel biopsy Multiple genetic loci shared, including HLA-DR3, DQ2, and DQ8 Associated Conditions SELECTIVE IGA DEFICIENCY Association well established/serologic testing errors! IgA deficiency affects between 1 in 400/1 in 800 members of general population Occurs in 2 to 3% of patients with CD DOWN SYNDROME Prevalence of biopsy-proven celiac disease has been reported to be as high as 16% 20-fold increase compared with the general population 10

11 Associated Conditions LIVER Mild chronic elevation in serum AST (ranging 29 to 80) and ALT (ranging ) In patients with cryptogenic transaminasemia celiac serology was positive in 6% and duodenal biopsies suggested celiac disease in 4% Gluten-free diet, normalize 63-90% within a year THYROID Increased incidence of autoimmune thyroid disease Hypothyroid is more frequent Age at Diagnosis Other Autoimmune Conditions % % % Over 20 34% Ventura, et al Associated Conditions INFLAMMATORY BOWEL DISEASE Associated more frequently with UC than Crohn s Risk of IBD in patients with celiac elevated 10-fold while risk of CD in patients with IBD was comparable to controls First-degree relatives of patients with celiac may be at a fivefold increased risk of developing UC compared with the general pop ATROPHIC GLOSSITIS Has been described in association with CD; responds to a glutenfree diet Oral symptoms frequent in patients with CD; helpful tool in diagnosing CD 11

12 Who Should Be Tested? Patients with S/S or labs showing malabsorption, chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain, bloating Iron deficiency anemia, folate or vitamin B12 deficiency, persistent elevation of liver enzymes, recurrent aphthous ulcerations or stomatitis, dental enamel hypoplasia, and idiopathic peripheral neuropathy Patients with type I DM as well as first-degree relatives of individuals with CD if they have signs, symptoms, or laboratory evidence of CD Diagnosis No single test can confidently establish the diagnosis of CD in every individual All testing should be performed while patients are on a gluten-rich diet for at least two weeks! Three components to diagnosis Serologic studies Endoscopic/histologic evaluation Genetics SEROLOGIC STUDIES Diagnosis IgA anti-tissue transglutaminase (TTG) antibody is the single preferred test for detection of CD with a sensitivity and specificity of 95% Greater titer = greater likelihood of a true positive result Other serologic tests Anti-gliadin Ab (lowest sensitivity and specificity) Anti-endomysial Ab (moderate sensitivity and specificity) Anti-deamidated gliadin peptides (moderate to high sensitivity and specificity) Presence of IgA deficiency is increased in those with CD (2-3%)! When there is a high probability of CD total IgA should be measured, especially if IgA serology is negative Alternative approach is to include both IgA and IgG-based testing 12

13 Diagnosis Endoscopic/histologic evaluation Patients with a positive serology, and patients with a high probability of CD, regardless of the serology, should undergo upper endoscopy with small bowel biopsies to confirm the diagnosis Two biopsies from the duodenal bulb (either 9- or 12-o clock position) and four from the second and third portion of the duodenum Mucosa may appear atrophic, have fissures, a nodular appearance, or folds may be scalloped, but these are not universally present and can be seen with other disorders Pathology Marsh proposed a sequence of progression of the celiac lesions Normal, preinfiltrative mucosa (stage 0) Increase in intraepithelial lymphocytes, infiltration of the lamina propria with lymphocytes (stage 1) Crypt hyperplasia (stage 2) Villus atrophy (stage 3) Feldman, Mark, Lawrence Friedman, and Lawrence Brandt, Schleisenger and Fordtran s Gastrointestinal and Liver Disease. Philadelphia, PA: Saunders, Elsevier, Print. 13

14 Pathology 14

15 Diagnosis OTHER CAUSES OF VILLOUS ATROPHY; NOT ALL VILLOUS ATROPHY IS CELIAC! Tropical sprue Small-bowel bacterial overgrowth Drug-associated enteropathy Whipple s disease Collagenous sprue Crohn s disease Eosinophilic enteritis Intestinal lymphoma/tuberculosis Infectious enteritis Malnutrition AIDS enteropathy Diagnosis DISORDERS SEEN WITH LYMPHOCYTIC DUODENOSIS Helicobacter pylori Medications (NSAID s) Small bowel bacterial overgrowth Systemic autoimmune disorders GENETIC TESTING Diagnosis HLA-DQ2/DQ8 genotype testing should be used to effectively rule out the disease in selected clinical situations 1. Equivocal small-bowel histology in seronegative patients 2. Evaluation of patients on a GFD in whom no testing for CD was done before GFD 3. Patients with discrepant celiac-specific serology and histology More than 99% of patients with CD have HLA DQ2 and/or DQ8 compared with 40% of general population High negative predictive value (>99%) essentially excludes the possibility of CD if neither HLA DQ2 or DQ8 are present! 15

