Management Celiac Disease Yesterday, Today, Tomorrow. Chris Mulder 20th of September 2016 Brisbane

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1 Management Celiac Disease Yesterday, Today, Tomorrow Chris Mulder 20th of September 2016 Brisbane

Sidney Haas Pediatrician New York City 1924 1870-1964 Albumin Milk - Dates Pot

2 Sidney Haas Pediatrician New York City Albumin Milk - Dates Pot cheese - Oranges 4 8 Bananas each day - Vegetables - Meat Office 47 West 86 th. Street

Willem Karel Dicke 1905-1962 Coeliac Disease Investigation of the harmful effects of

4 Willem Karel Dicke Coeliac Disease Investigation of the harmful effects of certain types of cereal on patients suffering from Coeliac Disease PhD thesis Utrecht 1950

5 Tomorrow s Treatment Should improve: Quality of life Natural history Costs Symptom control Histology: fast response (> 50 yrs) Availability GFD products and/or Easier to follow compared to current standard of care, GFD

6 White Bread Fairy Tale USA Air Force May 1945 Swedish White Bread

7 Age at diagnosis 2016 T. v Gils, n > 6000 slow responders GFD above 50 yrs

8 Spectrum of gluten related disorders Wheat Allergy Coeliac Disease Dermatitis herpetiformis Gluten - Ataxia Non-Coeliac Gluten Sensitivity Allergy Autoimmunity Innate-immunity?

9 Spectrum of gluten related disorders Wheat Allergy Coeliac Disease Dermatitis herpetiformis Gluten - Ataxia Non-Coeliac Gluten Sensitivity Allergy Autoimmunity Innate-immunity?

10 2006

11 Coeliac disease Symptomatic : GFD : No problem Asymptomatic : GFD : - Economic burden - Restrictive - Quality of life - 25 % regrets to be diagnosed Lee J.Hum.Nutr.Diet 2007, Whitaker J. APT 2009

12 Gluten Free Diet Symptoms: Improved Constipation and IBS might develop Natural History does improve: Osteoporosis, Nutrient deficiencies, Catch-up growth Quality of life Expensive; Isolation for some Compliance 50 mg can induce Villous atrophy Compliance, < 75% à 80% in Symptomatics

13 Gluten Free Diet Labelling legislation in East/West and the rest? Gluten is everywhere - Binder in pharmaceuticals - Deserts, Flavourings, Sauces - as Protein in Meat products Composition of Raw Material : India, South- America - even Food Industry doesn t know Gluten free as GFD as possible in: gluten Ataxia and Refractory Coeliacs slow responders : Gluten is everywhere

14 Gluten Free Diet Disease healing Slow & Incomplete Persistent villous atrophy increases long-term risk Patient satisfaction Poor Excellent Difficult therapy Underprivileged Developing countries Lack of interest of professionals doctors/dietitians Catholic Priests/Nuns Traveling : airline services

17 GFD as treatment Disease healing: Slow & Incomplete Persistent villous atrophy increases long-term risk Patient satisfaction: Poor Difficult therapy Excellent : Underprivileged : Developing countries : Lack of interest of professionals doctors/dietitians : Catholic Priests/Nuns : Traveling : airline services

19 Tomorrow s Treatment Should improve: Symptom control Quality of life Natural history Costs Histology: fast response (> 50 yrs) Availability GFD products and/or Easier to follow compared to current standard of care, GFD

20 Middle-East staple food is wheat 80% of caloryintake is wheat-based Glutenfree diet is the problem

21 What could drugs do? 1. Heal intestine quicker with drugs 2. Improve effectiveness of GFD (Supplement) 3. Allow a normal diet 4. Treat Refractory Coeliac Disease prevent : SB CA EATL 5. Money for CD-research = opportunistic Next slides Jason Tye Din, Melbourne

inhibitors HLA-DQ binders Biologicals Coeliac disease Autologous BMT (RCD II) AMG714

22 Reduce Permeability Zonulin antagonist (AT-1001) Intraluminal Glutenases Non-toxic gluten Pre-treatment Dampen adaptive immunity Immunosuppression (Budesonide) 2CDA Transglutaminase inhibitors HLA-DQ binders Biologicals Coeliac disease Autologous BMT (RCD II) AMG714 (Anti-IL-15) Anti-CD3 (Visilizumab? Monoclonals? Jason Tye Din, Melbourne 2014 Adapted from Mowat, Lancet 2003

Intraluminal Oral Enzymes: Glutenases Compound Formulation Company Gluteguard Caracain (papaya) Glutagen, Melbourne ALV003 Two recombinant proteases Alvine, USA AN-PEP DSM, Netherlands CM = my

23 Intraluminal Oral Enzymes: Glutenases Compound Formulation Company Gluteguard Caracain (papaya) Glutagen, Melbourne ALV003 Two recombinant proteases Alvine, USA AN-PEP DSM, Netherlands CM = my conflict of interest STAN1 Food grade enzymes from Aspergillus niger and Aspergillus oryzae HeimPal Children s Hospital, Hungary Only Phase I - II World J Gastroenterol. Sep 21, 2013; 19(35):

24 Coeliac Disease CD is no gut disorder but a systemic immune disease caused by an antigen delivered in the Gut. Foggy Mind no Fairy Tale Dubois 2010; Hunt 2008; Hwang 2011

