What is the diagnosis and management of sarcoidosis?

Sarcoidosis: Comprehensive Clinical Overview

What is Sarcoidosis?

Sarcoidosis is a multisystem granulomatous inflammatory disease diagnosed by three essential criteria: compatible clinical presentation, nonnecrotizing granulomas on tissue biopsy (though not always required), and exclusion of alternative granulomatous diseases. 1 The disease can affect any organ but most commonly involves the lungs and intrathoracic lymph nodes. 2

Clinical Presentation and Recognition

Spectrum of Disease

• Presentation ranges from completely asymptomatic to progressive, life-threatening disease with potential for pulmonary fibrosis, sudden cardiac death from arrhythmias, or congestive heart failure from myocarditis. 1
• Mortality is significantly elevated in certain populations, with African American women showing 2.4-times higher mortality compared to matched controls without sarcoidosis. 1

Pathognomonic Clinical Syndromes

Three clinical presentations are so specific they are considered diagnostic without requiring biopsy: 1, 3, 4

• Löfgren's syndrome (bilateral hilar adenopathy, erythema nodosum, arthritis, fever)
• Lupus pernio (chronic violaceous skin lesions on nose, cheeks, ears)
• Heerfordt's syndrome (uveitis, parotid gland enlargement, facial nerve palsy, fever)

Highly Suggestive Features

• Bilateral hilar adenopathy without B symptoms (fevers, night sweats, weight loss) is strongly associated with sarcoidosis. 1
• Perilymphatic nodules on chest CT are highly characteristic. 4

Common Symptoms by Organ System

• Pulmonary (most common): persistent dry cough, progressive dyspnea, chest discomfort 5, 6
• Constitutional: fatigue, unintentional weight loss, night sweats, fever 5, 6
• Cutaneous: erythema nodosum, lupus pernio, maculopapular lesions 3
• Ocular: uveitis, optic neuritis, scleritis, retinitis 3
• Cardiac: arrhythmias, heart block, congestive heart failure 1
• Neurologic: cranial nerve palsies (especially facial nerve VII), meningitis 3
• Hepatic: often asymptomatic, elevated alkaline phosphatase 7
• Renal: hypercalcemia, hypercalciuria, nephrolithiasis 3

Diagnostic Approach

Initial Baseline Testing

All patients with suspected sarcoidosis should undergo the following baseline screening: 1, 3

• Serum calcium (strong recommendation) - screens for abnormal calcium metabolism 1, 3
• Serum creatinine - screens for renal involvement 1, 3
• Serum alkaline phosphatase - screens for hepatic involvement 1, 3
• ECG - screens for cardiac involvement 1, 3
• Chest X-ray and high-resolution CT scan - detects bilateral hilar adenopathy, perilymphatic nodules, parenchymal infiltrates 3

Vitamin D Assessment

• If vitamin D assessment is needed, measure BOTH 25-OH and 1,25-OH vitamin D levels before replacement to properly evaluate vitamin D metabolism in sarcoidosis. 1, 3

When to Pursue Tissue Diagnosis

Tissue biopsy showing nonnecrotizing granulomas is typically required unless one of the pathognomonic syndromes is present. 1, 4

• Bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) is the preferred initial approach for pulmonary disease 3, 4
• Biopsy the most accessible involved site when multiple organs are affected 3
• BAL lymphocytosis or elevated CD4:CD8 ratio supports the diagnosis but is not diagnostic alone 4
• In patients with highly suggestive clinical features, biopsy may be avoided on a case-by-case basis, but these patients require close clinical follow-up 1, 3

Histopathology Features

Characteristic granulomas show: 1

• Well-formed, concentrically arranged immune cells
• Central core of macrophage aggregates and multinucleated giant cells
• Outer layer of loosely organized lymphocytes (mostly T cells)
• Typically nonnecrotizing, though nodular pulmonary sarcoidosis can show mixed necrotic and nonnecrotic granulomas 1

