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

Johns Hopkins University Zhimin Song John McDyer Ed Chen Rubin Tuder Brian Greenlee Robert Cotter Matt Willett Lisa Marzilli David Moller Ying Zhang Karolinska Institutet Jan Wahlström Johan Grunewald Anders Eklund

Researchers/Collaborators: Pathobiology of Sarcoidosis

Support provided by:

National Heart, Lung and Blood Institute

Eudowood Foundation Life and Breath Foundation Foundation for Sarcoidosis Research/American Thoracic Society

University City Dublin Seamas Donnelly University of Freiburg Joachim Müller- Quernheim

Sarcoidosis- the basics

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

Diverse Clinical Manifestations of Sarcoidosis

Acute Sarcoidosis Chronic, Fibrocystic Lung D. Erythema nodosum

Diverse Clinical Manifestations of Sarcoidosis

Cardiac Involvement Neurologic Involvement Inflammation of Optic nerves

Heart muscle granulomas

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

Common Patient Questions

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

IFN

Granuloma Formation Chronic Inflammation and Fibrosis IL12

TNF

Dominant T helper 1 immune response Remission IL18 Inflammatory chemicals

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

• Geographical differences
• Temporal differences
• Space time clusters
• Conclude: Genes +

environmental factors important

• More than one cause

1.6 2.3 1.3 1.5 1.0 1.0 1.0 Relative Risk of Sarcoidosis

720 patients with newly diagnosed sarcoidosis 720 control subjects of same sex, age, race, area

Baltimore, MD Boston, MA Charleston, SC Cincinnati, OH Denver, CO Detroit, MI Iowa City, IA New York, NY Philadelphia Washington, DC Bethesda, MD

A C ase C

• ntrol

E tiologic S tudy of S arcoidosis (ACCESS)

ACCESS

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

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

Am J Resp Crit Care Med. 2004; 170:1324-30

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
• rganisms 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

• 50% of Sarcoidosis

patients in both the U.S. and Sweden have immune responses to mKatG

• Immune responses to

mKatG in Sarcoidosis are similar to those who have had tuberculosis infection or vaccinated with BCG

mKatG

PPD-sarc PPD+ PPD-sarc PPD+

20 40 60 80 100

US Sweden

p<0.05 p<0.05 p<0.05 p<0.05 Percent positive mKatG ELISPOT

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

• f 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

• f an abnormal host response

involving Serum Amyloid A (SAA)

SAA

Chen et al. Am J Respir Crit Care Med. 2010;181:360-73

• Dramatic increase in deposition

within granulomas in Sarcoidosis

• Known to misfold and

progressively self-aggregate together (amyloidosis)

• SAA and aggregates of SAA

cause inflammation

mKatG

• 1. Triggered by Microbial infection

Antigens T cell

APC

SAA IFN TNF

Model of Sarcoidosis

Chronic disease Remove SAA/microbial proteins to get remission

• 2. Hyperreactive

Immune response kills microbes but leaves debris

SAA aggregation

+

• 3. Host protein

serum amyloid A misfolds + aggregates, stimulating granulomatous inflammation

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 1st+2nd relatives

4.6 (p<0.0006)

• Spouses

0.2 (p=0.058)

Am J Hum Genet 73:720, 2003

Am J Respir Crit Care Med 164: 2085, 2001

Will my children get sarcoidosis?

Organ involvement on Presentation: ACCESS

• Lungs

95%

• Skin

15%

• Eye

10-15%

• Liver

10%

• Neurologic

10-15%

• Cardiac

10 %

Am J Resp Crit Care Med 164:1885, 2001

At 2 year followup, only 20% of patients had additional organ involvement Does Sarcoidosis Inflammation Spread?

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

How is Sarcoidosis treated?

Therapeutic Options in Systemic Sarcoidosis:

None are approved by FDA (U.S.)

• Anti-malarials

– Hydroxychloroquine – Chloroquine

• Anti-inflammatory

– Minocycline, doxycycline – Pentoxifylline

• Immunosuppressants

– 1. Methotrexate – 2. Azathioprine – 3. Mycophenylate mofetil – 4. Leflunimide – 5. Cyclophosphamide

• Anti-TNF biologics

– Infliximab – Adalimumab “Relatively safer” “More toxic”

Is there anything else but Prednisone?

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%)

• Cardiac involvement

(30-85%)

• Neurologic involvement

(5-15%)

50% 35% 15% pulmonary cardiac neurologic

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

Clinical type Genetic profile Immune Response

Sarcoidosis population

Diagnostic Tools Course Prediction Treatment response New therapies ? Cure ? Prevent microbial triggers host response

go raibh míle maith agat

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,