Sarcoidosis

Definition and Overview

Epidemiology

• More common in women and African Americans in the United States (African Americans are affected at a rate 3-4x that of White Americans)
• Peak incidence in adults aged 20-40 years; a second peak occurs in women over 50
• Global variation: Scandinavian countries have some of the highest reported rates worldwide
• Organ involvement data from two large U.S. cohorts (n=2700):

Etiology and Pathogenesis

• Genetic susceptibility: HLA-DRB1 alleles strongly implicated; GWAS studies (the GRADS study) identified multiple genetic associations
• Immune dysregulation: Polarization toward a Th1 (and Th17) immune response with excessive TNF-alpha, IL-2, and IFN-gamma production
• Antigen-driven inflammation: Serum amyloid A accumulation within granulomas is hypothesized to sustain chronic disease
• Autoimmune features: Low-titer ANAs, rheumatoid factor, and hypergammaglobulinemia can be present, though no disease-specific autoantibody has been identified
• TGF-beta and mTOR pathways correlate with parenchymal (fibrotic) involvement; IL-7 + IL-2 correlate with airway involvement - Fishman's, p. 924

Histopathology - The Cornerstone

• Central core: Epithelioid cells (differentiated mononuclear phagocytes) + CD4+ T lymphocytes + mature macrophages
• Periphery: CD4+, CD8+ T cells, and B lymphocytes
• Giant cells with cytoplasmic inclusions:
  • Schaumann bodies (calcium- and iron-laden)
  • Hamazaki-Wesenberg bodies
• Focal fibrinoid necrosis is acceptable; caseating (cheese-like) necrosis is NOT a feature of sarcoidosis - its presence mandates exclusion of tuberculosis and fungal infection
• In the lung, granulomas cluster along lymphatic routes (peribronchial, perivascular, and subpleural)

Clinical Features

Constitutional (>50%)

Pulmonary (>90%)

• Dyspnea and dry cough are most common
• Restrictive or obstructive impairment, reduced diffusing capacity (DLCO)
• Fibrocystic disease, pulmonary hypertension, bronchiectasis
• Tracheal/bronchial stenosis, cavitating nodules, mycetomas

Skin (20-30%)

• Erythema nodosum (tender red nodules on shins): part of Löfgren syndrome (acute sarcoidosis with excellent prognosis)
• Lupus pernio: indurated, violaceous plaques on nose, cheeks, ears, lips - highly associated with chronic disease and pulmonary granulomatous infiltration of the upper airway
• Scar granulomas, tattoo infiltration, alopecia
• Classic lesions are red-brown, non-scaly papules/plaques on the face around nose and mouth - Textbook of Family Medicine, p. 481

Ocular (23-33%)

• Anterior uveitis is most common (acute, painful with red eye)
• Posterior uveitis, panuveitis, chorioretinitis
• Heerfordt syndrome (uveoparotid fever): fever + parotid enlargement + facial palsy + uveitis + bilateral hilar adenopathy

Cardiac (4-5%, but up to 25% at autopsy)

• Complete heart block and ventricular arrhythmias are the leading causes of sudden death
• Cardiomyopathy, pericardial effusion
• FDG-PET is the most sensitive imaging tool for active cardiac sarcoidosis
• Cardiac involvement warrants ECG, echocardiography, and cardiac MRI or FDG-PET evaluation

Neurologic (9-14%)

• CN VII palsy (facial nerve) is most common
• Aseptic meningitis, optic neuropathy, hypothalamic/pituitary insufficiency
• Sarcoidosis can involve the optic chiasm, causing blindness

Musculoskeletal

• Löfgren syndrome: erythema nodosum + bilateral hilar adenopathy + periarticular ankle inflammation
• Lytic bone lesions (punched out lesions on X-ray, especially small bones of hands/feet)
• Myopathy: rare, but may present with elevated CK

Calcium Metabolism

• Hypercalciuria (more common) and hypercalcemia (up to 30% of patients)
• Mechanism: autonomous 1-alpha-hydroxylase activity in macrophages and epithelioid cells converts 25(OH)D to active 1,25(OH)2 vitamin D3
• Consequences: nephrocalcinosis, kidney stones, renal failure

Hepatic/Splenic

• Elevated alkaline phosphatase (more than transaminases)
• Liver biopsy positive for granulomas in most patients even without symptoms
• End-stage hepatic fibrosis is uncommon

Diagnosis

1. Compatible clinical + radiographic presentation
2. Histological confirmation: noncaseating epithelioid granulomas in ≥1 organ
3. Exclusion of other granulomatous diseases (TB, fungal infections, berylliosis, foreign body reactions, Crohn's disease)

Investigations

Biopsy Sites (in order of preference)

• Transbronchial biopsy (yield ~70-90% if lung involved)
• EBUS-guided sampling of mediastinal lymph nodes (high yield)
• Skin lesions (easy, high yield when present)
• Liver (high granuloma prevalence even when asymptomatic)
• Avoid biopsy: erythema nodosum (yield low, nonspecific)

FDG-PET

Complications

Sarcoidosis-Associated Pulmonary Hypertension (SAPH)

• Overall incidence: 5-15% in all sarcoidosis patients
• In moderate-to-severe pulmonary disease, rates are much higher
• Mechanisms: LV diastolic dysfunction, pulmonary arterial vasculitis, pulmonary veno-occlusive disease, fibrosis, hypoxia - Murray & Nadel's, p. 2131

Aspergilloma

• Forms in cavities created by fibrocystic sarcoidosis
• Can cause life-threatening hemoptysis

Fibrotic Sarcoidosis (Stage IV)

• Progressive fibrosis leading to honeycombing, traction bronchiectasis
• Carries the worst prognosis

Treatment

• Threatened organ function (eye, heart, brain, kidney)
• Progressive pulmonary disease
• Hypercalcemia
• Significant systemic symptoms

Treatment Ladder

• SAPH: Bosentan (1A), sildenafil (1B), inhaled iloprost (2B), prostacyclin (1B)
• Fatigue: d-methylphenidate (1A), armodafinil (1A)
• Lung transplantation: For end-stage fibrotic disease (Stage IV)

Important: A 2025 systematic review and meta-analysis in Thorax (PMID 40393718) evaluated biologic and targeted synthetic therapies in sarcoidosis, providing updated evidence on anti-TNF agents and other biologics that may refine current treatment algorithms.

Prognosis and Course