Sarcoidosis

 

What is Sarcoidosis?

  • Sarcoidosis is a multisystem granulomatous disease of unknown cause that primarily affects the lung and lymphatic systems1
    • Leads to the formation of granulomas in organs and tissues throughout the body2
Lungs are affected in more than 90% of patients with sarcoidosis1

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Beegle SH et al. Drug Design, Development and Therapy. 2013:7 325–338.

What is Sarcoidosis? (cont’d)

  • Sarcoidosis is a multisystem granulomatous disease of unknown cause that primarily affects the lung and lymphatic systems1
    • Leads to the formation of granulomas in organs and tissues throughout the body2
20% of these patients develop fibrosis3

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Beegle SH et al. Drug Design, Development and Therapy. 2013:7 325-338. 3. Patterson KC et al. Ann Am Thorac Soc. 2013;10(4):362-70.

Epidemiology / Risk Factors

Certain factors increase the risk an individual will develop sarcoidosis1-5
 
Age
Genetics
Race
Gender

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018. 3. Coker RK. Ther Clin Risk Manag. 2009;5(3):575-84. 4. Baughman RP et al. Ann Am Thorac Soc. 2016;13(8):1244-52. 5. Swigris JJ et al. Am J Respir Crit Care Med. 2011;183(11):1524-30.

Epidemiology / Risk Factors (cont’d)

Certain factors increase the risk an individual will develop sarcoidosis1-5
 
Age
  • Typically found in young and middle aged adults1 (20-40 y1-3)
  • Two peak ages of incidence: 25-29 and 65-694
 
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018. 3. Coker RK. Ther Clin Risk Manag. 2009;5(3):575-84. 4. Baughman RP et al. Ann Am Thorac Soc. 2016;13(8):1244-52. 5. Swigris JJ et al. Am J Respir Crit Care Med. 2011;183(11):1524-30.

Epidemiology / Risk Factors (cont’d)

Certain factors increase the risk an individual will develop sarcoidosis1-5
 
Race
  • Increased risk for African Americans1
  • In the United States, the adjusted annual incidence of sarcoidosis is over 3 times greater in African Americans than Caucasians5
    • 35.5 cases vs 10.9 cases per 100,000 population5

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018. 3. Coker RK. Ther Clin Risk Manag. 2009;5(3):575-84. 4. Baughman RP et al. Ann Am Thorac Soc. 2016;13(8):1244-52. 5. Swigris JJ et al. Am J Respir Crit Care Med. 2011;183(11):1524-30.

Epidemiology / Risk Factors (cont’d)

Certain factors increase the risk an individual will develop sarcoidosis1-5
 
Gender
  • Risk is slightly increasedfor women4
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018. 3. Coker RK. Ther Clin Risk Manag. 2009;5(3):575-84. 4. Baughman RP et al. Ann Am Thorac Soc. 2016;13(8):1244-52. 5. Swigris JJ et al. Am J Respir Crit Care Med. 2011;183(11):1524-30.

Epidemiology / Risk Factors (cont’d)

Certain factors increase the risk an individual will develop sarcoidosis1-5

Genetics
  • Pattern of familial clustering suggests there is a genetic predisposition1,2
  • Increased familial risk with mutations to antigen recognition proteins1:
    • HLA-A11
    • HLA-B81
    • HLA-DR31
HLA, human leukocyte antigen.
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018. 3. Coker RK. Ther Clin Risk Manag. 2009;5(3):575-84. 4. Baughman RP et al. Ann Am Thorac Soc. 2016;13(8):1244-52. 5. Swigris JJ et al. Am J Respir Crit Care Med. 2011;183(11):1524-30.

