What is the recommended treatment for a patient with a high‑titer p‑ANCA (>1:320), negative MPO and PR3 antibodies, hematuria, and impaired renal function (creatinine ~2 mg/dL) that has now plateaued?

Management of p-ANCA Positive, MPO/PR3 Negative Vasculitis with Renal Involvement

This patient requires kidney biopsy to confirm vasculitis before initiating immunosuppressive therapy, since both MPO-ANCA and PR3-ANCA are negative despite positive p-ANCA by immunofluorescence. 1

Critical Diagnostic Considerations

This clinical scenario represents a diagnostic challenge because:

• The patient has a positive p-ANCA pattern by immunofluorescence (titer 1:320) but negative antigen-specific assays (MPO and PR3). 1 This discordance occurs in approximately 10-20% of cases and requires tissue confirmation before treatment. 2

• MPO-ANCA and PR3-ANCA detected by antigen-specific immunoassays (ELISA) are the gold standard for ANCA-associated vasculitis diagnosis, not immunofluorescence patterns alone. 3 The immunofluorescence pattern without antigen specificity is insufficient to diagnose ANCA-associated vasculitis. 3

• Approximately 10% of true ANCA-associated vasculitis patients are persistently ANCA-negative by antigen-specific assays, but these patients still require compatible clinical features and tissue biopsy confirmation. 3, 4

Biopsy Strategy

Proceed with kidney biopsy immediately, as the patient's creatinine has stabilized (around 2 mg/dL), making this an appropriate time for tissue diagnosis. 1

• The kidney biopsy has a diagnostic yield of 91.5% in ANCA-associated vasculitis and will provide both diagnostic confirmation and prognostic information. 3

• Since the patient is not rapidly deteriorating (creatinine has plateaued rather than rising), there is time to obtain histologic confirmation before initiating potentially toxic immunosuppressive therapy. 1

• Do NOT delay biopsy while waiting for additional serologic testing. 1 The biopsy will definitively establish whether this is pauci-immune crescentic glomerulonephritis, which would support ANCA-associated vasculitis even with negative antigen-specific antibodies. 3

Alternative Diagnoses to Exclude

The positive p-ANCA by immunofluorescence with negative MPO/PR3 raises concern for:

• Non-ANCA-associated vasculitis conditions that can produce atypical ANCA patterns, including systemic lupus erythematosus, inflammatory bowel disease, infections, or drug-induced vasculitis. 2 These conditions require different treatment approaches than ANCA-associated vasculitis. 3

• Check ANA, anti-dsDNA, complement levels (C3, C4), hepatitis B and C serology, and HIV testing to exclude mimicking conditions. 3 Infections and malignancies can closely mimic small-vessel vasculitis. 3

Treatment Algorithm Based on Biopsy Results

If Biopsy Confirms Pauci-Immune Crescentic Glomerulonephritis:

Initiate glucocorticoids combined with rituximab immediately after biopsy confirmation. 1, 4

• With creatinine ~2 mg/dL (<4 mg/dL or <354 μmol/L), rituximab plus glucocorticoids is the preferred regimen. 1, 4 Rituximab is equally effective as cyclophosphamide for less severe renal disease. 4

• Rituximab dosing: 375 mg/m² weekly for 4 weeks or 1 g at weeks 0 and 2. 4

• Glucocorticoid dosing (weight-based tapering schedule): 1, 4

  • Week 1: 50 mg (<50 kg), 60 mg (50-75 kg), 75 mg (>75 kg)
  • Week 2: 25 mg (<50 kg), 30 mg (50-75 kg), 40 mg (>75 kg)
  • Weeks 3-4: 20 mg (<50 kg), 25 mg (50-75 kg), 30 mg (>75 kg)
  • Continue tapering to 5 mg daily by weeks 19-20, then maintain through week 52

• Mandatory Pneumocystis jirovecii prophylaxis: Trimethoprim-sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily for all patients receiving rituximab. 4, 5

If Creatinine Worsens or Patient Deteriorates Before Biopsy:

Consider cyclophosphamide plus glucocorticoids if creatinine rises above 4 mg/dL (>354 μmol/L) or patient requires dialysis. 1, 4

• Cyclophosphamide is preferred for severe glomerulonephritis with markedly reduced or rapidly declining GFR. 1

• A combination of 2 intravenous pulses of cyclophosphamide with rituximab can also be considered in this severe setting. 1

Referral and Monitoring

Transfer this patient to a center with expertise in ANCA-associated vasculitis management. 1, 3 These centers have:

• Rapid access to kidney biopsy with expert nephropathology interpretation 3
• Experience managing ANCA-negative vasculitis cases 3
• Access to rituximab infusion protocols and intensive monitoring 3

Monitor ANCA levels during follow-up, as persistence of ANCA positivity, increase in ANCA levels, or change from negative to positive may predict future disease relapse. 1

Common Pitfalls to Avoid

• Do not assume positive p-ANCA by immunofluorescence alone is sufficient to diagnose ANCA-associated vasculitis. 3, 2 Antigen-specific assays (MPO and PR3) are the gold standard. 3

• Do not initiate immunosuppressive therapy without tissue confirmation when antigen-specific ANCA assays are negative. 1, 3 The exception is rapidly deteriorating patients with positive MPO or PR3 antibodies. 1

• Recognize that 10% of ANCA-associated vasculitis is ANCA-negative by antigen-specific assays; these patients receive the same treatment as ANCA-positive patients once biopsy confirms pauci-immune glomerulonephritis. 3, 4

• Do not delay biopsy in a stable patient (plateaued creatinine at 2 mg/dL) to pursue additional serologic testing. 1 The biopsy provides definitive diagnostic and prognostic information. 3