Advanced Imaging for Specific Scenarios

Cardiac involvement suspected: 1, 3

• Cardiac MRI is the preferred test over echocardiography
• If cardiac MRI unavailable, use dedicated PET scan rather than echocardiography for diagnostic and prognostic information 1

Pulmonary hypertension suspected: 1

• Initial screening with transthoracic echocardiography (TTE) 1
• If TTE suggests pulmonary hypertension, perform right heart catheterization to definitively confirm 1
• If TTE does NOT suggest pulmonary hypertension but clinical suspicion remains high, determine need for right heart catheterization case-by-case 1

Multiorgan involvement or unclear biopsy site:

• PET scan helps detect multiorgan involvement and guide biopsy site selection 3

Routine Screening NOT Recommended

• Do NOT perform routine baseline transthoracic echocardiography or 24-hour Holter monitoring in asymptomatic patients without cardiac symptoms, though these can be considered case-by-case given low risk 1

Critical Differential Diagnoses to Exclude

Failure to exclude alternative causes is a common diagnostic pitfall. 3, 4 Always rule out:

Infectious Causes

• Tuberculosis (most critical to exclude) 4, 2
• Fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis) 4

Other Granulomatous Diseases

• Chronic beryllium disease (occupational exposure history) 4
• Hypersensitivity pneumonitis (environmental exposure) 4
• ANCA-associated vasculitides (granulomatosis with polyangiitis) 4
• IgG4-related disease 4

Malignancy-Associated Reactions

• Sarcoid-like reactions in patients with known or suspected neoplasms 4
• Drug-induced sarcoid-like reactions, especially with immunotherapeutics and anti-TNF agents 3

Organ-Specific Consensus Criteria

The World Association of Sarcoidosis and Other Granulomatous Disorders established standardized criteria in 2014 using Delphi methodology with >70% expert consensus, classifying organ involvement as highly probable, probable, or possible. 1 Specific criteria have been developed for cardiac and neurologic sarcoidosis using similar methodology. 1

When to Refer to Specialists

Cardiac involvement: Refer to cardiologist for ECG abnormalities, cardiac symptoms, or positive imaging 3

Ocular symptoms: Refer to ophthalmologist for uveitis, optic neuritis, scleritis, or retinitis 3

Skin manifestations: Refer to dermatologist for lupus pernio, erythema nodosum, or other cutaneous lesions 3

Neurologic symptoms: Refer to neurologist for cranial nerve palsies or other neurologic manifestations 3

Renal involvement: Refer to nephrologist for elevated creatinine, hypercalciuria, or nephrolithiasis 3

Significant hepatic abnormalities: Refer to hepatologist for alkaline phosphatase >3x normal 3

Treatment Principles

Indications for Treatment

Corticosteroids are indicated for symptomatic sarcoidosis per FDA labeling 8, and represent the mainstay of therapy for significantly symptomatic or progressive pulmonary disease and serious extrapulmonary disease. 2

First-Line Therapy

• Prednisone is the first-line treatment for active, symptomatic disease 8, 6, 2
• Treatment decisions depend on clinical status at presentation 7

Refractory Disease

• Immunosuppressive or biologic therapies are used for steroid-refractory cases 6, 2

End-Stage Disease

• Transplantation (lung or heart) may be considered for advanced end-stage disease in eligible patients 6, 2

Critical Pitfalls to Avoid

Do NOT rely solely on ACE levels - they lack sensitivity and specificity for diagnosis 3, 4

Do NOT miss cardiac involvement - it can be fatal and requires specific imaging beyond routine echocardiography 3

Do NOT forget to review medications - consider drug-induced sarcoid-like reactions, especially with immunotherapeutics 3

Do NOT skip close clinical monitoring in patients who do not undergo biopsy 3

Do NOT assume asymptomatic disease is benign - progression can occur, and certain populations have significantly elevated mortality 1

Prognosis

Prognosis is highly variable and depends on epidemiologic factors (race, ethnicity), mode of onset, initial clinical course, and specific organ involvement. 2 Despite aggressive treatment, some patients develop life-threatening complications from severe progressive pulmonary, cardiac, or neurologic disease. 2