3/20/2014 Type 1 Diabetes, treatment, prediction and prevention Going to school Carla Greenbaum MD Director, Diabetes Program • Math • History • English • Philosophy • Civics MATH 1
3/20/2014 MATH: Absolute and Relative Risk Type 1 diabetes runs in families TRUE or FALSE Raise your hand if you are a health care provider for someone with type 1 diabetes 2
3/20/2014 Keep your hand up if you are a health care provider to those with more than one family member with type 1 diabetes Paradox? How is it that most people do not have multiple family members with diabetes and yet , type 1 diabetes runs in families? Families with diabetes ~5% Families without diabetes 15X 0.3% 100 Newly diagnosed patients with type 1 diabetes 10 90 3
3/20/2014 300 people without a family member X 0.3% = 1 with diabetes with diabetes and (300 ‐ 15) = 285 without diabetes 300 people with a family member X 5 % = 15 with diabetes with diabetes Risk summary • About 0.3 ‐ 0.5% or 3 ‐ 5/1000 people have T1D. – This is the same as saying that the absolute risk of having T1D in the general population is 3 ‐ 5/1000 • About 5% of those with a family member have T1D – This is the same as saying that the absolute risk of having T1D in families is 5/100 or 50/1000 • The Relative Risk of a family member is thus 15X greater than someone in the general population. HISTORY 4
3/20/2014 HISTORY: Type 1 Diabetes and the immune system Type 1 diabetes is a immune disease “insulitis” 1970’s Normal islet Islet missing insulin producing beta cells Lots of immune cells 2014’s Insulitis not seen in every islet Type 1 diabetes is a immune disease Islet Cell Antibodies (ICA) 1980’s Insulin autoantibodies (IAA) Jerry Palmer, University of Washington ICA512 (IA ‐ 2); ZnT8 ab; GAD ab 5
3/20/2014 Type 1 diabetes is a immune disease Risk Group Type 1 diabetes Population 1:300 Family members 1:20 Jerry Nepom, MD, PhD 1980’s Benaroya Research Institute Association with class II HLA type and HLA involves the immune system Eisenbarth Model-T1D Natural History (?Precipitating Event) Genetic Overt Predisposition Immunologic abnormalities Progressive loss insulin release Beta cell mass 1986 Normal insulin release Overt Glucose diabetes normal C-peptide present No C-peptide Age (years+ The modified model of disease: 2014 Its really complicated - when you get diabetes depends upon: • Number of beta cells you start with • When and how fast the immune system starts destroying beta cells • Whether you slow or turn off the disease • How much insulin you need to control glucose 6
3/20/2014 Number of beta cells you start with 1. Each person who eventually develops T1D starts out with a variable amount of beta cell mass/function John Joe Jim Number of beta cells you start with 1. Each person who eventually develops T1D starts out with a variable amount of beta cell mass/function 2. If the beta cells are destroyed at the same rate, they will get diabetes at different times Joe Beta cell function John Jim Time When and how fast the immune system attacks the beta cells 1. The rate at which the immune system attacks the cells also determines when you get diabetes Joe Beta cell function John Jim Time 7
3/20/2014 Whether you can turn off the immune attack 1. If you control or turn off the immune attack, you may delay or never get T1D Joe Beta cell function John Jim Time How much insulin you need to control glucose 1. Clinical Diabetes occurs when there is not enough insulin secretion to keep up with demand Diabetes No Diabetes Even though it is complicated; we can predict who will get disease (?Precipitating Event) Genetic Overt Predisposition Immunologic abnormalities Progressive loss insulin release Beta cell mass Normal insulin release Overt Glucose diabetes normal C-peptide present No C-peptide Age (years+ 8
3/20/2014 ENGLISH ENGLISH: Determining Risk for T1D Genetic Risk: HLA testing or Family History Sensitivity : Proportion of people with disease who test positive: Number of people who have genetic risk who will get diabetes Number of people with diabetes Specificity : Proportion of people without diabetes who test negative: Number of people without genetic risk and who do not get diabetes Number of people without diabetes About 75% of people with Type 1 diabetes have high risk HLA, but 25% do not. About 10% of people with type 1 diabetes have a family member with disease, but 90% do not Genetic risk alone is neither very sensitive nor specific 9
