Alessio Fasano

AI Auto Immune

Self Attacking Self The Planning Committee for this event has done the following in the interest of Mitigating Potential Bias:

• All PPC members and speakers have signed a COI form. • All speakers have been emailed the certification/accreditation requirements for their presentation. • Each presentation will be reviewed by the Academic Coordinator prior to its delivery. The coordinator will be looking for any signs of bias including use of brand names and logos of pharmaceutical companies. • If bias is detected the PPC would review it and the speaker would be notified so that the bias can be corrected before the presentation is given. If the bias cannot be corrected or removed the session would be cancelled. • If a bias is detected by a planning committee member during the presentation they would question the speaker about it. • All biases would be reviewed at the next PPC meeting. Disclosures

• None. Disclosures

• None

• I don’t like broccoli Goals

• After having attended this session participants will be able to:

1) Describe a structure on how to view autoimmune disease.

2) Discuss theoretic treatment options for Autoimmune disease.

Case

46 year old lady Case

46 year old lady

PMHx: Smoker mild allergies mild asthma GERD NAFLD sinusitis peri-auricular infections in the previous year. Case

2012 Autoimmune hepatitis Case

Admitted to TGH for 26 days

Dx’s: Autoimmune hepatitis (bx proven) Vasculitis Neuritis (Mononeuritis Multiplex) Purpura (unexplained) Arterial thombosis Insulin dependent diabetic Antiphospholipid + Case

Discharged with appoints with:

1) Gastroenterology 2) Dermatology 3) Hematology 4) Rheumatology 5) Neurology Morbidity Autoimmune Disease Morbidity

#1 Cardiovascular disease. 27 M Americans

#2 Cancer 15M Americans (NCI 2018)

?? Autoimmune Disease (AI) >50 M Americans

(AI Health care costs almost double cancer.) Autoimmune Disease

Why so unrecognized?

It is perceived as a 80-120 different diseases all treated by different medical specialties.

The result is a low level of public awareness of the totality of the illness. Autoimmune Disease

More common than cancer or heart disease but:

When asked to name an autoimmune disease, most people (90%) have no answer.

“The Unknown Disease” Autoimmune Disease

Autoimmune disease is:

• #2 most common cause of chronic disease.

• 3rd leading cause of Social Security Disability.

• 8th leading cause of death in women.

• Health Care burden $120 Billion. • ( Cancer $70 B) • (CVD >$200 B) Autoimmune Disease

Chronic disease cost for Canadians in 2010

$190 B

Approx 67% of health care dollars spent are on chronic disease.

In the USA according to CDC 84% of all health care spending is for the costs of chronic disease (2006) Autoimmune Disease

Canadian Public Health “Burden of Chronic Disease”

Public Health Agency of Canada Tasked with “enhancing chronic disease surveillance.”

(DM, CVD, Cancer, COPD, Mental Illness, Neuro-degen.) Does not mention AI disease

Against the Growing Burden of Disease

Aging population Today, 14% of the population is over 65 years. By 2036, this number will increase to almost 25%, or 10 million people

Increase in chronic disease prevalence Canadians are living longer and more likely to experience chronic conditions more common at older ages, including neurological diseases

Living with chronic diseases earlier in life Chronic disease rates are increasing faster among Canadians aged 35-64 years than Canadians aged 65 years and over More children are being affected by chronic diseases previously only seen in adults

Aboriginal peoples at higher risk Experience higher rates of diseases such as heart disease, diabetes, cancer, and asthma Aboriginal population expected to grow at more than twice the rate of 0.7% of the general population (1.8% annually)

7 Against the Growing Burden of Disease

Common Risk Factors 80% of heart disease, diabetes and respiratory diseases and 40% of cancers are preventable by eliminating four Tobacco Unhealthy Physical Harmful use common risk factors use diets inactivity of alcohol Cardiovascular diseases

Diabetes Chronic Diseases Cancer

Respiratory

diseases Source: WHO, Raising the priority of non-communicable disease in development work at global and national levels.

