What is the recommended evaluation and management approach for a patient with sarcoidosis?

Evaluation and Management of Sarcoidosis

The evaluation of sarcoidosis requires establishing three diagnostic criteria—compatible clinical presentation, histopathologic confirmation of noncaseating granulomas, and exclusion of alternative diagnoses—followed by systematic organ-specific screening and risk-stratified treatment decisions based on mortality risk and quality of life impairment. 1

Diagnostic Approach

Core Diagnostic Criteria

The diagnosis rests on three pillars that must all be satisfied: 1, 2

• Compatible clinical and radiologic presentation with bilateral hilar adenopathy, perilymphatic nodules on chest CT, or characteristic syndromes 1, 3
• Histopathologic evidence of noncaseating (non-necrotizing) granulomas from tissue biopsy 1
• Exclusion of alternative causes of granulomatous disease including infections (tuberculosis, fungal), berylliosis, hypersensitivity pneumonitis, malignancy, and drug-induced reactions 1, 3

When Tissue Diagnosis Can Be Omitted

For patients with highly specific clinical syndromes—Löfgren's syndrome (bilateral hilar adenopathy, erythema nodosum, arthritis), lupus pernio, or Heerfordt's syndrome—lymph node sampling is NOT recommended as these presentations have sufficient diagnostic specificity. 1, 4 However, these patients require close clinical follow-up to confirm the diagnosis remains accurate. 1

Tissue Sampling Strategy

For all other patients, obtain tissue confirmation: 1, 4

• Target the most accessible involved site (peripheral lymph node, skin lesion, or endobronchial ultrasound-guided transbronchial biopsy) 5, 4
• EBUS-guided lymph node sampling has 87% diagnostic yield with 98% confirming sarcoidosis and 2% identifying alternative diagnoses (lymphoma, tuberculosis, lung cancer), with complication rate <0.1% 4
• Look for noncaseating epithelioid granulomas with macrophage aggregates, multinucleated giant cells, and minimal surrounding lymphocytic inflammation 4, 3

Baseline Laboratory Evaluation

Mandatory Screening Tests

Perform these tests on all patients with suspected or confirmed sarcoidosis: 1, 5, 4

• Serum calcium (strong recommendation)—abnormal calcium metabolism occurs frequently and hypercalcemia requires urgent treatment 1, 5
• Serum creatinine—screens for renal involvement, as hypercalcemia causes renal insufficiency in 42% of untreated patients 1, 5
• Serum alkaline phosphatase—screens for hepatic sarcoidosis even in asymptomatic patients 1, 5
• Complete blood count—evaluates for cytopenias from bone marrow or splenic involvement, and reactive thrombocytosis from systemic inflammation 5, 3
• Baseline ECG—mandatory for all patients to screen for cardiac involvement 1, 5

Vitamin D Assessment

• Measure both 25-OH and 1,25-OH vitamin D levels before any vitamin D replacement, as sarcoidosis granulomas produce excess 1α-hydroxylase converting 25-OH to active 1,25-OH vitamin D, which worsens hypercalcemia 5, 4
• Avoid vitamin D supplementation in patients with active sarcoidosis and hypercalcemia 5

Optional Tests

• Serum ACE level may be elevated and correlates with disease activity, but lacks sensitivity and specificity for diagnosis and should not be relied upon 5, 4

Cardiac Screening Protocol

Cardiac involvement occurs in approximately 25% of sarcoidosis patients and is a leading cause of death, requiring systematic screening even in asymptomatic patients. 1, 4, 6

Baseline Screening for All Patients

• Perform baseline ECG on every patient with extracardiac sarcoidosis, even without cardiac symptoms 1, 5, 4
• Do NOT perform routine transthoracic echocardiography or 24-hour Holter monitoring in asymptomatic patients with normal ECG 1, 4

Advanced Cardiac Imaging Indications

Proceed to cardiac MRI if any of the following are present: 1, 5, 4

• Abnormal baseline ECG
• Cardiac symptoms (chest pain, syncope, palpitations, dyspnea)
• Clinical suspicion despite normal ECG

Cardiac MRI with late gadolinium enhancement is the first-line imaging modality for detecting myocardial inflammation and fibrosis; abnormalities predict a 9-fold increase in cardiac mortality. 1, 4