3/20/2014 Antibody testing Antibody: Protein made by the immune system to identify and destroy foreign* objects (like infections) *in autoimmune disease the immune system makes a mistake and destroys “self” not foreign objects Risk of diabetes among those with genetic risk (family members) 5 year risk Longer term risk No antibodies Less than 1% Likely less than 3% One antibody ~3% Likely less than 5% Two antibodies 35% Likely more than 90% Two antibodies and 85% Likely almost everyone abnormal glucose More antibodies = greater risk ICA, IAA, GAD, IA-2 ICA, IAA, GAD, IA-2 Survival Distribution Function 1.0 1 ab 0.9 0.8 0.7 2 ab 0.6 3 ab 0.5 4 ab 0.4 0.3 0.2 n = 26799 0.1 0.0 1 2 3 4 5 6 7 8 Years Followed ALL babies with multiple antibodies will get T1D Ziegler, et al, JAMA 2013 10
3/20/2014 PHILOSOPHY PHILOSOPHY: When should we stop the immune attack? 11
3/20/2014 Stages of Diabetes Pre-islet Islet Abnormal autoimmunity autoimmunity Glucose Tolerance 100 % Beta cell function Clinical onset of disease Honeymoon Longstanding DM with or without Time insulin secretion When do autoantibodies occur? (How soon does “diabetes” start?) 64% of children who got T1D before puberty had antibodies by age 2 95% of children who got T1D # children before puberty had antibodies by age 5 0 2 4 6 8 10 12 14 Age (yrs) Parikka et al; Diabetologia (2012) 1936 Is having two or more antibodies a “disease’”? 5 year risk Longer term risk No antibodies Less than 1% Likely less than 3% One antibody ~3% Likely less than 5% Two antibodies 35% Likely more than 90% Two antibodies and 85% Likely almost abnormal glucose everyone Islet Autoimmunity 12
3/20/2014 Is having two or more antibodies a “disease’”? Islet Autoimmunity Having islet autoimmunity has no symptoms, but it puts you at risk for getting diabetes Hypertension (high blood pressure) Having mild high blood pressure has no symptoms, but it puts you at risk for getting heart disease and stroke Islet Autoimmunity PHILOSOPHY: Thought experiment PHILOSOPHY: Thought experiment Disease Hypertension Islet autoimmunity Consequence within 4-5 ~5/100 get coronary heart 35/100 get T1D years disease or stroke Relative risk reduction Treating hypertension Prevention studies (effect size) of treatment reduces heart disease by designed with effect size 16% and stroke by 40% of 40% Absolute benefit of Treating 100 patients with Treating 100 people would treatment high blood pressure keep 14 from getting T1D prevents 2 people from getting heart disease or stroke Severity of event Heart disease or stroke – T1D is a manageable severe disability or death disease Risk of therapy Blood pressure treatment Cost, risk of adverse is costly, but adverse events, psychological effects tolerated and effects, treating children alternatives available 13
3/20/2014 What therapy is being tested to treat islet autoimmunity? • Age 2 or older Oral Insulin Daily capsule • Two antibodies “oral tolerance” • One antibody is insulin autoantibody • Age 6 or older Monthly IV Abatacept • Two antibodies, but not infusion for 1 year insulin autoantibody • Age 8 or older Teplizumab 14 days IV infusion • Two antibodies and just once abnormal glucose 4 year delay to diabetes onset in a subgroup of people treated with oral insulin (Post ‐ hoc analysis) 1.0 Oral Insulin Oral Insulin; N=63 Placebo Proportion without T1D 0.8 Proportion Free of Diabetes 0.6 0.4 Placebo; N=69 0.2 Log-rank P=0.01 0.0 0 1 2 3 4 5 6 Years Does immunotherapy scare you? 14
3/20/2014 Immunotherapy is used to treat autoimmune disease. There are more than 80 million Americans with autoimmune disease many of these are treated with immunotherapy Alopecia areata Myasthenia gravis Ankylosing spondylitis Pernicious anemia Addisons disease Polyarteritis Hemolytic anemia Polychondritis Autoimmune Hepatitis Polymyositis Thrombocytopenic purpura Psoriasis Behcets disease Rheumatoid arthritis Pemphigus Scleroderma Crohns disease Sjogren’s syndroms Dermatomyositis Stiff man syndrome Lupus Giant cell Arteritis Graves disease Ulcerative colitis Hashimotos Thyroiditis Vasculitis Multiple sclerosis Uveitis Vitiligo Rituximab (anti CD20) Rituxan T Cell B Cell Adult Rheumatoid Arthritis Rituximab Treatment period 0.8 * * 0.7 Overall C ‐ peptide pmol/ml p < 0.001 0.6 * Rituximab 0.5 Placebo * p < 0.020 0.4 0 3 6 12 Time in months Pescovitz, NEJM 2006 15
3/20/2014 Abatacept (CTLA4 Ig) Orencia T Cell B Cell Adult Rheumatoid Arthritis Juvenile Idiopathic Arthritis (JIA), age 6 or older Abatacept (CTLA4 ‐ Ig) (co ‐ stimulation blockade) Treatment period Orban, Lancet 2012 Teplizumab (anti CD 3) T Cell B Cell 16
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