10 Autoimmune Disease

• Life expectancy has reached 80.9

• 90% of T2DM, 80% CAD, 33% of cancers are preventable by lifestyle changes

• More focus needed on prevention strategies.

• Number of years lived in “good health” has been steadily decreasing since 1996. Autoimmune Disease

• Number of years lived in “good health” has been steadily decreasing since 1996.

• We are living longer but less healthy lives. Autoimmune Disease

• Number of years lived in “good health” has been steadily decreasing since 1996.

• We are living longer but less healthy lives.

• AI was not mentioned in their report. Autoimmune Disease

• Their Recommendations: • Sodium restriction • Decrease trans-fat intake • Promote physical activity and lifestyles • Change children’s Fitness Tax Credit • Discourage tobacco use. • Regulate energy drinks • Ban unhealthy food advertising to children Autoimmune Disease

64 oz Coke

46 tsp sugar

Cheaper than Water.

Forced down to 50 oz. Autoimmune Disease Autoimmune Disease

Oct 2011-Feb 2012 House of Commons Standing Committee on Health

Held 17 meetings regarding chronic disease in Canada Autoimmune Disease

Oct 2011-Feb 2012 House of Commons Standing Committee on Health

Held 17 meetings regarding chronic disease in Canada

Autoimmunity was not mentioned Autoimmune Disease

WHO-Fact Sheet

Chronic Diseases: “The Major Cause of Death and Disability Worldwide”

Main Diseases CVD, Cancer, COPD, DM (Does not mention AI disease) Autoimmune Disease

American Journal of Medicine June 2009, Vol 122, pages 528-534

“Baby Boomers: Live Longer, But Not Healthier”

Compared baby boomers age 46-64 (between2007- 2010) vs similar ages (between 1988-1994) Autoimmune Disease

• In essence, the overall “system” is broken for autoimmune disease patients, putting patient safety at risk and opening the door for the additional barriers to care and wasteful healthcare expenditures: Medical practitioners do not recognize autoimmune diseases as a disease category. Medical history questionnaires do not inquire whether patients have a family history of autoimmune diseases. There are very few standardized tests for many of the 80-100 autoimmune diseases. Medical education provides minimal training about autoimmune diseases. Autoimmune Disease

• Conclusion: Autoimmune diseases will continue to be a mounting public health concern in the U.S. and around the world for the foreseeable future. The cost associated with these diseases, while difficult to pin down accurately for all 100+ diseases, has clearly been illustrated to be a major component in the healthcare spending picture, adding perhaps hundreds of billions of dollars to healthcare spending through cost to individual patients and Medicare/Medicaid, as well as loss of productivity in the U.S. workforce. Autoimmune Disease

Closing statement: “It is imperative that autoimmune diseases become a public health priority that is recognized throughout NIH institutes as well as amongst the congressional representatives who must represent the pressing needs of this growing constituency of Americans who live with autoimmune diseases. Autoimmune Disease

Ultimately, however, the true immediate need is for Americans to become aware of the vastness of this issue as a public health concern and for its overall financial burden to be understood by Congress as a means to motivate our representatives to make addressing these solutions a high priority agenda item today. Autoimmune Disease

Under the age of 50:

• 1 in 69 women will get breast cancer.

• 1 in 9 will get an autoimmune disease.

Female/male ratio 3/1 Autoimmune Disease

Mayo Clinic says Lupus has tripled in past 40 years.

Multiple Sclerosis has tripled in past 50 years in some countries and not others.

Rates of polymyositis, scleroderma, Crohn’s and Addison’s disease all increasing rapidly. Autoimmune Disease

Type 1 Diabetes

Has become 5 x more common in past 50 years.

Increasing at 6% per year under age of 4 years. Autoimmune Disease

“The Western Disease”

Dr. Michelle Petrie of John’s Hopkins has watched the incidence of Lupus skyrocket in her 30 years, in people from “Baltimore” and says she hopes:

“Doctors will learn to catch autoimmune disease earlier in their patients, before irreversible tissue damage has already occurred.” Autoimmune Disease

Medical school teaches more about syphilis than they do about autoimmune disease.