If cardiac MRI is unavailable or contraindicated, use dedicated cardiac PET scan rather than echocardiography for diagnostic and prognostic information. 1, 4

Pulmonary Hypertension Screening

Suspect pulmonary hypertension in patients with: 1

• Exertional chest pain or syncope
• Prominent P2 or S4 on examination
• Reduced 6-minute walk distance or desaturation with exercise
• Reduced DLCO
• Increased pulmonary artery diameter on CT
• Elevated brain natriuretic peptide
• Fibrotic lung disease (Stage IV)

For suspected pulmonary hypertension, perform initial screening with transthoracic echocardiography. 1 If echocardiogram suggests pulmonary hypertension, perform right heart catheterization to definitively confirm or exclude it. 1 If echocardiogram is NOT suggestive but clinical suspicion remains high, determine need for right heart catheterization case-by-case. 1

Additional Organ-Specific Screening

Ophthalmologic Evaluation

• Refer all patients to ophthalmology for baseline eye examination to screen for uveitis, which can be asymptomatic but cause permanent vision impairment if untreated 5, 6

Imaging Studies

• Chest X-ray and high-resolution CT scan detect bilateral hilar adenopathy, perilymphatic nodules, and parenchymal infiltrates characteristic of pulmonary sarcoidosis 4
• PET scan can detect multiorgan involvement and guide biopsy site selection 4

Treatment Decisions

Indications for Treatment

The two major reasons to treat sarcoidosis are to lower mortality/morbidity risk or to improve quality of life. 1 Treatment decisions require assessment of: 1

• Risk for death or organ failure (pulmonary, cardiac, neurologic, renal, ocular)
• Impact on quality of life from disease symptoms
• Impact on quality of life from treatment side effects

Patients Who Do NOT Require Treatment

Many patients with asymptomatic bilateral hilar lymphadenopathy have self-limited disease and do not require treatment. 3, 7 Spontaneous remissions occur in nearly two-thirds of patients. 7

First-Line Treatment

Glucocorticoids remain the first choice for initial treatment of symptomatic disease. 1, 8

• Typical starting dose: prednisone 20-40 mg daily for 2 weeks to 2 months 8
• Taper over 6-18 months if symptoms, spirometry, pulmonary function tests, and radiographs improve 8
• Prolonged prednisone may be required to stabilize disease 8

Glucocorticoid-Sparing Alternatives

For patients requiring prolonged prednisone ≥10 mg/day or experiencing adverse effects from glucocorticoids, use second-line immunosuppressive agents (methotrexate, azathioprine) or third-line anti-TNF medications. 1, 8

Organ-Specific Treatment Considerations

The ERS guidelines provide 12 specific recommendations for treating: 1

• Pulmonary disease
• Cutaneous manifestations
• Cardiac sarcoidosis
• Neurologic involvement
• Sarcoidosis-associated fatigue

Prognosis and Monitoring

Risk Stratification

• Approximately 5% of patients die from sarcoidosis, with pulmonary and cardiac disease being the most common causes 1
• Stage IV fibrocystic disease with >20% fibrosis on HRCT or precapillary pulmonary hypertension has >40% mortality at 5 years 8
• Features associated with increased mortality risk include pulmonary hypertension, reduced lung function, and pulmonary fibrosis 1

Disease Course by Radiographic Stage

• Stages I and II: 30-80% radiographic remission 8
• Stage III: 10-40% chance of resolution 8
• Stage IV: no chance of resolution, with 40% progressing to fibroplasia, bronchiectasis, and fibrocystic disease 8

Relapse Rates

Relapse rates range from 13% to 75% depending on disease stage, number of organs involved, socioeconomic status, and geography. 8

Critical Pitfalls to Avoid

• Do not rely solely on ACE levels for diagnosis—they lack sensitivity and specificity 4
• Do not miss cardiac involvement—it can be fatal and requires specific screening beyond routine echocardiography 4
• Do not fail to exclude alternative diagnoses—consider infections (especially tuberculosis), berylliosis, hypersensitivity pneumonitis, vasculitis, and drug-induced sarcoid-like reactions 4, 3
• Do not supplement vitamin D in patients with hypercalcemia—it will worsen the condition 5
• Do not skip ophthalmology referral—asymptomatic eye involvement can cause permanent vision loss 5, 6