Treatment of GPA - EULAR 2022 Recommendations

REMISSION INDUCTION

A. Organ-threatening or Life-threatening GPA (Recommendation 3)

• First-line: Combination of high-dose glucocorticoids (GCs) + Rituximab (RTX) OR Cyclophosphamide (CYC)
• RTX is preferred in relapsing disease
• RTX is also preferred in patients wishing to preserve fertility (male or female), and in those with previous high CYC exposure
• RTX dosing (RAVE protocol): 375 mg/m² per week × 4 weeks OR 1 g at weeks 0 and 2 (both comparable efficacy)
• RTX biosimilars have similar efficacy to the originator

B. Non-organ-threatening / Non-life-threatening GPA (Recommendation 4)

• First-line: Combination of GCs + RTX
• Alternatives to RTX:
  • Methotrexate (MTX) - can be continued if used to induce remission
  • Mycophenolate mofetil (MMF) - especially if RTX is contraindicated/not tolerated
  • CYC is not first-line here; may be considered only when RTX, MTX, and MMF cannot be used

GLUCOCORTICOID DOSING (Recommendation 5)

• Target: 5 mg/day by 4-5 months
• IV methylprednisolone pulses should be limited to severe organ-threatening disease (active renal involvement with eGFR <50, or DAH); no routine use

AVACOPAN (Recommendation 6) - NEW 2022

• Avacopan 30 mg twice daily (oral C5a receptor inhibitor) + RTX or CYC may be considered as part of a strategy to substantially reduce GC exposure
• Especially indicated in:
  • Patients at risk of GC-related adverse effects
  • Active glomerulonephritis with rapidly declining kidney function (better renal recovery shown vs GC in the ADVOCATE trial)
• Remission at week 26: avacopan 72.3% vs GC 70.1% (comparable)
• Sustained remission at week 52: avacopan 65.7% vs GC 54.9% (superior)
• Stop avacopan after 6-12 months - no data beyond 1 year; longer-term use not recommended

PLASMA EXCHANGE (Recommendation 7)

• May be considered in patients with serum creatinine >300 µmol/L due to active glomerulonephritis (reduced from >500 µmol/L threshold in 2016 guidelines)
• Not routinely recommended for alveolar haemorrhage in GPA
• PLEX reduces ESKD risk at 12 months but increases serious infections - use requires individual risk-benefit discussion
• PLEX is recommended for patients with anti-GBM antibody overlap

REFRACTORY GPA (Recommendation 8)

• Thorough reassessment of disease status and comorbidities
• Consider switching from CYC to RTX or vice versa
• RTX + CYC combination considered by many centres
• IV immunoglobulins (IVIG) can be an option for persistent disease with increased infection risk
• These patients should be managed at vasculitis expert centres

REMISSION MAINTENANCE

GPA/MPA Maintenance (Recommendation 9)

• First-line: Rituximab - recommended after induction with either RTX or CYC
• RTX regimen: 500 mg every 6 months (preferred fixed schedule); higher dose (1 g) or shorter interval (every 4 months) may be considered for patients who relapse on 500 mg q6 months
• Alternatives to RTX:
  • Azathioprine (AZA)
  • Methotrexate (MTX)
  • MMF (if intolerance/contraindications to RTX, AZA, MTX)
  • Leflunomide (in GPA with intolerance to all above drugs)
• T/S (trimethoprim-sulfamethoxazole) does not reduce relapse risk; not recommended for relapse prevention
• Belimumab + AZA: no benefit shown in RCT

Duration of Maintenance (Recommendation 10)

• 24-48 months for new-onset disease
• Longer duration should be considered in:
  • Relapsing patients
  • Those with increased relapse risk (GPA > MPA; PR3-ANCA positive; ANCA positivity persisting in remission; B cell repopulation <12 months after RTX; respiratory tract involvement)
• Balance against patient preferences and immunosuppression risks

MONITORING DURING TREATMENT

Recommendation 15

• Structured clinical assessment (using BVAS scoring) should drive treatment decisions - not ANCA or CD19+ B cell testing alone
• ANCA/B cell counts have insufficient predictive value to guide individual patient decisions

Recommendation 16

• Measure serum immunoglobulin levels before each course of RTX to detect secondary immunodeficiency (hypogammaglobulinaemia develops in 21% after 36 months of RTX)

INFECTION PROPHYLAXIS (Recommendation 17)

• Trimethoprim-sulfamethoxazole (T/S) 800/160 mg on alternate days or 400/80 mg daily is recommended for all GPA patients receiving:
  • CYC
  • RTX
  • GCs ≥30 mg/day for ≥4 weeks
• Purpose: Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) and other infections
• Continue T/S for ~3 months after last CYC dose; ~6 months after last RTX dose or until B cell reconstitution
• Alternatives if T/S not tolerated: dapsone, atovaquone, aerosolised pentamidine

OVERARCHING PRINCIPLES

• Shared decision-making between patient and physician (considering efficacy, safety, costs)
• Patient education on disease, warning symptoms, treatment side effects
• Periodic screening for treatment-related adverse effects and comorbidities (cardiovascular risk, osteoporosis, CKD, bladder cancer if on CYC)
• Multidisciplinary management at centres with vasculitis expertise; access to clinical trials important for relapsing/refractory disease

Source: Hellmich B, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2024;83:30-47.

RTX vs CYC for Induction in GPA - Decision Guide

Both are equally effective for new-onset GPA

Choose RITUXIMAB when:

Choose CYCLOPHOSPHAMIDE when:

Note: RTX and CYC have comparable outcomes in severe disease including renal involvement and DAH (PEXIVAS trial included both agents) - the preference for CYC in severe renal/DAH is not evidence-based but practice-based per the task force.

The Trend: RTX is Increasingly Preferred

"There has been an increasing preference for RTX over CYC, mostly because of concerns about long-term safety of CYC."

"The use of RTX is lowering CYC exposure and reducing the risk of malignancy in patients with AAV."

Summary Algorithm (from the PDF)

New-onset GPA with organ/life-threatening disease
        ↓
   RTX or CYC (both acceptable)
        ↓
   Prefer RTX if: relapsing disease, 
   childbearing potential, prior CYC exposure,
   safety concerns

Relapsing GPA → RTX preferred
Non-organ-threatening GPA → RTX recommended
   (MTX or MMF as alternatives, NOT CYC first-line)