What is the best course of treatment for a male patient presenting with sinus pain and pressure, intermittent epistaxis, productive brown sputum cough, purpura (dark purplish rash) on the lower legs, weight loss, myalgias (muscle pain), arthralgias (joint pain), intermittent fevers, elevated Erythrocyte Sedimentation Rate (ESR), positive Anti-Neutrophil Cytoplasmic Antibody (ANCA), positive Rheumatoid Factor (RF), negative Anti-Nuclear Antibody (ANA), and urine findings of proteinuria and hematuria with Red Blood Cell (RBC) casts?

Treatment of ANCA-Associated Vasculitis with Renal Involvement

This patient has granulomatosis with polyangiitis (GPA) with severe, organ-threatening disease requiring immediate initiation of remission induction therapy with rituximab or cyclophosphamide plus high-dose glucocorticoids, without waiting for biopsy confirmation. 1

Immediate Management

Start Treatment Now

• Do not delay immunosuppressive therapy while awaiting kidney biopsy when clinical presentation strongly suggests AAV with positive ANCA serology, especially in rapidly deteriorating patients 1
• The combination of upper respiratory tract involvement (sinus pain, epistaxis), lower respiratory tract disease (brown sputum suggesting alveolar hemorrhage), palpable purpura, constitutional symptoms, positive ANCA, and glomerulonephritis with RBC casts is diagnostic for severe GPA 1
• About 90% of patients with small-vessel vasculitis have ANCA directed against MPO or PR3, and a positive test with compatible clinical features is sufficient to begin treatment 1, 2

Remission Induction Regimen

First-line therapy options: 1

• Rituximab 375 mg/m² IV weekly for 4 weeks OR 1000 mg IV on days 1 and 15

  • Rituximab is conditionally recommended for remission induction in severe GPA/MPA 1
  • This is the preferred agent for maintenance therapy and has shown superiority over azathioprine for preventing relapses 3

• Cyclophosphamide (alternative if rituximab unavailable)

  • IV pulse: 15 mg/kg (max 1200 mg) every 2-4 weeks for 3-6 months
  • Oral: 2 mg/kg/day for 3-6 months 1

Plus high-dose glucocorticoids: 1

• Methylprednisolone 500-1000 mg IV daily for 3 days, followed by
• Prednisone 1 mg/kg/day (max 80 mg/day) orally, with gradual taper over 4-6 months to 5-7.5 mg/day 1, 2

Consider Plasma Exchange

• Strongly consider plasma exchange in this patient given the combination of:
  • Rapidly progressive glomerulonephritis (proteinuria, hematuria, RBC casts) 1, 2
  • Pulmonary hemorrhage (brown sputum suggesting alveolar bleeding) 1, 2
• Plasma exchange should be performed in patients with severe AKI or diffuse alveolar hemorrhage with hypoxemia 2

Maintenance Therapy (After Achieving Remission)

Duration and Agents

• Begin maintenance therapy after achieving remission (typically by 4-6 months) 1
• Rituximab at fixed intervals is superior to azathioprine for maintaining remission and preventing relapses 3
  • Dosing: 500 mg IV every 6 months for at least 18-24 months 1

Alternative maintenance options: 1, 2

• Azathioprine 1.5-2 mg/kg/day for 18-24 months, then 1 mg/kg/day until 4 years after diagnosis 2
• Mycophenolate mofetil 2000 mg/day in divided doses (subtherapeutic dosing substantially increases relapse risk) 4

Glucocorticoid Continuation

• Continue prednisone 5-7.5 mg/day for 2 years, then slowly reduce by 1 mg every 2 months 2
• This low-dose maintenance is within recommended ranges for AAV in remission 4

Monitoring for Relapse

High-Risk Features in This Patient

• Upper respiratory tract involvement (sinus disease, epistaxis) is a negative predictor of achieving prolonged remission 5
• Lung involvement is also associated with higher relapse risk 5
• Persistent hematuria beyond 6 months after achieving remission significantly increases renal relapse risk (hazard ratio 3.99) 6

Surveillance Strategy

• Serial urinalysis with microscopy to monitor for dysmorphic RBCs and RBC casts 1, 4, 7
• ANCA titers (MPO and PR3) to evaluate serologic activity 4
• Serum creatinine and inflammatory markers (CRP, ESR) 4
• Persistent hematuria (not proteinuria) is the most significant predictor of future renal relapse, with median time to relapse of 22 months 6

Critical Pitfalls to Avoid

Subtherapeutic Immunosuppression

• This is a major relapse risk factor and must be avoided 4
• If using mycophenolate, ensure full 2000 mg/day dosing 4
• Studies show no improvement in relapse rates over the past 2 decades, emphasizing the need for adequate maintenance therapy 3

Positive Rheumatoid Factor

• The positive RF in this patient represents an overlap phenomenon, as GPA rarely presents with rheumatoid arthritis 8
• This does not change the treatment approach, which should focus on the life-threatening vasculitis 8
• The negative ANA helps exclude lupus-ANCA overlap 4

Treatment Setting

• Patients with AAV should be treated at centers with experience in AAV management, given the complexity of induction therapy, monitoring for treatment toxicity, and long-term relapse prevention 1