What are the clinical presentation, diagnostic work‑up, and management recommendations for sarcoidosis?

Sarcoidosis: Clinical Presentation, Diagnosis, and Management

Clinical Presentation

Sarcoidosis presents along a spectrum from asymptomatic disease to progressive multi-organ involvement, with intrathoracic manifestations occurring in 90% of patients, typically showing bilateral hilar lymphadenopathy and diffuse lung micronodules along lymphatic structures. 1

Pulmonary and Thoracic Manifestations

• Bilateral hilar adenopathy with or without pulmonary parenchymal involvement is the hallmark finding, present in over 90% of cases. 1, 2
• Persistent dry cough and unexplained dyspnea are the most common respiratory symptoms. 3, 4
• Progressive pulmonary fibrosis develops in approximately 25% of patients and represents a major cause of mortality. 5, 2

Highly Specific Clinical Syndromes (Diagnosis Without Biopsy)

• Löfgren's syndrome (bilateral hilar lymphadenopathy + erythema nodosum + acute periarticular arthritis, especially ankles) is considered diagnostic and does not require tissue confirmation. 5, 6
• Lupus pernio (chronic violaceous skin lesions on nose, cheeks, ears) is pathognomonic for sarcoidosis. 5
• Heerfordt's syndrome (uveoparotid fever: anterior uveitis + parotid gland enlargement + facial nerve palsy + fever) is diagnostic without biopsy. 5, 6

Common Extrapulmonary Manifestations (25-50% prevalence)

• Skin lesions (erythema nodosum, papules, plaques, lupus pernio), anterior uveitis, hepatosplenomegaly, peripheral lymphadenopathy, and peripheral arthritis. 1

High-Risk Organ Involvement (<10% prevalence but critical for mortality)

• Cardiac sarcoidosis causes sudden cardiac death from arrhythmias or heart failure from myocarditis—this is a leading cause of sarcoidosis-related mortality. 5
• Neurosarcoidosis can present with cranial neuropathies (especially facial nerve palsy), aseptic meningitis, or mass lesions. 1
• Renal involvement occurs in 7% overall but up to 25-30% of those with renal disease; it is often clinically silent and progresses to end-stage renal failure without treatment. 7
• Hypercalcemia and hypercalciuria from dysregulated vitamin D metabolism can cause nephrocalcinosis. 7

Prognostic Factors

• African American women with sarcoidosis have 2.4-times higher mortality compared to matched controls without the disease. 5
• Pulmonary hypertension, reduced lung function, and pulmonary fibrosis are associated with increased risk of death. 5

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Diagnostic Work-Up

The diagnosis of sarcoidosis requires three criteria: (1) compatible clinical and/or radiologic presentation, (2) histologic evidence of nonnecrotizing granulomas in tissue (not required for Löfgren's, lupus pernio, or Heerfordt's syndromes), and (3) exclusion of alternative causes of granulomatous disease such as infections (tuberculosis, fungal) or malignancy. 5

Initial Evaluation for All Patients

• Chest radiography or CT scan to assess for bilateral hilar lymphadenopathy and parenchymal disease. 5, 6
• Baseline serum creatinine in every patient with systemic sarcoidosis, even without renal symptoms, to detect silent renal involvement. 7
• Serum angiotensin-converting enzyme (ACE) levels can support the diagnosis but are neither sensitive nor specific. 6, 8
• Complete blood count, comprehensive metabolic panel, serum calcium, 24-hour urinary calcium, and liver function tests. 7, 3

Tissue Diagnosis (When Required)

• Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the preferred method for obtaining tissue from mediastinal/hilar lymph nodes. 4
• Skin, peripheral lymph node, or liver biopsy if easily accessible lesions are present. 3
• Histology must show nonnecrotizing (noncaseating) granulomas; special stains and cultures are mandatory to exclude mycobacterial and fungal infections. 5, 3

Cardiac Screening (Critical for Mortality Reduction)

• Obtain baseline electrocardiogram (ECG) in all patients; if abnormal ECG findings are present with cardiac symptoms (chest pain, syncope, palpitations), the risk of cardiac sarcoidosis increases to 27.5%. 9
• For suspected cardiac involvement, cardiac MRI is the preferred imaging modality; if unavailable, dedicated cardiac PET scan is suggested over transthoracic echocardiography (TTE) for diagnostic and prognostic information. 5
• Holter monitoring or implantable loop recorder if arrhythmia is suspected. 9

Pulmonary Hypertension Screening

• For patients with exertional chest pain, syncope, reduced 6-minute walk distance, desaturation with exercise, reduced DLCO, increased pulmonary artery diameter on CT, elevated BNP, or fibrotic lung disease, obtain TTE as initial screening. 5
• If TTE is suggestive of pulmonary hypertension, perform right heart catheterization to definitively confirm or exclude it. 5
• If TTE is not suggestive but clinical suspicion remains high, right heart catheterization should be considered on a case-by-case basis. 5