16 Treatment Six key elements in the management of patients with CD Consultation with a skilled dietitian Education about the disease Lifelong adherence to a GFD Identification and treatment of nutritional deficiencies Access to an advocacy group Continuous long-term follow-up by a multidisciplinary team DIETARY COUNSELING Treatment A GFD is the only effective treatment for CD Recommended for patients with classic CD, atypical CD, and asymptomatic or silent CD Patients with latent CD (positive IgA endomysial antibody, but normal small bowel biopsy) are currently not advised to be on a GFD, but should continue to be monitored and re-biopsied if symptoms develop GLUTEN FREE DIET Principle sources are wheat, barley, and rye Not completely possible to eliminate due to contamination of foods with trace amounts of gluten Gluten free indicates a diet that contains gluten at such a low level as to be considered harmless 16

17 2012, $4.2 BILLION 2017, $6.6 BILLION Treatment In general, the following dietary advice can be given to all patients Avoid wheat, rye, and barley Soybean or tapioca flours, rice, corn, buckwheat, and potatoes are safe Read labels to look for additives that may contain gluten Distilled alcoholic beverages and vinegars, as well as wine, are gluten free. Beer, ale, lagers, and malt vinegars should be avoided Oats should be introduced into the diet with caution and patients should be monitored for adverse reactions. Oat consumption should be limited to g/day (approximately 2 ounces) in patients with mild disease upon presentation or whose disease is in remission after a stringent GFD. The latter patients should be followed carefully for clinical or serologic evidence of disease recurrence after reintroducing oats. Patients with severe disease should avoid oats altogether! Treatment MONITORING RESPONSE TO A GFD Rapidity of response is variable ~70% of patients have noticeable clinical improvement in two weeks Symptoms improve faster than histology Patient labs re-evaluated 4-6 weeks following initiation of a GFD: CBC, CMP, B12, iron studies and serologic testing IgA TTG or IGA DGP should be used to monitor the response to a GFD A pre-treatment antibody level should be determined at the time of diagnosis Exclusion of gluten = gradual decline in serum antibody levels (t1/2 is 6 to 8 weeks). Normal baseline values in 3 to 12 months Normal antibody levels do not indicate recovery from villous atrophy If levels are not falling the patient is usually continuing to ingest gluten either intentionally or inadvertently 17

18 Treatment SMALL BOWEL BIOPSY Need for follow-up biopsy in patients with clinical improvement has been debated since serologic testing can be used to monitor recovery and compliance with the diet Endoscopy with biopsy should be performed in patients with established CD who fail to respond to a GFD or who relapse with symptoms despite a GFD Treatment NON-RESPONDERS Individuals who have persistent symptoms or serologic and/or histologic abnormalities after two years on a GFD ~5% fail to respond to diet changes Those who fail to respond fall into 5 main categories Poor compliance or inadvertent gluten ingestion Clinical or histologic features that overlap with celiac disease but are caused by other disorders Concurrent disorders No response to GFD (refractory CD) Patients with ulcerative jejunitis or intestinal lymphoma Treatment REFRACTORY CELIAC DISEASE 1 to 2%) Type I RCD, lymphocyte infiltration of the small-intestinal mucosa is similar to that seen in untreated CD (MC type in the US) Type II RCD, CD3-positive intraepithelial T-cells exhibit a lack of expression of normal cell surface differentiation markers such as CD8 These T-cell abnormalities are associated with a significantly less favorable prognosis as compared to Type I RCD 18

19 Treatment TYPE I RCD Exclude inadvertent gluten exposure and evaluation for and treatment of nutritional deficiencies Severe cases use systemic steroid therapy with prednisone or a similar agent If incomplete response to steroids or if recurs when the dose is reduced Azathioprine, budesonide or mesalamine can be used TYPE II RCD Treatment Same as Type I RCD, however, symptoms and signs of disease are more severe and are less likely to respond to further therapy Malnutrition may be severe and require TPN Systemic corticosteroids, budesonide, azathioprine, 6-MP, methotrexate, cyclosporine, anti-tnf antibodies Transformation to enteropathy-associated T-cell lymphoma (EATCL) is a prominent risk and may require treatment by surgery, chemotherapy, or bone marrow transplantation In some patients EATCL may run a prolonged, non-aggressive course but the overall prognosis remains poor ULCERATIVE JEJUNITIS Treatment Can progress into lymphoma. Consider in patients nonresponsive to steroids Multiple chronic, benign-appearing ulcers, most commonly in jejunum Intestinal strictures can lead to small bowel obstruction Evaluate with abdominal CT/MR enterography or upper endoscopy. If negative, follow with capsule endoscopy Responds poorly to a GFD and is associated with poor prognosis (~1/3 of patients die from complications) Prognosis can be improved if the ulcerated or strictured segment can be resected 19

