Researchers/Collaborators: Karolinska Institutet Pathobiology of - PowerPoint PPT Presentation

Sarcoidosis: what everyone wants to know David R. Moller, M.D. Johns Hopkins University Baltimore, USA

Researchers/Collaborators: Karolinska Institutet Pathobiology of Sarcoidosis Jan Wahlström Johan Grunewald Johns Hopkins University Anders Eklund Zhimin Song John McDyer University City Dublin Ed Chen Rubin Tuder Brian Greenlee Robert Cotter Seamas Donnelly Matt Willett Lisa Marzilli David Moller Ying Zhang University of Freiburg Joachim Müller- Quernheim Support provided by: National Heart, Lung and Blood Institute Eudowood Foundation Life and Breath Foundation Foundation for Sarcoidosis Research/American Thoracic Society

Sarcoidosis- the basics • Inflammatory disorder • Non-caseating granulomas • Lungs involved >90% • Other organs >50%

Diverse Clinical Manifestations of Sarcoidosis Chronic, Fibrocystic Lung D. Acute Sarcoidosis Erythema nodosum

Diverse Clinical Manifestations of Sarcoidosis Cardiac Involvement Neurologic Involvement Inflammation of Optic nerves Heart muscle granulomas

Common Patient Questions • What causes sarcoidosis? • Are my children going to get it? • Will it spread? • Will I die from it? • Is there anything else but Prednisone?

What causes Sarcoidosis? • Risk of Sarcoidosis – Genes – Immune system • Environmental triggers • Interaction must cause granulomatous inflammation

Sarcoidosis is associated with an hyper-enhanced Th1 immune response Triggers of sarcoidosis T-cells Macrophages IL12 IFN  Dominant T helper 1 IL18 Inflammatory chemicals TNF immune response Granuloma Formation Remission Chronic Inflammation and Fibrosis

What in the environment can cause Sarcoidosis? • Dusts? • Food? • Chemicals? • Microbes?

Sarcoidosis in Ireland: Regional differences in prevalence and mortality from 1996-2005 T.T. Nicholson, B.J. Plant, M.T. Henry, C.P. Bredin Cork University Hospital,Wilton, Cork, Ireland SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2010; 27; 111-120 1.6 1.0 • Geographical differences • Temporal differences 2.3 1.5 • Space time clusters 1.0 1.3 • Conclude: Genes + 1.0 environmental factors important Relative Risk of • More than one cause Sarcoidosis

A C ase C ontrol E tiologic S tudy of S arcoidosis (ACCESS) Iowa City, Detroit, MI Boston, MA IA Philadelphia New York, NY Cincinnati, OH Denver, CO Baltimore, MD Bethesda, MD Washington, DC Charleston, SC ACCESS 720 patients with newly diagnosed sarcoidosis 720 control subjects of same sex, age, race, area

CONTROL SUBJECTS FROM RANDOM DIGIT DIALING Sarcoidosis Case Control Phone #: 555-1234 555-XXXX Age + 5 yrs Race same Sex same

ACCESS Study Results: Major Positive Risk Factors for Sarcoidosis Am J Resp Crit Care Med. 2004; 170:1324-30 Only a modest 1½ times greater risk of Sarcoidosis if you were exposed to: Insecticide exposure (work) Pesticide-using industry Exposure mold/mildew (work) Musty odors (work) Agricultural employment Conclusion: microbial rich environments

Environmental and Occupational Factors Not Associated with Sarcoidosis Risk in the ACCESS Study • Wood Dust Exposure • Occupational Metals • Silica • Dusty trades • Rural residence (birth to 10 years) • Unable to test: – Firefighting – Military

Conclusion: ACCESS study No dominant environmental risk factor was identified – Infectious causes supported – Likely more than one cause – Genes: environmental interactions important Am J Resp Crit Care Med. 2004; 170:1324 J Occup and Environ Med 2005; 47:226

Is Sarcoidosis triggered by microbes? Studies suggest microbes that cause tuberculosis or related organisms are linked to Sarcoidosis (mycobacterial organisms) • Nucleic acids (DNA) from mycobacterial organisms in Sarcoidosis tissues • Remnant proteins from these organisms are in Sarcoidosis tissues • The immune system of Sarcoidosis patients react strongly to proteins from these organisms

M. tuberculosis catalase-peroxidase (mKatG) is present in Sarcoidosis tissues and induces immune responses in Sarcoidosis mKatG 100 Percent positive mKatG ELISPOT • 50% of Sarcoidosis p<0.05 p<0.05 patients in both the U.S. and 80 Sweden have immune p<0.05 p<0.05 responses to mKatG 60 • Immune responses to mKatG in Sarcoidosis are 40 similar to those who have had tuberculosis infection or 20 vaccinated with BCG 0 PPD-sarc PPD+ PPD-sarc PPD+ US Sweden

