What is sarcoidosis and how is it diagnosed and treated?

Sarcoidosis: Definition, Diagnosis, and Treatment

What is Sarcoidosis?

Sarcoidosis is a chronic multi-system inflammatory disease characterized by non-caseating (non-necrotizing) granulomas that can affect virtually any organ, though it predominantly involves the lungs and intrathoracic lymph nodes. 1, 2

• The disease involves well-formed, concentrically arranged immune cell aggregates with a central core of macrophages and multinucleated giant cells, surrounded by T lymphocytes (predominantly CD4+ cells). 1, 2
• Sarcoidosis affects approximately 8-60 cases per 100,000 people annually, with higher prevalence in African Americans and northern Europeans (particularly Scandinavians). 1, 2
• The disease carries significant mortality risk, with African American women experiencing 2.4 times higher mortality compared to matched controls without sarcoidosis. 1, 2
• Up to one-third of patients experience spontaneous resolution within two years, while 10-40% develop progressive fibrotic disease with substantial morbidity. 1, 3

Clinical Presentation

Highly Specific Presentations (Nearly Diagnostic)

Certain clinical syndromes are so characteristic that they are considered virtually diagnostic of sarcoidosis without requiring tissue confirmation:

• Löfgren's syndrome (bilateral hilar adenopathy with erythema nodosum and/or periarticular arthritis) is highly specific and associated with excellent prognosis. 1, 2
• Lupus pernio (violaceous indurated skin lesions on the nose, cheeks, and ears) is pathognomonic for sarcoidosis. 1
• Heerfordt's syndrome (fever, parotid enlargement, uveitis, and facial nerve palsy) is highly characteristic. 1

Common Organ Manifestations

• Pulmonary involvement (90% of cases): Bilateral hilar adenopathy, perilymphatic nodules on chest CT, upper lobe or diffuse infiltrates, and progressive dyspnea or cough. 1, 4
• Skin manifestations: Erythema nodosum, maculopapular lesions, subcutaneous nodules, and lupus pernio. 1
• Ocular involvement: Uveitis (most common), optic neuritis, scleritis, retinitis, and lacrimal gland swelling. 1
• Cardiac involvement: Cardiomyopathy, atrioventricular block, ventricular tachycardia, and sudden cardiac death (leading cause of death in Japanese populations). 1, 3
• Upper respiratory tract: Nasal obstruction, crusting, nodularity, and bone erosion (3-4% of cases). 1
• Neurologic involvement: Seventh cranial nerve paralysis, basal meningeal involvement, and seizures. 1

Diagnostic Approach

The diagnosis of sarcoidosis requires three essential criteria: (1) compatible clinical and radiologic presentation, (2) histopathologic evidence of non-caseating granulomas, and (3) exclusion of alternative causes of granulomatous disease. 1, 5

Step 1: Clinical and Radiologic Assessment

• Obtain chest X-ray or CT showing bilateral hilar adenopathy, perilymphatic nodules, or upper lobe infiltrates. 1
• Document extrapulmonary manifestations through targeted examination (skin, eyes, cardiac evaluation). 1
• High-resolution chest CT is superior to plain radiography for detecting parenchymal disease and nodularity. 1, 4

Step 2: Tissue Confirmation (When Required)

• Biopsy is NOT required for Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome due to their high specificity. 1, 2
• For all other presentations, obtain tissue from the most accessible involved organ (endobronchial biopsy, lymph node biopsy, or skin biopsy). 1
• Histopathology must demonstrate well-formed, non-caseating granulomas with macrophage aggregates and multinucleated giant cells. 1
• Critical caveat: Nodular pulmonary sarcoidosis can present with mixed necrotic and non-necrotic granulomas, which may be confused with tuberculosis or fungal infection. 1

Step 3: Exclusion of Mimics

This is the most critical step to avoid misdiagnosis, as many conditions produce granulomas:

• Infectious causes to exclude: Tuberculosis (AFB smear/culture, interferon-gamma release assay), histoplasmosis (urine/serum antigen), fungal infections (cultures, serology), and atypical mycobacteria. 1, 6
• Non-infectious mimics: Chronic beryllium disease (blood lymphocyte proliferation test is diagnostic), granulomatosis with polyangiitis, hypersensitivity pneumonitis, and drug-induced granulomatous reactions. 1
• Malignancy: Lymphoma (flow cytometry, immunohistochemistry) and sarcoid-like reactions to tumors must be excluded. 1, 6
• Perform bronchoalveolar lavage to exclude infection and assess for lymphocytosis with elevated CD4:CD8 ratio (supportive but not diagnostic). 1

Supportive Laboratory Testing

• Serum angiotensin-converting enzyme (ACE): Elevated in 60% of cases but has poor sensitivity (60%) and specificity (70%). 1
• Serum and urinary calcium: Hypercalcemia or hypercalciuria with abnormal vitamin D metabolism (elevated 1,25-dihydroxyvitamin D with normal/low 25-hydroxyvitamin D and normal/low PTH) is highly supportive. 1
• Alkaline phosphatase: Elevation >3 times upper limit of normal suggests hepatic involvement. 1
• FDG-PET scanning: Useful for detecting extrapulmonary involvement and monitoring treatment response in severe cases. 1

