How should I evaluate, diagnose, and treat sarcoidosis in an adult presenting with unexplained dyspnea, cough, chest pain, skin lesions, or visual changes?

Sarcoidosis: Evaluation, Diagnosis, and Treatment

Begin with chest imaging (chest X-ray or CT) in any adult presenting with unexplained dyspnea, cough, chest pain, skin lesions, or visual changes, looking specifically for bilateral hilar adenopathy—the hallmark finding present in approximately 90% of sarcoidosis cases. 1, 2

Initial Diagnostic Approach

Highly Probable Clinical Presentations (Diagnostic Without Biopsy)

If Löfgren's syndrome is present (bilateral hilar adenopathy + erythema nodosum and/or periarticular arthritis), you can diagnose sarcoidosis without tissue biopsy. 1, 3, 2 This presentation is so specific that histological confirmation is unnecessary.

Physical Examination Findings

Look for these highly specific features that strongly support sarcoidosis 1, 2:

Highly Probable:

• Lupus pernio (chronic violaceous lesions on nose, cheeks, ears) 2
• Uveitis (most common extrapulmonary manifestation) 1, 2
• Optic neuritis 1, 2
• Erythema nodosum (tender raised nodules on shins) 1, 2

Probable:

• Maculopapular, erythematous, or violaceous skin lesions 1, 2
• Seventh cranial nerve paralysis (facial nerve palsy) 1, 2
• Symmetrical parotid gland enlargement 1, 2
• Lacrimal gland swelling 1, 2
• Hepatomegaly/splenomegaly 1, 2

Essential Imaging Studies

Order chest CT (not just X-ray) to identify: 1, 3

• Bilateral hilar adenopathy (present in ~90% of cases) 2
• Perilymphatic nodules 1, 3
• Upper lobe or diffuse infiltrates 1
• Peribronchial thickening 1

Diagnostic Confirmation Strategy

When Tissue Biopsy is Required

For all cases except Löfgren's syndrome, obtain tissue biopsy showing noncaseating granulomas. 3, 4 Select the most accessible site based on clinical manifestations 3:

• Bronchoscopy with endobronchial ultrasound-guided biopsy for lung/mediastinal involvement 5
• Skin biopsy if skin lesions present 3
• Peripheral lymph node biopsy if accessible 3

Critical: Exclude Alternative Diagnoses

Before confirming sarcoidosis, you must rigorously exclude infections, malignancy, and other granulomatous diseases—this is the most common cause of misdiagnosis. 1, 2, 6

Mandatory exclusion testing: 1

• Beryllium lymphocyte proliferation test (chronic beryllium disease mimics sarcoidosis exactly) 1
• Bronchoalveolar lavage (BAL) to exclude infections and malignancy 1, 3
• Fungal and mycobacterial cultures/stains on tissue specimens 1
• ANCA testing (MPO/PR3) to exclude granulomatosis with polyangiitis 1
• Serum IgG4 levels to exclude IgG4-related disease 1
• Review medication history for drug-induced sarcoid-like reactions (immune checkpoint inhibitors, anti-TNF agents) 1

Supportive Laboratory Testing

Order these tests to support diagnosis, but never rely on them alone: 1, 3

• Elevated ACE level (>50% above upper limit of normal) 1, 3—but has limited sensitivity/specificity 3
• Hypercalcemia or hypercalciuria with abnormal vitamin D metabolism (normal-low PTH, normal-elevated 1,25-dihydroxyvitamin D, normal-low 25-hydroxyvitamin D) 1, 3
• BAL showing lymphocytosis or elevated CD4:CD8 ratio 1, 3
• Alkaline phosphatase >3× upper limit of normal (suggests hepatic involvement) 1

Screening for Life-Threatening Organ Involvement

Cardiac Sarcoidosis (CRITICAL)

Screen ALL sarcoidosis patients for cardiac involvement—it is present in 25% of cases but only symptomatic in 5%, yet carries significant mortality risk. 2, 6, 7

Obtain: 1, 2

• 12-lead ECG looking for new-onset third-degree AV block in young/middle-aged adults 1, 2
• Echocardiogram to assess for reduced LVEF without other risk factors 1, 2
• Cardiac MRI with gadolinium if ECG/echo abnormal or high suspicion (shows inflammatory activity) 1, 2
• Consider PET scan for inflammatory activity 1
• Holter monitor if arrhythmia suspected (spontaneous/inducible VT without risk factors) 1, 2

Neurosarcoidosis

If any neurologic symptoms present (occurs in 5-15% of patients), obtain gadolinium-enhanced MRI of brain and spine—the most sensitive test for neurosarcoidosis. 6, 7 Look for leptomeningeal enhancement, cranial nerve enhancement, or parenchymal lesions. 6

Ocular Sarcoidosis

Screen ALL patients with ophthalmologic examination even if asymptomatic—eye involvement may cause permanent vision impairment. 7 Uveitis is the most common ocular manifestation. 2

Treatment Decisions

When to Treat

Initiate treatment when there is significant impact on quality of life, progressive pulmonary disease, or serious extrapulmonary involvement (cardiac, neurologic, ocular). 3, 8, 4 Many cases resolve spontaneously, so observation is appropriate for asymptomatic or minimally symptomatic patients. 8, 4

First-Line Therapy

Start oral corticosteroids as first-line treatment for symptomatic or progressive disease. 3, 8, 4 For severe or refractory cases (especially neurosarcoidosis), use high-dose IV methylprednisolone. 6

Steroid-Sparing Agents

Add methotrexate as the first-choice steroid-sparing agent when corticosteroids are ineffective or to enable tapering. 3, 8

Alternative steroid-sparing options: 3

• Azathioprine for hepatic and pulmonary involvement 3
• Mycophenolate for interstitial lung disease 3
• Hydroxychloroquine as second-line option 8

Refractory Disease

For refractory cases, use TNF inhibitors (infliximab or adalimumab). 3, 6 These are particularly effective for refractory neurosarcoidosis. 6

Consider IV immunoglobulin (IVIg) for persistent small-fiber neuropathy. 3

Critical Pitfalls to Avoid

• Never diagnose sarcoidosis without excluding infections—this is the most common diagnostic error 2, 6
• Never rely solely on elevated ACE levels—limited sensitivity and specificity 3
• Never assume all neurologic symptoms in sarcoidosis patients are neurosarcoidosis—exclude other causes 6
• Never fail to screen for cardiac involvement—it may present subtly with conduction abnormalities before life-threatening arrhythmias 2, 6
• Never discontinue therapy prematurely—risk of relapse is significant 3
• Never overlook extrapulmonary manifestations—particularly neurosarcoidosis requiring aggressive treatment 3, 2