Behavioral and Environmental Risk Factors

  • Found more commonly in nonsmokers1
  • Increased incidence in winter and spring (unknown reason)2
  • Potential causative agents1
Inorganic Agents1
Organic Agents1
Infectious Agents1

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Behavioral and Environmental Risk Factors (cont'd)

  • Found more commonly in nonsmokers1
  • Increased incidence in winter and spring (unknown reason)2
  • Potential causative agents1
Inorganic Agents1
  • Aluminum, zirconium, talc exposure1
  • Often occupational exposure1
Infectious Agents1
  • Mycobacterium tuberculosis and other mycobacteria1
  • Mycoplasma1
  • Viruses1
  • Borrelia burgdorferi1
  • Propionibacterium acnes1
Organic Agents1
  • Pine tree pollen, clay1​​​​​​​
  
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Disease Pathogenesis

 

Sarcoidosis Pathogenesis

Exposure of specific environmental antigens to genetically susceptible hosts leads to disease1,2

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Beegle SH et al. Drug Design, Development and Therapy. 2013:7 325–338.

Sarcoidosis-Associated Granulomas

  • Granuloma lesions form a characteristic discrete, compact, noncaseating epithelioid cell granuloma1
  • Lesion is composed of differentiated mononuclear phagocytes and lymphocytes1
  • Central portion of the granuloma consists of CD4+ lymphocytes with CD8+ lymphocytes present in periphery1
  • Fibrotic changes begin in the periphery and travel centrally1
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.
 

Presenting Signs and Symptoms1

Fatigue
Malaise
Weakness
Anorexia
Weight loss
Low-grade fever
  • Symptoms depend on the site and degree of involvement, varying over time
  • Can range from spontaneous remission to chronic indolent illness
  • It is common for patients with sarcoidosis to not have presenting symptoms

1. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis.August 2017. Accessed August 6, 2018.

Mortality From Sarcoidosis

  • From 1988-2007, 4.32 per 1,000,000 people (adjusted for average age and gender) suffered sarcoidosis-related mortality1
  • Sarcoidosis is fatal in 1%-5% of patients2
    • Death is typically due to respiratory failure caused by pulmonary fibrosis2
    • Less often due to pulmonary hemorrhage caused by aspergilloma2
In patients with severe sarcoidosis contributing to death:
9% had pulmonary fibrosis1
25% had cardiac involvement1

1. Swigris JJ et al. Am J Respir Crit Care Med. 2011;183(11):1524-30. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Disease Manifestations

 

Sarcoidosis Comes in Many Forms

Sarcoidosisprimarily impacts the lung and lymphatic system, but can manifest in many parts of the body1
  • Pulmonary system1,2
  • Lymphoid system2
  • Cardiac system2
  • Musculoskeletal sarcoidosis2
  • Renal system2
  • Hepatic system2
  • Spleen and bone marrow1,2
  • Neurosarcoidosis (rare)2
  • Gastrointestinal system2
  • Cutaneous tissue2
  • Parotid glands2
  • Reproductive organs2
  • Endocrine system2
  • Ocular lesions2
 
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Clinical Presentation of Pulmonary Sarcoidosis

Symptomatic patients display:
  • Dyspnea, cough, chest pain1  
  • Lung crackles1  
  • Clubbing on occassion1
Pulmonary sarcoidosis is typically found by abnormal chest X-ray, often incidentally2
  • Often asymptomatic – if symptomatic, most commonly dyspnea, cough, nonspecific chest discomfort, crackles3
  • If wheezing is present, this is often a sign of fibrosis4`

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Criado E et al. Radiographics. 2010;30(6):1567-86. 3. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018. 4. Patterson KC et al. Ann Am Thorac Soc. 2013;10(4):362-70.