20 Treatment OTHER ASPECTS OF MANAGEMENT Repletion of nutritional deficiencies Vitamins A, D, E, K, B6, B12, copper, zinc, carotene, folate, ferritin, iron, thiamine, magnesium, and selenium Prevention of bone loss Should be evaluated for bone loss using a DEXA scan yearly Vaccinations Vaccinate for encapsulated organisms due to hyposplenism Screening family members Currently, screening 1st-degree relatives (especially siblings) should be considered Who should be screened? Symptoms, signs, or laboratory evidence suggestive of malabsorption, chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain, and bloating. (Strong recommendation, high level of evidence) Patients with symptoms, signs, or laboratory evidence for which CD is a treatable cause should be considered for testing for CD. (Strong recommendation, moderate level of evidence) Patients with a first-degree family member who has a confirmed diagnosis of CD should be tested if they show possible signs or symptoms or laboratory evidence of CD. (Strong recommendation, high level of evidence) Consider testing asymptomatic relatives of a first-degree family member with a confirmed diagnosis of CD. (Conditional recommendation, high level of evidence) If have elevated serum aminotransferase levels when no other etiology is found. (Strong recommendation, high level of evidence) Patients with Type I DM if any digestive symptoms, or signs, or laboratory evidence suggestive of CD. (Strong recommendation, high level of evidence) 20

21 Complications Ulcerative Jejunitis Malignancy risk Enteropathy associated T-cell lymphoma and GI cancers Refractory Disease to GFD can develop with chronic non-adherence to diet. Patients who have no initial response to a gluten-free diet Patients who experience initial clinical improvement on a gluten-free diet, but, after a period of remission, develop disease refractory to gluten abstinence Ulcerative Jejunitis Typically seen in refractory sprue presents with Benign-appearing ulcers most often in the jejunum and symptoms of malabsorption, nausea, anorexia, fever, abdominal pain, and diarrhea. Evaluate with CT, MRI, and EGD. If nothing is found capsule endoscopy is required. Responds poorly to GFD. Up to 1/3 of patients die from complications, outcome seems to be better if strictures can be surgically removed. T-cell Lymphoma Fever, hepatomegaly, splenomegaly, duodenal mass, or ascites, may help with the diagnosis, but their presence implies more advanced disease. Other presentations: acute perforation, gastrointestinal obstruction, gastrointestinal hemorrhage. Diagnose with CT, MRI, upper endoscopy, and capsule endoscopy. Hard to distinguish lymphoma from occult celiac disease. A full thickness biopsy may be required to make the diagnosis when radioimaging is inconclusive. 5 year survival only 10% 21

22 Refractory Sprue Type 1: A normal population of intraepithelial lymphocytes. Type 2: An aberrant or premalignant population of intraepithelial lymphocytes. Can progress to enteropathy-associated T-cell lymphoma and ulcerative jejunitis. Diagnosis is based upon clonality analysis of T-cell receptors and immunophenotyping. The diagnosis can be established on biopsy; CT, MRI, and 18F-FDG PET scans can help identify suspicious areas. Differentiating is important as it can predict the progression of disease. A study assessed survival rate after 5 years for type 1 and type 2. At 5 years survival rate was 96% for type 1 vs. 58% for type 2. These findings were mostly like do to the development of T-cell lymphoma Refractory Sprue Type 1: treat with budesonide Treatment for severely ill patient s - hydrocortisone 100 mg IV Q6H, for those that can tolerate food use prednisolone mg PO QD. Type 2: prednisolone mg PO QD + Azathroprine or 6- mercaptopurine 2mg/kg/day. For those that can not tolerate Azathroprine or 6-MP use methotrexate 25 mg/week. Other agents: mesalamine, cladribine, and TNF-a inhibitors Research Kansas Farmers and glutenfree wheat research Lactobacillus to pre-treat flour or dough Immune modulation with the use of Necator americanus (hookworm) to desensitize celiac patients 22

23 Future Therapies Alvine Pharmaceuticals, ALV003 Degrades 33-AA long leftover chain Phase 2b study BioLineRx, BL7010 Binds to immunogenic portion of gluten preventing gliadin from entering blood Randomized, placebo controlled study in latter 2015 Celimmune, AMG 714 Monoclonal Ab to IL-15 (cytokine that leads to loss of tolerance) Phase 2 study Future Therapies Alba Therapeutics, Larazotide Acetate Oral peptide that regulates tight junctions in the bowel Prevents leaky gut Phase 2b studies ImmunosanT, Nexvax2 Intradermal, disease modifying immunotherapy Makes tolerant or reprograms their immune system to gluten Recruiting for phase 2 trials Patient Resources / Celiac disease foundation / Gluten Intolerance Group of N. America / Natl. Found. For Celiac Awareness / Canadian Celiac Association / Celiac Sprue Association Blumer, I. and Crowe, Sheila. Celiac Disease for Dummies, Wiley,

24 Thank You! 24