Sarcoidosis – Insights in ILD

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Sarcoidosis – Insights in ILD

What is Sarcoidosis? – Insights in ILD

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? (Continued) – Insights in ILD

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 and Risk Factors – Insights in ILD

Certain factors increase the risk an individual will develop sarcoidosis^1-5

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 and Risk Factors (Continued) – Insights in ILD

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

Age

Typically found in young and middle aged adults¹ (20-40 y^1-3)
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 and Risk Factors (Continued) 1 – Insights in ILD

Certain factors increase the risk an individual will develop sarcoidosis^1-5

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

Epidemiology and Risk Factors (Continued) 2 – Insights in ILD

Certain factors increase the risk an individual will develop sarcoidosis^1-5

Gender

Risk is slightly increasedfor women⁴

Epidemiology and Risk Factors (Continued) 3 – Insights in ILD

Certain factors increase the risk an individual will develop sarcoidosis^1-5

Genetics

Pattern of familial clustering suggests there is a genetic predisposition^1,2
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 – Insights in ILD

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 – Insights in ILD

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

Disease Pathogenesis – Insights in ILD

Sarcoidosis Pathogenesis – Insights in ILD

Exposure of specific environmental antigens to genetically susceptible hosts leads to disease^1,2

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 – Insights in ILD

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 Symptoms – Insights in ILD

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 – Insights in ILD

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.

Sarcoidosis Disease Manifestations – Insights in ILD

Sarcoidosis Comes in Many Forms – Insights in ILD

Sarcoidosisprimarily impacts the lung and lymphatic system, but can manifest in many parts of the body¹:

Pulmonary system^1,2
Lymphoid system²
Cardiac system²
Musculoskeletal sarcoidosis²
Renal system²
Hepatic system²
Spleen and bone marrow^1,2
Neurosarcoidosis (rare)²
Gastrointestinal system²
Cutaneous tissue²
Parotid glands²
Reproductive organs²
Endocrine system²
Ocular lesions²

Clinical Presentation of Pulmonary Sarcoidosis – Insights in ILD

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.

How is Sarcoidosis Diagnosed? – Insights in ILD

Sarcoidosis primarily impacts the lung and lymphatic system, but can manifest in many parts of the body¹:

Pulmonary system^1,2
Lymphoid system²
Cardiac system²
Musculoskeletal sarcoidosis²
Renal system²
Hepatic system²
Spleen and bone marrow^1,2
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

Diagnostic Tests – Insights in ILD

Sarcoidosis primarily impacts the lung and lymphatic system, but can manifest in many parts of the body¹:

Pulmonary system^1,2
Lymphoid system²
Cardiac system²
Musculoskeletal sarcoidosis²
Renal system²
Hepatic system²
Spleen and bone marrow^1,2
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

Patient Evaluation – Insights in ILD

Sarcoidosis primarily impacts the lung and lymphatic system, but can manifest in many parts of the body¹:

Pulmonary system^1,2
Lymphoid system²
Cardiac system²
Musculoskeletal sarcoidosis²
Renal system²
Hepatic system²
Spleen and bone marrow^1,2
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

Patient Evaluation: Laboratory and Physical Examinations – Insights in ILD

Systemic involvement also varies by race, sex, and age^1a

System¹Estimated Frequency¹
Pulmonary >90%
Muscle 50%-80%
Hepatic 40%-75%
Joints 25%-50%
Hematologic <5%-30%
Dermatologic 25%
Ocular 25%

System¹Estimated Frequency¹
Psychiatric 10%
Renal 10%
Splenic 10%
Neurologic <10%
Nasal sinus <10%
Cardiac 5%
Bone 5%

System¹Estimated 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.

Common Histologic and Immunologic Findings – Insights in ILD

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

Staging of Sarcoidosis by Chest X-ray – Insights in ILD

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

CT Scans – Insights in ILD

CT Scans: Classical Findings – Insights in ILD

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.

CT Scans: Classical Findings (Continued) – Insights in ILD

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 DL_CO
- Most likely to indicate functional impairment
- Can uncover both restrictive and obstructive function
Baseline assessment
- Instrumental to monitor improvement or deterioration of lung disease

DL_CO, diffusing capacity of the lung; PFT, pulmonary function test.
1. American Thoracic Society. Am J Respir Crit Care Med. 1999;160(2):736-55.

Less Common Findings by CT Scan – Insights in ILD

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.

Treatment and Symptom Management – Insights in ILD

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.

Disease and Symptom Management – Insights in ILD

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.

Treatment Recommendations – Insights in ILD

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 Findings¹

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.

Treatment Recommendations – Insights in ILD

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 outcomes^1,2

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.

Sarcoidosis Summary – Insights in ILD

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.

Sarcoidosis Summary (Continued) – Insights in ILD

Honeycombing¹
Cyst formation and bronchiectasis¹
Alveolar consolidation¹

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