Sarcoidosis Comes in Many Forms (cont’d)

 Sarcoidosis primarily impacts the lung and lymphatic system, but can manifest in many parts of the body1
  • Pulmonary system1,2
  • Lymphoid system2
  • Cardiac system2
  • Musculoskeletal sarcoidosis2
  • Renal system2
  • Hepatic system2
  • Spleen and bone marrow1,2
  • Neurosarcoidosis (rare)2
  • Gastrointestinal system2
  • Cutaneous tissue2
  • Parotid glands2
  • Reproductive organs2
  • Endocrine system2
  • Ocular lesions2 
Lofgren’s syndrome
  • More commonly found in Caucasians1
  • Characterized by:
    • Erythema nodosum1
    • Bilateral hilar lymphadenopathy1
    • Fever1
    • Polyarthritis1

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Sarcoidosis Comes in Many Forms (cont’d)

 Sarcoidosis primarily impacts the lung and lymphatic system, but can manifest in many parts of the body1
  • Pulmonary system1,2
  • Lymphoid system2
  • Cardiac system2
  • Musculoskeletal sarcoidosis2
  • Renal system2
  • Hepatic system2
  • Spleen and bone marrow1,2
  • Neurosarcoidosis (rare)2
  • Gastrointestinal system2
  • Cutaneous tissue2
  • Parotid glands2
  • Reproductive organs2
  • Endocrine system2
  • Ocular lesions2 
Erythema nodosum
  • Acute, painful red bumps often on the lower leg2
Lupus pernio
  • Associated with painful blue lesions2
  • Often causes discoloration of the face and extremities2

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Sarcoidosis Comes in Many Forms (cont’d)

 Sarcoidosis primarily impacts the lung and lymphatic system, but can manifest in many parts of the body1
  • Pulmonary system1,2
  • Lymphoid system2
  • Cardiac system2
  • Musculoskeletal sarcoidosis2
  • Renal system2
  • Hepatic system2
  • Spleen and bone marrow1,2
  • Neurosarcoidosis (rare)2
  • Gastrointestinal system2
  • Cutaneous tissue2
  • Parotid glands2
  • Reproductive organs2
  • Endocrine system2
  • Ocular lesions2  
Uveitis
  • Pain, redness, and swelling of the eyes2
  • Can cause visual abnormalities2
  • Is associated with complications such as glaucoma or cataracts2

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Rates of Systemic Involvement

Systemic involvement also varies by race, sex, and age1a
 
System1   Estimated Frequency1
Pulmonary >90%
Muscle 50%-80%
Hepatic 40%-75%
Joints 25%-50%
Hematologic <5%-30%
Dermatologic 25%
Ocular 25%

System1   Estimated Frequency1
Psychiatric 10%
Renal 10%
Splenic 10%
Neurologic <10%
Nasal sinus <10%
Cardiac 5%
Bone 5%

System1   Estimated Frequency1
Oral <5%
Gastrointestinal Rare
Endocrine Rare
Pleural Rare
Reproductive Rare

aMost common systemic manifestations: Bilateral hilar lymphadenopathy, Pulmonary infiltration, Ocular and skin lesions.2

1. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018. 2. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.

Heterogeneity in Disease Presentation Worldwide

Extrathoracic manifestations are more common in certain populations1:

American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image: Copyright ©motifolio.com

Heterogeneity in Disease Presentation Worldwide

 Extrathoracic manifestations are more common in certain populations1:

American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heterogeneity in Disease Presentation Worldwide (cont’d)
Extrathoracic manifestations are more common in certain populations: 1
COD, cause of death.
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.
  • African Americans more severely affected 1,2
  • Chronic uveitis commonly develops1,2
Lupus pernio1,2
Erythema nodosum1,2
  • Cardiac and ocular sarcoidosis1,2
  • Most frequent COD in sarcoid patients: myocardial involvement1,2
Caucasians more likely to be asymptomatic1,2

How Is Sarcoidosis Diagnosed?

Diagnostic Tests

Workup should achieve 4 things1
  • Histologic confirmation of sarcoidosis
  • Assessment of extent and severity of organ involvement
  • Assessment of disease stability or likelihood to progress
  • Determine if therapy will be beneficial to the patient
Diagnostic Tools1
  • Patient Evaluation 
  • Histology and Immunological Screening
  • Chest X-Ray
  • CT Scans

CT, computed tomography.
American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.