Neurologic Evaluation

• Brain and spine MRI with gadolinium if neurosarcoidosis is suspected (cranial neuropathies, seizures, cognitive changes, focal deficits). 1
• Lumbar puncture may show lymphocytic pleocytosis and elevated protein. 1

Renal Work-Up (When Dysfunction Detected)

• Immediately assess calcium metabolism: serum calcium, 24-hour urinary calcium, and vitamin D levels (1,25-dihydroxyvitamin D). 7
• Renal biopsy should be pursued when imaging is nonspecific or the cause of renal dysfunction is unclear, as it provides definitive histologic confirmation and excludes alternative granulomatous diseases. 7

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Management Recommendations

Who to Treat

Treatment decisions are based on two factors: (1) risk for death or irreversible organ failure (cardiac, neurologic, renal, ocular, severe pulmonary disease), and (2) significant impairment of quality of life (troublesome fatigue, small-fiber neuropathy symptoms, disabling symptoms). 5

• Asymptomatic patients with stable radiographic findings (e.g., isolated bilateral hilar adenopathy) can be observed without treatment. 3
• Löfgren's syndrome typically has a self-limited course with excellent prognosis and may not require immunosuppression; however, NSAIDs or short-course corticosteroids may be used for symptomatic relief of arthritis. 6, 9

First-Line Therapy: Corticosteroids

Systemic corticosteroids are the first-line therapy for symptomatic or progressive pulmonary disease and serious extrapulmonary disease (cardiac, neurologic, renal, ocular). 5, 3

• For renal sarcoidosis, approximately 90% of patients receiving corticosteroid therapy experience improvement or normalization of renal function; corticosteroids address both granulomatous inflammation and vitamin D-mediated hypercalcemia. 7
• Typical initial dose: prednisone 20-40 mg daily, tapered over 6-12 months based on response. 5, 3
• Relapse upon corticosteroid withdrawal after 1-2 years occurs in 20-80% of patients, often necessitating prolonged or indefinite therapy. 5

Second-Line Therapy: Steroid-Sparing Agents

For patients with corticosteroid-refractory disease, intolerable steroid side effects, or requirement for prolonged high-dose steroids, add methotrexate or azathioprine as steroid-sparing agents. 5

• Methotrexate 10-25 mg weekly is the most commonly used second-line agent. 5
• Withdrawal of methotrexate after 2 years of chronic therapy is associated with 80% re-institution of systemic therapy due to relapse. 5

Third-Line Therapy: Biologic Agents

For advanced or refractory sarcoidosis unresponsive to corticosteroids and conventional immunosuppressants, infliximab (anti-TNF-α) is recommended. 5

• Infliximab is particularly effective for refractory pulmonary, cutaneous (lupus pernio), and neurologic sarcoidosis. 5
• Discontinuation of infliximab after 6-12 months is associated with relapse in more than 50% of cases. 5

Organ-Specific Management Considerations

Cardiac Sarcoidosis

• Aggressive immunosuppression with high-dose corticosteroids is indicated to prevent sudden cardiac death and heart failure. 5, 9
• Implantable cardioverter-defibrillator (ICD) placement for patients with sustained ventricular arrhythmias or reduced ejection fraction despite therapy. 9

Neurosarcoidosis

• High-dose corticosteroids (prednisone 1 mg/kg/day) with early addition of steroid-sparing agents. 5

Renal Sarcoidosis

• Corticosteroids are the preferred initial treatment for hypercalcemia, hypercalciuria, and granulomatous interstitial nephritis; adjunctive intravenous hydration may be added. 7
• Delaying renal biopsy after detection of renal dysfunction should be avoided; biopsy enables targeted immunosuppressive therapy and rules out other conditions. 7

Ocular Sarcoidosis

• Topical corticosteroids for anterior uveitis; systemic therapy for posterior uveitis or refractory cases. 1
• Adalimumab has been studied for non-infectious uveitis but specific data for ocular sarcoidosis are limited. 5

Common Pitfalls

• Failing to screen for cardiac involvement in all patients—cardiac sarcoidosis is a leading cause of death and may be clinically silent until sudden cardiac death occurs. 5
• Not obtaining baseline renal function—renal sarcoidosis is often asymptomatic and progresses inexorably without treatment. 7
• Premature discontinuation of therapy—relapse rates are high (20-80%) and many patients require prolonged or indefinite immunosuppression. 5
• Assuming bilateral hilar adenopathy without B symptoms is always sarcoidosis—always exclude lymphoma, tuberculosis, and fungal infections with appropriate testing. 5