What is sarcoidosis?

What is Sarcoidosis

Sarcoidosis is a chronic multi-system inflammatory disease characterized by the formation of non-caseating (non-necrotic) granulomas that can affect virtually any organ, though most commonly involves the lungs and intrathoracic lymph nodes. 1

Core Pathophysiology

The disease involves an exaggerated immune response with specific histological features 2, 1:

• Granuloma structure: Well-formed, concentrically arranged layers of immune cells with a central core of macrophage aggregates and multinucleated giant cells, surrounded by loosely organized lymphocytes (predominantly T cells) 2, 1
• Immune mechanism: T cells play a central role with accumulation of CD4+ T cells, accompanied by release of IL-2 and formation of non-caseating granulomas 1
• Necrosis pattern: Granulomas are typically non-necrotic, distinguishing them from tuberculosis, though variants (particularly nodular pulmonary sarcoidosis) can present with mixed necrotic and non-necrotic granulomas 2, 1

Epidemiology

The disease shows significant demographic variation 1:

• Age-adjusted incidence is approximately 11 cases per 100,000 in Caucasians, with higher prevalence in northern Europe 1
• In the United States, sarcoidosis is more prevalent in African Americans than whites 1
• Women experience higher morbidity, mortality, and extrapulmonary involvement 1
• African American women have 2.4 times higher mortality compared to matched cohorts without sarcoidosis 1

Clinical Manifestations by Organ System

Highly Probable Features for Diagnosis

Löfgren's syndrome is the most specific clinical presentation, characterized by bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis 2, 3

Skin manifestations 2, 1:

• Lupus pernio (highly specific)
• Maculopapular, erythematous, or violaceous lesions
• Erythema nodosum
• Subcutaneous nodules

Ocular involvement 2, 1:

• Uveitis
• Optic neuritis

Pulmonary Manifestations

The lungs are the most commonly affected organ 1, 4:

• Bilateral hilar adenopathy on chest X-ray or CT 2, 3
• Perilymphatic nodules on chest CT 2, 3
• Dyspnea and chest pain 4

Extrapulmonary Manifestations

Cardiac involvement presents with cardiomyopathy, atrioventricular block, or ventricular tachycardia 1

Neurosarcoidosis occurs in approximately 5-15% of patients and can present with seizures due to parenchymal brain involvement or leptomeningeal disease 5

Hepatic involvement presents with elevated liver enzymes, hepatomegaly, and imaging showing enlargement or nodules 5

Upper respiratory tract involvement occurs in approximately 3-4% of patients with generalized disease 1

Bone involvement shows osteolysis, cysts/punched-out lesions, or trabecular pattern on imaging 2

Constitutional Symptoms

Common systemic symptoms include fatigue, fever, and weight loss 4, 6

Diagnostic Approach

The diagnosis of sarcoidosis requires three essential components 2, 5, 3:

1. Compatible clinical and radiologic presentation
2. Pathologic evidence of non-caseating granulomas
3. Exclusion of alternative causes of granulomatous inflammation

Key Diagnostic Tests

Imaging studies 2, 5:

• High-resolution CT scan of the chest showing bilateral hilar adenopathy and perilymphatic nodules
• Gadolinium-enhanced MRI for CNS involvement showing leptomeningeal enhancement
• PET scan showing parotid uptake
• Cardiac MRI for suspected cardiac involvement

Laboratory testing 5:

• Serum ACE level
• Serum calcium and 24-hour urine calcium (hypercalcemia or hypercalciuria with abnormal vitamin D metabolism is highly probable for diagnosis) 2
• Alkaline phosphatase
• Complete blood count
• Liver function tests

Tissue sampling 2, 5:

• Biopsy of the most accessible affected organ to demonstrate non-caseating granulomas
• Bronchoalveolar lavage showing lymphocytosis or elevated CD4:CD8 ratio 1

Critical Differential Diagnosis

Must exclude these alternative causes 2, 3:

• Tuberculosis: Shows robust necrotizing granulomas with cavitation; requires AFB smear, culture, and interferon-gamma release assay 3
• Histoplasmosis: Shows large acellular necrotizing granulomas; requires histoplasma urine/serum antigen and fungal cultures 3
• Chronic beryllium disease: Has similar histology; blood lymphocyte proliferation test is diagnostic 2
• Lymphoma: Shows monoclonal B-cell population on immunohistochemistry; requires flow cytometry and tissue biopsy 3
• Brucellosis: Shows non-caseating granulomas with positive cultures or serology 3
• Drug-induced sarcoid-like reactions: Associated with immune checkpoint inhibitors, anti-TNF-α, and other immunotherapeutics 2

Disease Course and Prognosis

Many patients with asymptomatic bilateral hilar lymphadenopathy have self-limited disease and do not require treatment 1, 5

The disease can undergo spontaneous regression, though chronic forms progressively threaten involved organs through fibrotic damage 4

Treatment Principles

Corticosteroids are the mainstay of treatment for symptomatic sarcoidosis, particularly with neurologic and hepatic involvement 5

Steroid-sparing agents like methotrexate are frequently needed for neurosarcoidosis with seizures 5

TNF inhibitors (infliximab, adalimumab) are effective for refractory cases 5

Monitoring: Regular assessment of liver function tests, complete blood count, and serum calcium every 6-12 months is recommended 5