What is Sarcoidosis
Sarcoidosis is a chronic multi-system inflammatory disease characterized by the formation of non-caseating (non-necrotizing) granulomas that can affect virtually any organ, though the lungs and intrathoracic lymph nodes are involved in over 90% of cases. 1, 2
Core Pathophysiology
The disease involves abnormal immune responses with accumulation of CD4+ T cells that release pro-inflammatory cytokines (IL-2, TNF), leading to formation of well-organized granulomas consisting of tightly packed epithelioid histiocytes and multinucleated giant cells surrounded by lymphocytes. 1, 3
These granulomas are characteristically non-caseating (lacking the cheese-like necrosis seen in tuberculosis), though variants can occasionally present with minimal ischemic necrosis. 4, 1
The granulomas distribute in a perilymphatic pattern—around bronchovascular bundles, fibrous septa containing pulmonary veins, and near the visceral pleura. 4
Epidemiology and Risk Factors
The age-adjusted incidence is approximately 11 cases per 100,000 in Caucasians, with higher rates in northern Europeans and Scandinavians. 1, 5
African Americans have significantly higher prevalence and worse outcomes than whites, with African American women experiencing 2.4 times higher mortality compared to matched cohorts without sarcoidosis. 1
The disease typically affects young to middle-aged adults. 5
Clinical Manifestations
Pulmonary Involvement (>90% of cases)
Common presentations include unexplained cough, dyspnea, chest pain, or constitutional symptoms (fatigue, fever, weight loss). 3, 5
Less than half of patients initially have respiratory symptoms—the disease is often detected incidentally as bilateral hilar lymphadenopathy on chest imaging. 2
Bilateral hilar adenopathy and perilymphatic nodules on chest CT are highly characteristic findings. 1, 6
Extrapulmonary Manifestations
Skin: Lupus pernio (violaceous facial lesions), maculopapular lesions, erythema nodosum, subcutaneous nodules. 1, 6
Eyes: Uveitis and optic neuritis are highly probable diagnostic features. 1
Cardiac: Cardiomyopathy, atrioventricular block, ventricular tachycardia (cardiac involvement is a leading cause of sarcoidosis-related death, especially in Japan where >70% of deaths are cardiac). 1, 7
Neurologic: Neurosarcoidosis occurs in 5-15% of patients, presenting with seizures, cranial nerve palsies, or leptomeningeal disease. 6
Hepatic: Elevated liver enzymes, hepatomegaly, hepatic nodules. 6
Upper respiratory tract: Affects 3-4% of patients with generalized disease. 1
Pathognomonic Syndromes
Three syndromes are diagnostic of sarcoidosis without requiring biopsy: 2
- Löfgren's syndrome: Acute onset with bilateral hilar lymphadenopathy, erythema nodosum, arthritis, and fever (85% spontaneous remission rate). 1, 8
- Heerfordt's syndrome: Fever, parotid enlargement, uveitis, facial nerve palsy. 4
- Lupus pernio: Chronic violaceous skin lesions on the face. 4, 1
Diagnostic Approach
Diagnosis requires three criteria: 1, 6, 5
- Compatible clinical and radiologic presentation
- Pathologic evidence of non-caseating granulomas
- Exclusion of alternative causes (infections, malignancy, other granulomatous diseases)
Key Diagnostic Tests
High-resolution chest CT showing bilateral hilar adenopathy and perilymphatic nodules. 1, 6
Tissue biopsy from the most accessible affected organ demonstrating compact, non-caseating granulomas with negative microorganism stains and cultures. 4, 1, 6
Bronchoalveolar lavage showing lymphocytosis or elevated CD4:CD8 ratio. 1
Laboratory tests: serum ACE level, serum calcium, alkaline phosphatase, complete blood count, creatinine. 1, 6
For suspected cardiac involvement: cardiac MRI (preferred imaging). 1, 6
For suspected neurosarcoidosis: gadolinium-enhanced brain MRI. 6
Important Caveat
In asymptomatic patients with bilateral hilar lymphadenopathy and classic presentation (especially Löfgren's syndrome), the American Thoracic Society suggests NOT sampling lymph nodes, as 85% will have sarcoidosis and the condition is self-limited, though close clinical follow-up is required. 4, 8
Natural History and Prognosis
30-65% of cases resolve spontaneously within 2-3 years, with resolution rates varying by disease stage: 8
- Stage I (hilar adenopathy only): 65-80% spontaneous remission
- Stage II (adenopathy + parenchymal infiltrates): 50-65% remission
- Stage III (parenchymal infiltrates without adenopathy): 10-30% remission
- Stage IV (pulmonary fibrosis): No spontaneous resolution
Patients with persistent disease beyond 3 years are likely to develop chronic sarcoidosis requiring treatment. 8
10-40% of patients develop progressive pulmonary disease, with Stage IV fibrocystic disease carrying >40% mortality at 5 years. 7
Overall 5-year mortality is approximately 7%, with >60% of sarcoidosis deaths due to advanced cardiopulmonary failure (pulmonary hypertension, respiratory infections). 7
Treatment Principles
Many patients with Stage I disease and minimal symptoms require only observation given the high spontaneous resolution rate. 8, 2
Approximately 75% of patients can be managed symptomatically with NSAIDs while awaiting potential spontaneous resolution. 8
Corticosteroids (prednisone 20-40 mg daily) are first-line treatment for symptomatic disease, progressive pulmonary involvement, or serious extrapulmonary disease (cardiac, neurologic, ocular). 1, 6, 5, 7
Second-line immunosuppressive agents (methotrexate, azathioprine) are used for patients requiring prolonged prednisone ≥10 mg/day or those with steroid-related adverse effects. 2, 7
Third-line anti-TNF agents (infliximab, adalimumab) are effective for refractory cases. 6, 7
Relapse rates range from 13-75% depending on stage, organ involvement, and population. 7
Monitoring Requirements
Regular monitoring with pulmonary function tests every 6-12 months for pulmonary involvement. 8
Complete blood count, liver function tests, and serum calcium every 6-12 months. 6
Organ-specific monitoring for extrapulmonary involvement (echocardiography for cardiac, ophthalmologic exams for ocular disease). 1, 8