25 Neurological manifestations of Coeliac Disease Gluten Ataxia Lancet Dietary treatment of gluten ataxia Dietary treatment of gluten neuropathy Muscle and Nerve Lancet JNNP Neurology Lancet Neurology Does cryptic gluten autonome body Gluten Sensitivity sensitivity target of brain from gut to play part in and intestinal brain neurological in illness gluten ataxia

26 Hippocrates Bad Digestion Is the Root of all Evil Evidence of Intestine in systemic immune disease All arthritic diseases IBD, some infections cause arthritis Dietary gluten causes inflammation Kenny Fine 2011 Dallas : Alternative Gastroenterologist

27 Non Coeliac Gluten Sensitivity Immune sensitivity to gluten without coeliac damage of SB ill-making in many ways : not just intestinal Surprisingly prevalent 11% of adult Americans : blood test 3 7 x more frequent in stool (where food is) A musician physician on a Mission, Kenny Fine

28 Australia 10 % of adults on GFD 50/50 partially GF vs. totally GF 15% females, 5% males 50% due to GI symptoms, small number prior Dx of Coeliac Disease GFD is everywhere Morell, CSIRO, Grain Summit Minneapolis 2012

30 Fructose Fructans Lactose Galactans Polyols Osmotic gradient GALT interaction Microbiota fermentation Water load Luminal Distension Gas production Hypersensitivity Abdominal bloating Abdominal pain Other GI symptoms Low-FODMAP for dietary-therapy intervention for IBS?

31 Spectrum of gluten related disorders Wheat Allergy Coeliac Disease Dermatitis herpetiformis Gluten - Ataxia Non-Coeliac Gluten Sensitivity Allergy Autoimmunity Innate-immunity?

32 Misconceptions in modern The Gluten Conspiracy medicine If wheat causes symptoms it must be the gluten If gluten-free diet improves symptoms, it must be due to the withdrawal of gluten

Misconceptions in modern The Gluten Conspiracy medicine If wheat causes symptoms it must be the gluten If gluten-free diet improves symptoms, it must be due to the

33 Misconceptions in modern The Gluten Conspiracy medicine If wheat causes symptoms it must be the gluten If gluten-free diet improves symptoms, it must be due to the withdrawal of gluten But: nearly all challenges are performed with wheat e.g., slices of bread or wheat flour in capsules Wheat contains gluten AND non-gluten proteins AND FODMAPs

34 Non Coeliac Gluten Sensitivity Coeliac Disease IBS-like Gluten Ataxia Classical CD Allergies Potential CD Non-Classical CD Wheat-allergy Latent CD Sub-clinical CD RCD/EATL

35 Non Coeliac Gluten Sensitivity NCGS relates to one or more immunological morphological symptomatic manifestations Precipicated by the ingestion of gluten Coeliac Disease should be excluded Oslo definitions, Gut 2011, The official CD Message

36 Non Coeliac Gluten Sensitivity Abdominal pain Bloating Diarrhea/Constipation Foggy Mind Fatique Eczema/Skin Rash Headache Depression Joint/Muscle Pain Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients Jun 18;7(6):

37 Non Coeliac Gluten Sensitivity Permanent or Transient Condition? Complications on the long run? Any Biomarkers? IgG AGA? Gluten-Challenge : Double Blind Placebo controlled? Pathogenesis?

38 Spectrum of gluten related disorders Wheat Allergy Coeliac Disease Dermatitis herpetiformis Gluten - Ataxia Non-Coeliac Gluten Sensitivity Allergy Autoimmunity Innate-immunity?

39 Hyderabad Juli 2008 Before Gluten Free Diet December 2008 After Gluten Free Diet

40 Mobile Hospital Ultra sound Upper GI Endoscopy Emergency resuscitation unit 2008

41 Non Coeliac Gluten Sensitivity Coeliac Disease IBS-like Gluten Ataxia Classical CD Allergies Potential CD Non-Classical CD Wheat-allergy Latent CD Sub-clinical CD RCD/EATL

42 Published in 2012 ATI s may have a pathogenic role: Is NCGS explained by this? Detlef Schuppan : Mainz

43 The Gluten Paradox: 2015 Patients with Celiac Disease Individuals on a Gluten-Free Diet Rubio-Tapia, et. Al. Am. J. Gastroenterol 2012

44 The Gluten Paradox Celiac Disease Non Celiac Gluten Sensitivity People Who Avoid Gluten (PWAG s) Rubio-Tapia, et. Al. Am. J. Gastroenterol 2012

45 The Gluten Paradox: 2020 Patients with Celiac Disease Individuals on a Gluten-Free Diet Rubio-Tapia, et. Al. Am. J. Gastroenterol 2012

46 T-cell lymphoma gluten reactive intra-epithelial lymphocytes Clonal T-cells low-grade malignancy Gluten-independent Ulcerative Jejunitis high grade malignancy 1th NHL in Coeliac Disease Meeting Ancona 1997

47 Conclusion Coeliac Disease GFD since 1933 NCGS: You can t deny this anymore, they ll come to you be aware of overdiagnosing (like in Australia) We need researchers to fully understand this

Gluten Sensitivity Fact from Myth. Disclosures OBJECTIVES 18/09/2013. Justine Turner MD PhD University of Alberta. None Relevant

Gluten Sensitivity Fact from Myth Justine Turner MD PhD University of Alberta Disclosures None Relevant OBJECTIVES Understand the spectrum of gluten disorders Develop a diagnostic algorithm for gluten