Cardiac and Neurologic Evaluation

• For suspected cardiac involvement: Obtain cardiac MRI (preferred imaging), ECG, echocardiogram for left ventricular ejection fraction, and consider Holter monitoring. 1, 2
• For suspected neurosarcoidosis: Brain MRI with gadolinium to detect basal meningeal enhancement or parenchymal lesions. 1

Treatment Strategy

When to Treat vs. Observe

Many patients with asymptomatic Stage I disease (bilateral hilar lymphadenopathy alone) do not require treatment, as 60-80% experience spontaneous resolution. 1, 2, 3

• Indications for treatment: Symptomatic pulmonary disease (dyspnea, cough) with abnormal pulmonary function tests, progressive radiographic disease, or involvement of critical organs (heart, brain, eyes, kidneys). 1, 7
• Stage II disease (hilar adenopathy plus parenchymal infiltrates): 65% spontaneously regress; treat if symptomatic or progressive. 1
• Stage III disease (parenchymal infiltrates without adenopathy): Only 10-30% remit spontaneously; most require treatment. 1, 3
• Stage IV disease (pulmonary fibrosis): No chance of spontaneous resolution; requires aggressive treatment and carries 40% 5-year mortality. 3

First-Line Therapy: Glucocorticoids

Oral corticosteroids remain the mainstay of initial therapy for symptomatic or progressive disease. 1, 7, 3

• Prednisone 20-40 mg daily for 2 weeks to 2 months, then taper over 6-18 months if clinical improvement occurs (symptoms, spirometry, radiographs). 7, 3
• The FDA label indicates prednisone for "symptomatic sarcoidosis" as a specific indication. 7
• Monitor for steroid toxicity, particularly in patients requiring prolonged therapy (>10 mg/day for >6 months). 1, 3
• Approximately 75% of patients can be managed with NSAIDs alone for mild constitutional symptoms without organ-threatening disease. 1

Second-Line Therapy: Immunomodulators (Steroid-Sparing Agents)

For patients requiring prolonged corticosteroids (≥10 mg/day prednisone), experiencing steroid toxicity, or with severe/extrapulmonary disease, add non-biologic immunomodulators. 1, 3

• Methotrexate (weekly dosing) is the preferred second-line agent based on expert consensus. 1, 3
• Azathioprine is an alternative second-line option. 1, 3
• Hydroxychloroquine/chloroquine are specifically effective for cutaneous, bone, and neurologic sarcoidosis, though retinal toxicity monitoring is required. 1
• These agents allow corticosteroid dose reduction while maintaining disease control. 1

Third-Line Therapy: Biologic Agents

TNF-α inhibitors should be considered as additive therapy when non-biologics are insufficiently effective or not tolerated. 1

• Infliximab is the preferred initial biologic agent based on expert consensus and evidence in refractory disease. 1
• Biologics are particularly effective for cutaneous, ophthalmic, hepatic, and neurosarcoidosis. 1
• Thalidomide has been used in highly refractory cases but requires careful monitoring. 1

Organ-Specific Considerations

• Nasal/sinus disease: Topical corticosteroid sprays/drops, saline irrigations, and regular debridement of crusts; systemic therapy often required for control. 1
• Cardiac sarcoidosis: Requires aggressive immunosuppression; consider implantable cardioverter-defibrillator for arrhythmias. 3
• Stage IV fibrotic disease with pulmonary hypertension: May respond to targeted pulmonary arterial hypertension medications; lung transplantation for end-stage disease (though 60% develop recurrence in allograft). 1, 3

Monitoring and Prognosis

• Monitor pulmonary function tests every 6-12 months in patients with lung involvement. 1
• Relapse rates range from 13-75% depending on disease stage, number of organs involved, and socioeconomic factors. 3
• Mortality over 5 years is approximately 7%, with 60% of deaths due to sarcoidosis itself (80% from cardiopulmonary failure). 3
• Patients with elevated serum ACE, extrapulmonary involvement, or Stage III/IV disease have higher relapse risk and may require prolonged treatment. 1

Critical Pitfalls to Avoid

• Do not assume all granulomas are sarcoidosis: Always exclude tuberculosis, fungal infections, and berylliosis before confirming diagnosis. 1
• Do not overlook cardiac involvement: Screen with ECG and consider cardiac MRI in patients with palpitations, syncope, or unexplained dyspnea, as cardiac sarcoidosis causes sudden death. 1, 3
• Do not treat asymptomatic Stage I disease: These patients have excellent prognosis with observation alone. 2, 3
• Do not rely on serum ACE for diagnosis: Its poor sensitivity and specificity make it unsuitable as a standalone diagnostic test. 1