What is the diagnostic workup and treatment for a patient suspected of having Wegener's granulomatosis (Granulomatosis with Polyangiitis)?

Diagnostic Workup and Treatment for Granulomatosis with Polyangiitis (Wegener's)

The diagnostic workup for Granulomatosis with Polyangiitis (GPA, formerly Wegener's) should include ANCA testing, comprehensive laboratory studies, imaging, and tissue biopsy, followed by treatment with a combination of systemic corticosteroids and either cyclophosphamide or rituximab for induction therapy. 1

Diagnostic Workup

Clinical Presentation Assessment

• Upper respiratory tract involvement (>90% of patients):
  • Persistent cough (often harsh and nonproductive)
  • Hemoptysis (>95% of patients)
  • Sinusitis, epistaxis, saddle nose deformity
  • Subglottic stenosis (5-23% of patients)
• Lower respiratory tract manifestations:
  • Dyspnea, wheezing
  • Respiratory insufficiency (can be rapidly progressive)
• Renal involvement:
  • Glomerulonephritis
  • Hematuria, proteinuria
• Other manifestations:
  • Skin lesions (purpura, ulcers)
  • Neurological symptoms (neuropathy)
  • Joint pain
  • Constitutional symptoms (fever, weight loss, fatigue)

Laboratory Testing

1. ANCA Testing (essential):

   • Test for both PR3-ANCA (C-ANCA) and MPO-ANCA (P-ANCA)
   • Note: 30-40% of GPA patients may be ANCA-negative, requiring additional diagnostic criteria 1, 2

2. Basic Laboratory Studies:

   • Complete blood count
   • Erythrocyte sedimentation rate (ESR)
   • C-reactive protein (CRP)
   • Renal function tests (BUN, creatinine)
   • Urinalysis (for hematuria, proteinuria, RBC casts)
   • Liver function tests

3. Additional Immunologic Testing:

   • Serum immunoglobulin levels
   • Complement levels
   • Anti-nuclear antibody (ANA)
   • Rheumatoid factor

Imaging Studies

1. Chest Imaging:

   • Chest X-ray: may show nodules, infiltrates, or cavitation
   • Chest CT scan: more sensitive for detecting pulmonary nodules, infiltrates, ground-glass opacities, and cavitation

2. Sinus Imaging:

   • CT scan of sinuses to evaluate for mucosal thickening, bony erosion, or destruction

3. Other Imaging:

   • Consider cardiac MRI if cardiac involvement is suspected

Tissue Biopsy

• Essential for definitive diagnosis

• Biopsy sites based on clinical presentation:

  • Lung biopsy (transbronchial or surgical)
  • Kidney biopsy
  • Nasal mucosa biopsy (often less diagnostic)
  • Skin biopsy if skin lesions present

• Characteristic histopathologic findings:

  • Necrotizing granulomatous inflammation
  • Vasculitis of small to medium-sized vessels
  • Tissue eosinophilia
  • Microabscesses and multinucleated giant cells 3

Treatment Approach

Induction Therapy (First 3-6 months)

1. Corticosteroids:

   • High-dose intravenous methylprednisolone (1000 mg/day for 1-3 days) for severe disease
   • Followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering 4

2. Plus one of the following:

   a) Cyclophosphamide:

   • Intravenous: 15 mg/kg every 2 weeks for 3 doses, then every 3 weeks 1
   • OR oral: 2 mg/kg/day (adjusted for renal function and white blood cell count)
   • Complete remission is achieved in >90% of patients; median time to remission is 12 months 1

   b) Rituximab (alternative, especially in younger patients wishing to preserve fertility):

   • 375 mg/m² IV once weekly for 4 weeks
   • Equally effective as cyclophosphamide for induction therapy 1, 4

3. Pneumocystis Prophylaxis:

   • Trimethoprim/sulfamethoxazole (800/160 mg on alternate days or 400/80 mg daily) for all patients receiving cyclophosphamide or rituximab 1

Maintenance Therapy (After Remission)

1. Azathioprine (preferred over mycophenolate mofetil):

   • 2 mg/kg/day for 12-18 months 1

2. Alternative Maintenance Options:

   • Methotrexate
   • Rituximab (for maintenance after rituximab induction)
   • Consider adding trimethoprim/sulfamethoxazole (800/160 mg twice daily) to reduce relapse risk 1

Management of Refractory Disease

• Switch from cyclophosphamide to rituximab or vice versa 1
• Consider referral to specialized vasculitis centers
• Evaluate for alternative diagnoses or complications

Monitoring

• Regular assessment of disease activity using validated tools
• Monitor for treatment-related complications
• Regular laboratory monitoring:
  • Complete blood count
  • Renal function
  • Urinalysis
  • ANCA levels (though correlation with disease activity is variable) 1
• Pulmonary function tests for patients with respiratory involvement
• Cardiac monitoring (ECG, echocardiography) 1

Special Considerations

• Patients with airway stenosis may require additional interventions (bronchoscopic dilation, stent placement) 1
• Patients with renal involvement may need close monitoring of kidney function
• Long-term monitoring for treatment-related complications (infections, malignancy, osteoporosis) is essential 1

Remember that early diagnosis and prompt treatment are critical to prevent organ damage and improve outcomes in GPA patients.