In the USA the average autoimmune patient sees six doctors before getting a correct diagnosis.

45% of patients feel they have been labeled hypochondriacs.

50% of AI women are told “there is nothing wrong with you.” Autoimmune Disease

In 2005, Mayo clinic researchers reported that RA patients have double the risk of CHF.

Lupus, DM and MS all carry increased risk of IHD.

Dr. Petri says some Lupus patients have 50 x greater risk of MI.

Many researchers believe that in some atherosclerosis disease, autoimmune processes are happening. Autoimmune Disease Autoimmune Disease Autoimmune Disease Autoimmune Disease

Summary • Explosive growth in past 50 years. • Incredible socio-economic/health burden. • Not a focus of chronic disease prevention. • Not medically treated as one disease. • Sx get treated in silo medicine fashion. • This is a western world phenomena • Inflammation is dangerous • AI disease, think increased risk of IHD!!

Scientific American

Celiac Disease Insights: Clues to Solving Autoimmunity Study of a potentially fatal food-triggered disease has uncovered a process that may contribute to many autoimmune disorders By Alessio Fasano

August 2009 Alessio Fasano, MD Chief, Division of Pediatric Gastroenterology and Nutrition Associate Chief, Department of Pediatrics, Basic, Clinical and Translational Research Director, Center for Celiac Research MassGeneral, Harvard Medical School Alessio Fasano

• Educated in Italy, through to completion of Pediatric Gastroenterology. Alessio Fasano

• Educated in Italy, through to completion of Pediatric Gastroenterology. • Moved to University of Maryland to become director and open first Celiac Disease Center in North America. • Chief of Pediatric Gastroenterology and Nutrition at Mass General/Harvard. Founded the Center for Celiac Research and Treatment in 1996. Alessio Fasano

• Original research interest was infectious diarrhea due to how many it killed. Alessio Fasano

• Original research interest was infectious diarrhea due to how many it killed. • Worked to understand the pathways of how pathogens cross talked with our metabolic pathways and thus make us sick. • The pathogens were using complex pathways that could not have been in place just to help them make us sick. They were hijackers. Alessio Fasano

• He noted that one consistent result of this interaction is increased permeability, and increased trafficking of macromolecules across the gut barrier. Alessio Fasano

• He noted that one consistent result of this interaction is increased permeability, and increased trafficking of macromolecules across the gut barrier. • At the same time, immunology researchers were starting to understand some of the mechanisms of AI and the triggers that lead to the loss of tolerance in genetically predisposed people. Alessio Fasano

• The focus for the immunologists was to find out how and why the immune system got aggressive and started to kill tissue. • This has been the “black box” of autoimmunity. Alessio Fasano

• The focus for the immunologists was to find out how and why the immune system got aggressive and started to kill tissue. • This has been the “black box” of autoimmunity. • For Dr. Fasano, studying how bacteria make the bowel more permeable became a link with the cascade of events that lead to AI. Alessio Fasano

• From starting with Cholera he was eventually led into understanding that the “community” of bacteria is what communicates with our immune system. Alessio Fasano

• From starting with Cholera he was eventually led into understanding that the “community” of bacteria is what communicates with our immune system. • When he first published this. It was totally rejected. Alessio Fasano

• Working on cholera vaccine in early 90s.

• He discovered ZOT toxin

• Complicated machinery, must be a mimick resulting in increased permeability.

• Discovered Zonulin. Controller of tight junctions.

• Question: “physiological to pathological.”

Alessio Fasano

• Celiac disease, his other interest, to the rescue. It became his test model. • Is zonulin involved??? Increased in CD? Alessio Fasano

• Celiac disease, his other interest, to the rescue. It became his test model. • Is zonulin involved??? Increased in CD? YES Alessio Fasano

• Celiac disease, his other interest, to the rescue. It became his test model. • Is zonulin involved??? Increased in CD? Yes? • 10 x more than controls. Alessio Fasano

• Celiac disease, his other interest, to the rescue. It became his test model. • Is zonulin involved??? Increased in CD? Yes? • 10 x more than controls. • Found increased permeability, well before small intestine damage. Alessio Fasano

