What are the clinical presentation, diagnostic workup, and management recommendations for sarcoidosis?

Sarcoidosis: Clinical Presentation, Diagnosis, and Management

Diagnostic Approach

Sarcoidosis diagnosis requires three essential criteria: compatible clinical/radiologic presentation, histologic evidence of nonnecrotizing granulomas (though not always required for certain presentations), and exclusion of alternative granulomatous diseases. 1

Highly Specific Clinical Presentations (No Biopsy Required)

These presentations are considered diagnostic without tissue confirmation 1:

• Löfgren's syndrome: Bilateral hilar adenopathy + erythema nodosum and/or periarticular arthritis 1, 2
• Lupus pernio: Chronic violaceous skin lesions on nose, cheeks, ears 1
• Heerfordt's syndrome: Parotid enlargement, uveitis, facial nerve palsy, fever 1

Clinical Presentation by Probability

Highly Probable Features 1:

• Bilateral hilar adenopathy on any imaging (CXR, CT, PET) 1
• Perilymphatic nodules on chest CT 1
• Lupus pernio on physical exam 1
• Uveitis or optic neuritis 1
• Hypercalcemia/hypercalciuria with abnormal vitamin D metabolism (normal-to-low PTH, normal-to-elevated 1,25-dihydroxyvitamin D) 1

Probable Features 1:

• Upper lobe or diffuse infiltrates on imaging 1
• Symmetrical parotid enlargement 1
• Hepatosplenomegaly 1
• Elevated ACE level 1
• BAL lymphocytosis or elevated CD4:CD8 ratio 1
• New-onset third-degree AV block in young/middle-aged adults 1

Critical Organ Involvement Assessment

Cardiac Sarcoidosis (Highest Mortality Risk)

Cardiac involvement causes sudden death from arrhythmias or heart failure and requires aggressive screening. 1

Screening algorithm 1:

1. Obtain baseline ECG in all patients 1
2. If cardiac symptoms (exertional chest pain, syncope, palpitations) OR abnormal ECG → cardiac MRI preferred 1
3. If cardiac MRI unavailable → dedicated cardiac PET 1
4. Look for: reduced LVEF without risk factors, ventricular tachycardia, AV blocks, gadolinium enhancement on MRI 1

Pulmonary Hypertension Screening

For suspected PH (exertional chest pain/syncope, prominent P2/S4, reduced 6-minute walk, desaturation with exercise, reduced DLCO, enlarged pulmonary artery on CT, elevated BNP, or fibrotic lung disease) 1:

1. Initial screening with transthoracic echocardiogram 1
2. If TTE suggestive of PH → right heart catheterization to confirm 1
3. If TTE NOT suggestive → case-by-case decision for RHC 1

Neurosarcoidosis

Look for seventh cranial nerve paralysis, which is a probable finding 1. Any neurologic symptoms warrant MRI with gadolinium showing enhancement 1.

Exclusion of Alternative Diagnoses

Critical differential diagnoses to exclude 1:

• Chronic beryllium disease: Blood lymphocyte proliferation test is diagnostic 1
• Infections: Mycobacterial, fungal (histoplasmosis, coccidioidomycosis) 1
• Malignancy: Lymphoma, metastatic disease 1
• Drug-induced: Immune checkpoint inhibitors, anti-TNF agents 1
• Hypersensitivity pneumonitis: BAL can identify cellular patterns 1

Histopathologic features alone cannot distinguish sarcoidosis from other granulomatous diseases—clinical context is essential 1.

Management Algorithm

Treatment Indications

Treat when there is risk of mortality, permanent organ damage, or significant quality of life impairment. 3, 4

First-Line Therapy: Glucocorticoids

For symptomatic disease with mortality/disability risk 3, 4:

• Prednisone 20-40 mg daily for 2-6 weeks 3, 4
• Maintenance: 5-10 mg daily or every other day 3
• Monitor bone density, blood pressure, serum glucose 3
• Continue 3-6 months minimum before assessing response 3

Second-Line: Steroid-Sparing Agents

Methotrexate is the preferred second-line agent 3, 4:

• Dose: 10-15 mg once weekly 3
• Add when glucocorticoids ineffective or cause unacceptable side effects 3, 4
• Improves/preserves lung function and quality of life 3
• Requires regular laboratory monitoring 4

Alternative second-line agents 3:

• Azathioprine 3
• Leflunomide 3
• Mycophenolate mofetil: 1000-3000 mg daily (divided twice daily), monitor CBC for leukopenia 3
  • Note: Less experience than methotrexate; allow 3-6 months to assess response 3

Third-Line: Biologic Therapy

Infliximab for refractory disease 3, 4:

• Indicated after failure of glucocorticoids and methotrexate 3, 4
• Strongest evidence among anti-TNF agents 4
• Consider for refractory cutaneous sarcoidosis 3

Organ-Specific Considerations

Cardiac sarcoidosis 3:

• Glucocorticoids ± immunosuppressives strongly recommended for functional cardiac abnormalities 3
• Consider early steroid-sparing agents due to significant morbidity of long-term glucocorticoid use 3

Neurosarcoidosis 3:

• First-line: Glucocorticoids 3
• Second-line: Add methotrexate if disease continues 3
• Third-line: Add infliximab if refractory 3

Cutaneous sarcoidosis 3:

• Hydroxychloroquine 200-400 mg daily with periodic ocular exams 3
• Infliximab for refractory skin disease 3

Sarcoidosis-associated fatigue 3:

• First-line: Pulmonary rehabilitation and/or inspiratory muscle strength training for 6-12 weeks 3
• Second-line: D-methylphenidate or armodafinil for 8 weeks 3

Monitoring Treatment Response

Assessment parameters 3, 4:

• Symptom improvement 3
• Pulmonary function tests (FVC, DLCO) 3, 4
• Radiographic changes on chest imaging 4
• For cardiac: LVEF and BNP 3
• For fatigue: 6-minute walk test 3

Treatment duration 3, 4:

• Continue 3-6 months minimum to assess response 3
• At least half of patients remain on treatment 2 years later 3
• May discontinue if stable for 2-3 years 4

Critical Pitfalls to Avoid

• Do not use inhaled glucocorticoids added to oral glucocorticoids—no significant benefit 3
• Do not prematurely discontinue steroid-sparing agents—allow 3-6 months minimum to assess response 3
• Do not miss cardiac involvement—African American women have 2.4-times higher mortality 1
• Do not assume Löfgren's syndrome is always benign—if atypical features like uveitis develop, more comprehensive evaluation required 2
• Do not forget to exclude berylliosis—histologically identical to sarcoidosis but requires specific lymphocyte proliferation testing 1