Patient Evaluation

A comprehensive evaluation for all patients should include1:
  • Patient history (occupational and environmental exposure, symptoms)
  • Physical exam and routine eye exam
  • Postero/anterior chest X-ray
  • PFTs: spirometry and DLCO
    • Most likely to indicate functional impairment
    • Can uncover both restrictive and obstructive function
  • Baseline assessment
    • Instrumental to monitor improvement or deterioration of lung disease
DLCO, diffusing capacity of the lung; PFT, pulmonary function test.
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.
 

Patient Evaluation: Laboratory and Physical Examinations

  • Peripheral blood counts1
    • White blood cells
    • Red blood cells
    • Platelets
  • Serum chemistries1:
    • Calcium
    • Liver enzymes
    • Creatinine
    • BUN
  • Urine analysis1
  • ECG1
  • Tuberculin skin test1
    • CT scans may be recommended in some patients pending results

BUN, blood urea nitrogen; ECG, electrocardiogram.
American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.

Common Histologic and Immunologic Findings

Histologic: TLB
  • Performed in presence of a compatible clinical picture1
  • Should be cultured for fungi and mycobacteria  to exclude other diagnoses2
Immunologic Features1:
  • Depression of cutaneous delayed-type hypersensitivity
  • Heightened TH1 immune response at sites of disease
  • Circulating immune complexes, along with signs of B cell hyperactivity, may also be found 
 
TH1, T helper cell type 1; TLB, transbronchial lung biopsy.
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55. 2. Ianuzzi MC et al. Sarcoidosis. Merck Manual Professional Version website. https://www.merckmanuals.com/professional/pulmonary-disorders/sarcoidosis/sarcoidosis. August 2017. Accessed August 6, 2018.

Staging of Sarcoidosis by Chest X-Ray

Stage 0
Normal chest X-ray1

Stage I
Bilateral hilar lymphadenopathy; may be accompanied by paratracheal adenopathy; parenchymal granulomas upon lung biopsy1

Stage II
Bilateral hilar adenopathy accompanied by pulmonary infiltration1

Stage III
Pulmonary infiltration without bilateral hilar lymphadenopathy1

Stage IV
Pulmonary fibrosis evidenced by honeycombing, hilar retraction, bullae, cysts, and emphysema1

1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.

CT Scans

Typically only used in the following instances1:
  • Atypical clinical and/or chest radiograph findings
  • Detection of complications due to lung disease
  • Normal chest radiograph, but clinical suspicion of disease
Classic Findings
  • Widespread small nodules with bronchovascular and subpleural distribution
  • Thickened interlobular septae
  • Architectural distortion
  • Conglomerate masses
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.

CT Scan: Classical Findings

The CT scans of 80 patients were evaluated by Abehsera and colleagues1
  • Fibrotic sarcoidosis and bronchial distortion (marked by traction bronchiectasis and airway angulation), linear scarring, and honeycombing were found1 
  • Extent and type of fibrosis in sarcoidosis varies, which may account for the variety of clinical findings and outcomes1,2  
 
47% Bronchial Distortion1
29% Honeycombing1
24% Linear Fibrosis1

1. Abehsera M et al. AJR Am J Roentgenol. 2000;174(6):1751-7. 2. Patterson KC and Strek ME. Ann Am Thorac Soc. 2013;10(4):362-70.

CT Scan: Classical Findings (cont’d)

  • Although fibrosis is often upper- and middle-lobe predominant, the distribution of fibrosis may be somewhat pattern specific1
    • In the study by Abehsera et al, honeycombing was observed more frequently in the upper lobes, and lower lung involvement was more common for diffuse linear fibrosis2
  • Regular follow-up of patients with ground-glass opacities may be warranted, even when there are minimal pulmonary symptoms initially1
1. Patterson KC and Strek ME. Ann Am Thorac Soc. 2013;10(4):362-70. 2. Abehsera M et al. AJR Am J Roentgenol. 2000;174(6):1751-7.

Less Common Findings by CT Scan

  • Honeycombing1
  • Cyst formation and bronchiectasis1
  • Alveolar consolidation1
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.