• “3rd act of serendipity” Alessio Fasano

• “3rd act of serendipity” • Vibrio toxin, (ZOT) and Zonulin; they found a fragment with AA similarities. Alessio Fasano

• “3rd act of serendipity” • Vibrio toxin, (ZOT) and Zonulin; they found a fragment with AA similarities. • So they built a synthetic fragment that blocked both ZOT and Zonulin. Alessio Fasano

• “3rd act of serendipity” • Vibrio toxin, (ZOT) and Zonulin; they found a fragment with AA similarities. • So they built a synthetic fragment that blocked both ZOT and Zonulin. • “These are early days of research into AI.” If it works to block gluten effects for CD? Alessio Fasano

• Double blind study:

• Stable CD pts all on a GFD.

--Half got gluten in the diet. Half got gluten plus the zonulin receptor blocker --Verified the concept of protection by minimizing permeability caused by zonulin. Alessio Fasano

• Now larger study of 1000 people taking it. Appears to be safe.

• Next is a Phase 3 Trial.

• None of this was expected. He was looking for a cholera vacine and he failed at that. Alessio Fasano Alessio Fasano

• His present question is:

“What does it take for someone who is genetically predisposed to eventually have this zonulin pathway go out of control and increase antigen trafficking that could lead to autoimmune disease?” Alessio Fasano

“2 Major Goals”

1) Find AI disease patients with this pathway activated, use this receptor blocker to decrease permeability, and see if this can decrease or elimimnate the AI process. Alessio Fasano

2) (“more ambitious goal”)

Can we prevent AI disease by studying the steps that lead to the loss of tolerance and cause a patient to move into tissue damage?

Celiac Disease to the rescue again. Alessio Fasano Alessio Fasano

• Study the families of CD patients because they have increased risk. • Follow +++ parameters through their lives from birth onward. • --mode of delivery. • --medications/antibiotics. • --breast or bottle. • --infections. • --pets in the home…… Alessio Fasano

• The goal of this:

“To create a life timeline to identify a chain of events that leads to a loss of tolerance and development of CD.” Alessio Fasano

Important questions

• Twin studies. 25% in the other twin. Why? • DQ2 DQ8 + Why do only 35% get CD? • Why does someone eat gluten for 70 years and then develop CD? • Why is CD doubling every 15 years? Alessio Fasano

• In this timeline study, they monitor microbiome samples. Alessio Fasano

• In this timeline study, they monitor microbiome samples.

• Dr Fasano’s conclusion:

• One of the strongest stimuli for zonulin release is. ______(Disclaimer) Alessio Fasano

• In this timeline study, they monitor microbiome samples.

• Dr Fasano’s conclusion:

• One of the strongest stimuli for zonulin release is. dysbiosis (Disclaimer) Alessio Fasano

Goal is:

“can we see this coming?” We can not change their genotype but can we manipulate the microbiome, minimize zonulin release, avoid the storm, and conversion to CD? Alessio Fasano

• Fasano quote:

“First of all we have to admit our ignorance about human biology.”

At this point he says things point to 5 pillars of AI Disease. Alessio Fasano

1) What comprises genetic predisposition? 2) What are the environmental triggers in play? 3) Why are the brakes on the immune system not turning off this damaging inflammation? 4) Why are our barriers allowing increased antigen trafficking? 5) What is the microbiome’s role in moving someone from tolerance to tissue damage? Fasano Triad

Alessio Fasano

• Humans do not possess the enzymes to break down gluten. Alessio Fasano

• Humans do not possess the enzymes to break down gluten. • There is absolutely zero nutritional value to gluten. Alessio Fasano

• Humans do not possess the enzymes to break down gluten. • There is absolutely zero nutritional value to gluten. • Gluten causes release of zonulin in all of us and transiently increases permeability. Alessio Fasano

• Traditional AI was “antigen mimicry.” • Exposed to a microorganism (bac, virus…) with some structural similarity to our own tissue. Our body is unable to distinguish. • Implies that once you have it you can never stop it. • Celiac disease taught us otherwise. • Have to interrupt the triad. • Remove one leg of the stool • Not just left to treat the inflamed target tissue • This was revolutionary Fasano

• “the microbiome… this mix of bacteria that live in our guts, within our own body has a great deal to do with how our immune system works and eventually functions.”

