What is the best treatment approach for a 34-year-old man with biopsy-proven crescentic and necrotizing glomerular lesions, non-oliguric renal failure, and severe lung involvement, who is positive for PR3 (Proteinase 3) and has not responded to initial treatment with pulse steroids, plasmapheresis (PLEX), and cyclophosphamide (CYC)?

Immediate Treatment Escalation for Severe PR3-ANCA Vasculitis with Refractory Disease

Add rituximab immediately without delay—this patient requires urgent escalation given the lack of response to initial cyclophosphamide and worsening lung disease. 1, 2

Critical Assessment of Current Situation

Your patient has life-threatening ANCA-associated vasculitis with:

• 90% crescentic/necrotizing glomerulonephritis requiring dialysis 1, 2
• Severe pulmonary hemorrhage with hypoxemia (not yet intubated) 1
• No response after 3 days of cyclophosphamide at 7.5mg/kg 1, 2
• Progressive worsening despite pulse steroids and 4 plasmapheresis sessions 1

This represents refractory disease requiring immediate treatment intensification. 1, 2

Recommended Treatment Algorithm

1. Add Rituximab Immediately (Highest Priority)

Rituximab should be added now as rescue therapy for cyclophosphamide-resistant disease. 1, 2

• Dosing: 375 mg/m² IV weekly for 4 weeks, or 1000 mg IV on days 1 and 15 1, 3
• Rationale: KDIGO guidelines specifically recommend adding rituximab for ANCA vasculitis resistant to induction therapy with cyclophosphamide and corticosteroids 1
• Timing concern addressed: While CD20 depletion takes days, rituximab begins working through multiple mechanisms beyond B-cell depletion, and waiting longer risks mechanical ventilation and death 1, 2

2. Continue Plasmapheresis Aggressively

Continue daily plasmapheresis given severe pulmonary hemorrhage and dialysis-dependent renal failure. 1, 2

• Target 7-14 total sessions or until clinical improvement 1, 4
• The PEXIVAS trial showed no benefit for routine ANCA vasculitis, but your patient has life-threatening pulmonary hemorrhage—a different scenario where plasmapheresis remains indicated 2, 4
• Plasmapheresis improves outcomes in dialysis-dependent ANCA vasculitis with severe disease 4

3. Do NOT Increase Cyclophosphamide Dosing to 15mg/kg

The cyclophosphamide dose of 7.5mg/kg is already at the upper limit; increasing to 15mg/kg weekly would be dangerously toxic and is not supported by any guideline. 1, 3

• Standard IV cyclophosphamide dosing is 15 mg/kg every 2-3 weeks (maximum 1.2g per dose), NOT weekly 1, 3
• The CYCLOPS regimen used 15mg/kg every 2 weeks, not weekly 1
• Your patient received 7.5mg/kg only 3 days ago—redosing now would cause severe bone marrow suppression, infection risk, and hemorrhagic cystitis 3
• Instead of increasing cyclophosphamide, add rituximab as the guideline-recommended approach for refractory disease 1, 2

4. Avacopan: Pursue but Don't Delay Other Interventions

Avacopan can be added as adjunctive therapy but should not delay rituximab administration. 3

• FDA-approved for ANCA vasculitis as a steroid-sparing agent 3
• Dosing: 30 mg PO twice daily 3
• Avacopan showed non-inferiority to prednisone taper when combined with rituximab or cyclophosphamide, with 65.7% sustained remission at 52 weeks 3
• Key limitation: Avacopan was studied as initial therapy, not rescue therapy for refractory disease 3
• If you can obtain it quickly, add it; if approval takes days, proceed with rituximab immediately 3

5. Eculizumab: NOT Recommended

Do not pursue eculizumab—it is not indicated for ANCA vasculitis and lacks evidence in this setting. 1

• Eculizumab is used for complement-mediated diseases like atypical HUS and C3 glomerulopathy, not ANCA vasculitis 1
• Your patient has pauci-immune crescentic GN (negative IF, no deposits on EM), which is not complement-mediated in the same way 1
• The 2023 KDOQI commentary discusses eculizumab only for C3 glomerulopathy, not ANCA disease 1
• Pursuing eculizumab approval will waste precious time while your patient deteriorates 1

Steroid Management

Continue high-dose corticosteroids but consider pulse-dose methylprednisolone if not already maximized. 1, 2

• If oral prednisone taper has begun, consider repeating IV methylprednisolone 500-1000 mg daily for 3 additional days given disease progression 1, 2
• Maintain oral prednisone at 1 mg/kg/day (not tapering yet) until disease control is achieved 1, 2

Monitoring for Mechanical Ventilation

Prepare for potential intubation while aggressively treating. 1

• Worsening hypoxemia, increasing hemoptysis, or respiratory fatigue are indications for intubation 1
• Early intubation may be protective in severe pulmonary hemorrhage 1
• Continue plasmapheresis even if intubated 1, 4

Critical Pitfalls to Avoid

1. Do not wait for avacopan or eculizumab approval before adding rituximab—every hour counts with worsening pulmonary hemorrhage 1, 2
2. Do not increase cyclophosphamide to 15mg/kg weekly—this is not a recognized regimen and risks life-threatening toxicity 1, 3
3. Do not stop plasmapheresis prematurely—continue until clinical improvement given dialysis-dependence and pulmonary hemorrhage 1, 4
4. Do not assume the patient is "too far gone" because of dialysis-dependence—even dialysis-dependent patients can recover with aggressive therapy if they have pulmonary hemorrhage or acute presentation 1

Expected Timeline

• Rituximab: Begin seeing clinical effects within 1-2 weeks, though B-cell depletion occurs within days 1
• Plasmapheresis: Immediate mechanical removal of ANCA and inflammatory mediators 4
• Combined therapy: Most patients show improvement within 2-4 weeks if they are going to respond 1, 2

Your instinct to escalate therapy is correct—this young man needs rituximab added immediately as rescue therapy for refractory disease. 1, 2