What investigations and treatment are recommended for a patient suspected of having sarcoidosis?

Investigations in Sarcoidosis

Diagnostic Foundation

The diagnosis of sarcoidosis requires three criteria: compatible clinical presentation, histopathologic evidence of noncaseating granulomas, and exclusion of alternative granulomatous diseases. 1 However, tissue sampling can be omitted in patients presenting with Löfgren's syndrome (bilateral hilar adenopathy, erythema nodosum, arthritis), lupus pernio, or Heerfordt's syndrome, as these have sufficiently high diagnostic specificity. 2

Mandatory Baseline Laboratory Tests

All patients with suspected sarcoidosis require baseline serum calcium measurement (strong recommendation), as abnormal calcium metabolism occurs even without symptoms due to granulomatous production of 1,25-OH vitamin D. 1, 2

Additional baseline screening includes:

• Serum creatinine to detect renal involvement 1, 2
• Serum alkaline phosphatase to screen for hepatic sarcoidosis 1, 2
• Both 25-OH and 1,25-OH vitamin D levels if vitamin D assessment is needed before any supplementation, as granulomas convert 25-OH to active 1,25-OH vitamin D, potentially worsening hypercalcemia 1, 2
• Complete blood count to evaluate for cytopenias from bone marrow or splenic involvement 3

Do not rely on serum ACE levels for diagnosis, as they lack adequate sensitivity and specificity despite potential correlation with disease activity. 2, 4

Imaging Studies

Chest X-ray and high-resolution CT scan are essential to detect bilateral hilar adenopathy, perilymphatic nodules, and parenchymal infiltrates—the most characteristic findings of pulmonary sarcoidosis. 2, 4

PET scan can be used to detect multiorgan involvement and guide biopsy site selection when tissue diagnosis is needed. 2

Cardiac Screening Protocol

Baseline ECG is mandatory for all patients with suspected sarcoidosis, even those without cardiac symptoms, as cardiac involvement occurs in approximately 25% of cases and can be fatal. 1, 2, 4

Do NOT perform routine transthoracic echocardiography or 24-hour Holter monitoring in asymptomatic patients with normal ECG. 1, 2

If ECG shows abnormalities or cardiac symptoms are present, proceed directly to cardiac MRI with late gadolinium enhancement as the first-line imaging modality, which predicts a 9-fold increase in cardiac mortality. 2, 3 If MRI is unavailable or contraindicated, use dedicated cardiac PET scan rather than echocardiography. 2, 3

Tissue Sampling Strategy

When biopsy is required (i.e., absence of Löfgren's, lupus pernio, or Heerfordt's syndrome):

• Target the most accessible involved site: skin lesions, palpable lymph nodes, or endobronchial sampling 2, 5
• EBUS-guided lymph node sampling has 87% diagnostic yield with <0.1% complication rate and can identify alternative diagnoses (lymphoma, tuberculosis, lung cancer) in 2% of cases 2
• Bronchoscopy with transbronchial biopsy and BAL is recommended for pulmonary involvement 2
• Look for noncaseating (non-necrotizing) epithelioid granulomas with macrophage aggregates, multinucleated giant cells, and minimal lymphocytic inflammation 2

Screening for Extrapulmonary Involvement

Baseline ophthalmologic examination is essential to screen for uveitis, optic neuritis, scleritis, or retinitis, even in asymptomatic patients. 2, 4

If pulmonary hypertension is suspected based on symptoms or exam findings, obtain transthoracic echocardiography first, followed by right heart catheterization if echocardiogram is suggestive. 2

Critical Pitfalls to Avoid

• Exclude alternative granulomatous diseases: tuberculosis, fungal infections, berylliosis, hypersensitivity pneumonitis, vasculitis, and drug-induced sarcoid-like reactions (especially immunotherapeutics and anti-TNF agents) 2, 4, 6
• Do not assume isolated organ disease will remain isolated: 50% of patients with cutaneous sarcoidosis develop systemic involvement within 4-9 years 4
• Do not miss cardiac involvement: it requires specific screening beyond routine physical examination and can be fatal 2, 4
• Patients who do not undergo biopsy require close clinical follow-up to monitor for disease progression 1, 2

Specialist Referrals Based on Findings

• Cardiologist: if ECG abnormalities, cardiac symptoms, or abnormal cardiac imaging 2, 3
• Ophthalmologist: for all patients to screen for ocular involvement 2, 4
• Nephrologist: if elevated creatinine, hypercalciuria, or nephrolithiasis 2, 4
• Hepatologist: if alkaline phosphatase >3× normal 2, 4
• Neurologist: if cranial nerve palsies (especially facial nerve) or other neurological symptoms 2
• Dermatologist: for ongoing management of skin manifestations 2

Treatment Considerations

Oral corticosteroids (prednisone 20-40 mg daily) are first-line treatment for symptomatic patients with parenchymal infiltrates and abnormal pulmonary function testing. 7, 8 Prednisone is specifically indicated for symptomatic sarcoidosis and hypercalcemia associated with cancer (which includes sarcoidosis-related hypercalcemia). 7

Avoid vitamin D supplementation in patients with hypercalcemia, as this will worsen the condition. 3

Treatment duration typically ranges from 6-18 months with gradual taper if symptoms, spirometry, and radiographs improve, though prolonged therapy may be required. 8 Second-line agents (methotrexate, azathioprine) and third-line anti-TNF medications are reserved for patients requiring prolonged prednisone ≥10 mg/day or those with glucocorticoid adverse effects. 8