• “We are highly influenced in the first three years of life by the microbiome. Fasano

“I believe the key element that is determining the content of the microbiome is nutrition.” Fasano

• “Of all the determinants out there, pollutants, chemicals, antibiotic use, the way we were born, by far the most influential environmental variable that shifts the microbiome is nutrition.”

• Consider that it was only three generations ago that we did not have refrigerators in our homes and we all ate “local and fresh.” Fasano

HYGIENE THEORY???? Fasano

HYGIENE THEORY????

Developmental countries. First step in hygiene is pipes for water/sewage. No increase of AI disease till they import our food. Autoimmune Triad

Genes Environment Gut Autoimmune Triad

Genes Environment Gut

Look for a Antecedent causes Increased family history permeability of of autoimmune gut lining. disease. Triggers Dysbiosis

Precipitating Event Access to the immune system to stimulate or activate the process Autoimmune Triad

Genes Environment Gut

Inflammation Autoimmune Triad

Genes Environment Gut

Inflammation

Silent autoimmunity Autoimmune Triad

Genes Environment Gut

Tissue Inflammation Damage Autoimmune Triad

Genes Environment Gut

Tissue Inflammation Damage

Traditional medical treatment Autoimmune Triad

Genes Environment Gut

Tissue Inflammation Damage

Traditional medical treatment Genes

Review of 20-30 studies conclude that genes account for approximately 25%-30% of autoimmune disease. The environment accounts for 70-75%. Twin studies validate these numbers. Genes

Do we give patients less hope than we should with “genetic fatalism.” Genes

Do we give patients less hope than we should with “genetic fatalism.”

“Nothing you could/can do.” Genes

Do we give patients less hope than we should with “genetic fatalism.”

“Nothing you could/can do.”

Genetic factors can not account for the rapid change AI disease in only the last 50 years. Not Genetic Fatalism

• We are just beginning to understand the field of “epigenetics.” (This term did not exist when I was in med school.!!! No “old” jokes please.

• BRCA example Not Genetic Fatalism

• Science. 2003 Oct 24;302(5645):643-6. • Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. • King MC1, Marks JH, Mandell JB; New York Breast Cancer Study Group. • Author information

• Abstract • Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. • The lifetime risk of breast cancer among female mutation carriers was 82%. Not Genetic Fatalism

• Abstract • Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%. • Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was____ Not Genetic Fatalism

• Abstract • Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%. • Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24% “Current Oncology” Vol 18, No 6, 2011

• the risk for women born during 1935–1950 is about 1% per year throughout their lives, but the risk for women born during 1970–1985 is almost 4% per year

• The enormous risks that young women with a mutation now face are a matter of concern. It is important that proper epidemiology studies be conducted so that the factors contributing to this risk can be identified. Not Genetic Fatalism

We are just now beginning to understand the epigenetic effects that our microbiome, our diet and our environment have on the expression of our genes.

The food we eat talks to our genes.

The genetic material in our colon talks to our genes. Nutrigenomics

Berit Johnansen Phd Norwegian University of Science and Technology

Studying gene expression for over 25 years. Nutrigenomics

Berit Johansen

A 65% carbohydrate diet, that the average Norwegian eats, causes increased transcription of many genes involved in increasing the inflammatory cascade.

It also increases transcription of genes involved with the development of CVD, some cancers, dementia, and DM2. Nutrigenomics Nutrigenomics Nutrigenomics

We are the very early stages of understanding the field of epigenetics.

We can no longer preach genetic fatalism. Autoimmune Triad

Genes Environment Gut

Tissue Inflammation Damage Environment Triggers and Antecedent Causes Diet Toxins Infection Obesity Mode of birth Breast fed

Often a precipitating event! Often infection (post strept glomerulonephritis) (Post Montezuma’s revenge- never the same) Lithium precipitating AI thyroiditis