What is sarcoidosis?

What is Sarcoidosis?

Sarcoidosis is a chronic multi-system inflammatory disease characterized by the formation of non-caseating granulomas in multiple organs, most commonly affecting the lungs and intrathoracic lymph nodes, with an unknown etiology. 1, 2

Pathophysiology

Sarcoidosis appears to result from an exaggerated immune response to an unknown antigen, characterized by:

• Formation of well-formed, concentrically arranged non-caseating granulomas
• Central core of macrophage aggregates and multinucleated giant cells
• Outer layer of loosely organized T lymphocytes with interposed dendritic cells
• Sometimes surrounded by isolated collections of B lymphocytes 1

The granulomas in sarcoidosis are typically:

• Compact and tightly formed
• Predominantly non-necrotic (though variants may show minimal ischemic necrosis)
• Distributed in a perilymphatic pattern (around bronchovascular bundles, fibrous septa, and near visceral pleura) 1

Epidemiology

• Higher prevalence in women than men (2:1 ratio)
• More common in African Americans (35.5/100,000) compared to whites (10.9/100,000) in the US
• Higher prevalence in Northern Europeans, particularly in Sweden and Iceland
• Typically affects young and middle-aged adults (peaks in third-fourth decades)
• Second peak in women between 45-65 years
• More common in non-smokers 2
• Higher mortality observed in African American women (2.4 times higher than matched cohorts) 1, 2

Clinical Manifestations

Sarcoidosis can affect virtually any organ system, with varying presentations:

Pulmonary (most common)

• Bilateral hilar lymphadenopathy
• Pulmonary infiltrates (typically upper lobe or diffuse)
• Cough (dry or with scant mucoid sputum) in 40-80% of patients
• Dyspnea and chest pain
• Approximately 50% of cases are asymptomatic and diagnosed by radiographic screening 1, 2

Cutaneous

• Lupus pernio (violaceous lesions on nose, cheeks, ears)
• Erythema nodosum
• Maculopapular or violaceous skin lesions
• Subcutaneous nodules 1, 2, 3

Ocular

• Uveitis
• Optic neuritis
• Scleritis
• Retinitis
• Lacrimal gland swelling
• Conjunctival nodules or granulomas 1, 2

Neurological

• Seventh cranial nerve paralysis
• Gadolinium enhancement on CNS MRI 1, 2

Metabolic/Laboratory

• Hypercalcemia (10-13% of patients)
• Hypercalciuria (approximately 30% of patients)
• Elevated angiotensin-converting enzyme (ACE) levels (60-83% of patients)
• Elevated alkaline phosphatase 1, 2

Diagnosis

Diagnosis relies on three criteria:

1. Compatible clinical and radiologic presentation
2. Pathologic evidence of non-caseating granulomas
3. Exclusion of other diseases with similar findings (infections, malignancy, berylliosis) 1, 2, 4

Specific Clinical Syndromes (may not require histological confirmation)

• Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis)
• Lupus pernio
• Heerfordt's syndrome (uveoparotid fever with facial nerve palsy) 1, 2

Differential Diagnosis

• Infections (particularly tuberculosis)
• Malignancy (lymphoma)
• Berylliosis (requires blood lymphocyte proliferation test for differentiation)
• Granulomatosis with polyangiitis
• IgG4-related disease
• Common variable immune deficiency with granulomatous-lymphocytic interstitial lung disease 1

Prognosis and Complications

• Disease progression varies widely among patients
• May lead to pulmonary fibrosis, respiratory failure, pulmonary hypertension
• Cardiac complications including sudden cardiac death (particularly common in Japanese patients)
• Mortality rate approximately 7% over 5 years 2, 5
• Stages I and II have radiographic remission in approximately 30-80% of cases
• Stage III only has a 10-40% chance of resolution
• Stage IV has no chance of resolution and highest risk of mortality (>40% at 5 years) 5

Treatment

• Treatment decisions should be based on organ involvement, risk for significant morbidity, and impact on quality of life
• Glucocorticoids remain first-line therapy for symptomatic disease (typically prednisone 20-40 mg daily)
• Second-line treatments include immunosuppressive agents (methotrexate and azathioprine)
• Third-line treatments include anti-TNF medications
• Relapse rates range from 13% to 75% depending on disease stage, organ involvement, socioeconomic status, and geography 2, 5

Key Points for Clinical Recognition

• Consider sarcoidosis in young or middle-aged adults with unexplained cough, shortness of breath, or constitutional symptoms
• Bilateral hilar lymphadenopathy on chest imaging is a classic finding
• BAL lymphocytosis or elevated CD4:CD8 ratio can support diagnosis
• Histopathological confirmation is often required, showing non-caseating granulomas
• Careful exclusion of alternative diagnoses is essential 1, 2, 4