The Puzzle in Sarcoidosis • Mycobacterial DNA and protein in Sarcoidosis tissue • Immune responses to mycobacterial proteins in Sarcoidosis • Sarcoidosis tissues do not show active infection • Patients treated with powerful drugs that suppress the immune system do not show reactivation of these infections What causes chronic sarcoidosis if there is not an active infection? Active Tuberculosis

Why is there no active infection in Sarcoidosis ? • Immune system overreacts to the triggering microbial infection • Kills the microbes in the tissues • Leaves microbial debris behind • DNA, proteins that are hard to break down • This hyperimmune response leads to damage to tissue proteins

Sarcoidosis may be the result of an abnormal host response involving Serum Amyloid A (SAA) SAA • Dramatic increase in deposition within granulomas in Sarcoidosis • Known to misfold and progressively self-aggregate together (amyloidosis) • SAA and aggregates of SAA cause inflammation Chen et al. Am J Respir Crit Care Med. 2010;181:360-73

1. Triggered by Microbial infection Model of Antigens Sarcoidosis  SAA mKatG 2. Hyperreactive 3. Host protein Immune APC serum amyloid A T cell response kills misfolds + microbes but IFN  aggregates, TNF leaves debris stimulating + granulomatous inflammation Remove SAA SAA/microbial aggregation proteins to get Chronic disease remission

Will my children get sarcoidosis? Familial Associations with Risk of Sarcoidosis: ACCESS • Familial risk estimate (risk ratio): • Sibs: 5.8 (p<0.019) • Parents : 3.8 (p<0.0007) • All 1 st +2 nd relatives 4.6 (p<0.0006) • Spouses 0.2 (p=0.058) Am J Respir Crit Care Med 164: 2085, 2001 Am J Hum Genet 73:720, 2003

Does Sarcoidosis Inflammation Spread? Organ involvement on Presentation: ACCESS • Lungs 95% • Skin 15% • Eye 10-15% • Liver 10% • Neurologic 10-15% • Cardiac 10 % At 2 year followup, only 20% of patients had additional organ involvement Am J Resp Crit Care Med 164:1885, 2001

How is Sarcoidosis treated? Treatment of Sarcoidosis: clinical observations • Patient responses differ • Corticosteroids effective and are first line drug – Well-defined threshold level of drug effect • Corticosteroid-sparing therapy is variably effective and selection is empiric based on safety • Different response on different tissues • Clinical studies lacking to help guide therapy

Is there anything else but Prednisone? Therapeutic Options in Systemic Sarcoidosis: None are approved by FDA (U.S.) “Relatively safer” “More toxic” • Immunosuppressants • Anti-malarials – 1. Methotrexate – Hydroxychloroquine – 2. Azathioprine – Chloroquine – 3. Mycophenylate mofetil • Anti-inflammatory – 4. Leflunimide – Minocycline, – 5. Cyclophosphamide doxycycline • Anti-TNF biologics – Pentoxifylline – Infliximab – Adalimumab

Clinical Monitoring of Sarcoidosis • Preventive treatment for adverse drug effects – Education re: corticosteroid side effects – Anti-osteoporosis medications – Avoid vitamin D, excess calcium intake – Antibiotic prophylaxis usually not indicated • Treat depression, pain, fibromyalgia

Sarcoidosis: Prognosis is variable • Good Prognosis: Acute sarcoidosis with arthritis chest xray with only lymph node enlargment • Poor Prognosis: chest xray with fibrosis severe multiorgan disease • Chronic >2-3 yrs: remissions uncommon • Remitting disease rarely relapses

Causes of Mortality in Sarcoidosis • Advanced pulmonary disease (30-70%) pulmonary 15% • Cardiac involvement cardiac (30-85% ) neurologic • Neurologic involvement (5-15%) 50% 35% United States Sarcoidosis is a treatable disease but may need long term treatment

Improvements in Treatment Approach for Sarcoidosis Patients • Education of physicians regarding current consensus treatment approaches • Education of patients regarding their disease and treatment options • Personalized medicine — finding the right treatment for each patient • Establish National and International registries • Clinical studies needed

Sarcoidosis: a potentially “solvable” disease Genetic profile Clinical Immune type Response microbial triggers Sarcoidosis population host response New therapies Diagnostic Course Prediction ? Cure Tools Treatment response ? Prevent

Rapid progress in understanding and treating Sarcoidosis will depend on an enlightened patient and physician interaction, and international cooperation for continued support of basic research and clinical studies. For your support of the world Sarcoidosis community, go raibh míle maith agat