Sarcoidosis: A Multisystem Granulomatous Disease
Sarcoidosis is a chronic multisystem inflammatory disease characterized by non-caseating granulomas that can affect virtually any organ, with the lungs being involved in up to 95% of cases, leading to significant morbidity and mortality particularly in certain populations. 1
Definition and Epidemiology
Sarcoidosis is defined as a systemic inflammatory disorder of unknown etiology characterized by the formation of non-caseating granulomas. Key epidemiological features include:
- Incidence: 11 cases/100,000 in Caucasians; higher in Northern Europe (20/100,000) 1
- Demographics:
- More prevalent in African Americans (35.5/100,000) than whites (10.9/100,000) in the US 1
- Twice as common in women, who experience higher morbidity, mortality, and extrapulmonary involvement 1
- Bimodal age distribution: peaks in 3rd-4th decades, with a second peak in women aged 45-65 1
- Mortality is 2.4 times higher in African American women compared to matched cohorts without sarcoidosis 1
Pathophysiology
The exact cause remains unknown, but current evidence suggests:
- An exaggerated immune response to an unidentified antigen in genetically susceptible individuals 1, 2
- Potential triggers include:
The immunopathology involves:
- T-cell mediated response with CD4+ T cell accumulation and IL-2 release 1
- Formation of well-formed, concentrically arranged granulomas with:
- Central core of macrophage aggregates and multinucleated giant cells
- Outer layer of loosely organized T lymphocytes
- Occasional surrounding B lymphocyte collections 1
- TH1 cytokine predominance (interferon, TNF) 1
- B cell hyperreactivity and immunoglobulin production 1
- Th17 cell involvement 1
Clinical Manifestations
Sarcoidosis can present in numerous ways, ranging from asymptomatic disease to severe multiorgan involvement:
Highly Specific Clinical Presentations
- Löfgren's syndrome: Bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis 1, 3
- Lupus pernio: Characteristic facial skin lesions 1, 3
- Heerfordt's syndrome: Uveoparotid fever with facial nerve palsy 1, 3
Organ-Specific Manifestations
Pulmonary (involved in up to 95% of cases) 1
- Bilateral hilar adenopathy
- Perilymphatic nodules on chest CT
- Upper lobe or diffuse infiltrates
- Peribronchial thickening
- Can progress to pulmonary fibrosis and respiratory failure 3
Cutaneous (common)
- Lupus pernio
- Erythema nodosum
- Maculopapular or violaceous lesions
- Subcutaneous nodules 3
Ocular (20-30%)
- Uveitis
- Optic neuritis
- Scleritis
- Retinitis
- Lacrimal gland swelling 3
Cardiac (5-10%, but often clinically silent)
- Cardiomyopathy
- Atrioventricular node block
- Ventricular tachycardia
- Reduced left ventricular ejection fraction
- Can lead to sudden cardiac death 3
Neurological (5-10%)
- Seventh cranial nerve paralysis
- CNS lesions visible on MRI with gadolinium enhancement 3
Upper Respiratory Tract (3-4%)
- Nasal blockage, crusting, and bleeding
- Nasal polyps
- Septal perforations (can lead to saddle nose deformity)
- Anosmia 1
Metabolic/Endocrine
Hepatic/Splenic
Renal
- Treatment-responsive renal failure
- Nephrolithiasis with calcium stones 3
Musculoskeletal
- Osteolytic lesions
- Cystic or punched-out bone lesions
- Inflammatory bone lesions visible on imaging 3
Diagnosis
The diagnosis of sarcoidosis is based on three criteria:
- Compatible clinical presentation
- Presence of non-necrotizing granulomatous inflammation on biopsy
- Exclusion of alternative causes 3
Diagnostic Workup
Laboratory findings:
Imaging:
- Chest X-ray/CT (bilateral hilar adenopathy, perilymphatic nodules)
- CT sinuses (in suspected upper respiratory involvement)
- Cardiac MRI or PET (for suspected cardiac involvement)
- FDG-PET CT (for assessment of inflammatory activity) 1
Histopathology (key features favoring sarcoidosis):
- Numerous, compact, tightly formed granulomas
- Non-necrotic or minimal ischemic necrosis
- Perilymphatic distribution
- Sparse surrounding lymphocytic infiltrate
- Negative microorganism stains and cultures 1
Disease Course and Prognosis
The clinical course is highly variable:
- Many patients with isolated hilar lymphadenopathy have self-limited disease 1
- Spontaneous remission occurs in 30-80% of patients with Stage I-II disease 4
- Only 10-40% of Stage III cases resolve spontaneously 4
- Stage IV disease (fibrotic) has no chance of spontaneous resolution 4
- Overall mortality rate is approximately 7% over 5 years 4
- 10-40% of patients develop progressive pulmonary disease 4
60% of sarcoidosis-related deaths are due to advanced cardiopulmonary disease 4
Treatment
Treatment is indicated for symptomatic disease or progressive organ dysfunction:
First-line therapy:
- Oral glucocorticoids (prednisone 20-40 mg daily for 2 weeks to 2 months)
- Tapered over 6-18 months if clinical improvement occurs 4
Second-line therapy (for steroid-dependent or steroid-intolerant patients):
- Immunosuppressive agents (methotrexate, azathioprine) 4
Third-line therapy:
- Anti-TNF agents 4
Supportive care for specific manifestations:
Despite treatment, relapse rates range from 13% to 75% depending on disease stage, organ involvement, socioeconomic status, and geography 4.
Key Considerations for Clinicians
- Diagnostic challenges: The highly variable clinical presentation can delay diagnosis
- Monitoring: Regular follow-up is essential to assess disease progression and treatment response
- Treatment decisions: Should be based on symptom severity, organ involvement, and disease progression
- Complication awareness: Be vigilant for development of pulmonary fibrosis, pulmonary hypertension, and cardiac complications
- Mortality risk: Higher in patients with pulmonary fibrosis, significant radiographic involvement (>20% fibrosis on HRCT), or pre-capillary pulmonary hypertension 4