What is the treatment for ANCA (Antineutrophil Cytoplasmic Antibody) vasculitis?

Treatment of ANCA-Associated Vasculitis

ANCA-associated vasculitis requires a two-phase treatment approach: remission induction with glucocorticoids plus either rituximab or cyclophosphamide, followed by prolonged maintenance therapy with rituximab or azathioprine to prevent relapse. 1

Initial Management Considerations

• All patients with AAV should be managed at centers with expertise in vasculitis treatment to ensure optimal outcomes and access to specialized care 1
• In patients with clinical presentation compatible with small-vessel vasculitis and positive MPO- or PR3-ANCA serology, do not delay starting immunosuppressive therapy while waiting for kidney biopsy results, especially in rapidly deteriorating patients 1
• Obtain tissue biopsy when feasible to confirm diagnosis, as histopathological evidence of pauci-immune glomerulonephritis or necrotizing vasculitis remains the gold standard 1

Remission Induction Therapy

First-Line Treatment Options

Glucocorticoids combined with either rituximab OR cyclophosphamide are recommended as initial treatment for new-onset AAV 1

Glucocorticoid Dosing

• Administer 1,000 mg intravenous methylprednisolone daily for 1-3 days prior to initial immunosuppressive therapy 2
• Follow with oral prednisone at reduced-dose regimen (0.5 mg/kg/day, maximum 80 mg/day) rather than standard high-dose (1 mg/kg/day), as the PEXIVAS trial demonstrated reduced serious infections without compromising efficacy 1, 3
• Taper glucocorticoids rapidly over 5-6 months using structured protocols 1

Rituximab Dosing

• 375 mg/m² intravenous weekly for 4 weeks 1, 2
• Premedicate with antihistamine and acetaminophen before each infusion 2
• Rituximab is preferred over cyclophosphamide for PR3-ANCA positive patients and those with relapsing disease, as post-hoc analysis showed superior remission rates (OR 2.11 for PR3-ANCA, OR 3.57 for relapsing disease) 1, 4

Cyclophosphamide Dosing

• Intravenous route: 15 mg/kg at weeks 0,2,4,7,10,13 (with additional doses at weeks 16,19,21,24 if needed) 1, 3
• Oral route: 2 mg/kg/day for 3-6 months 3
• Reduce dose by 2.5 mg/kg for IV or 0.5 mg/kg/day for oral if GFR <30 ml/min/1.73 m² 3
• Intravenous administration results in lower total cumulative dose and reduced leukopenia compared to oral, though slightly higher relapse rates may occur 1
• Cyclophosphamide is preferred for patients with severe renal impairment (serum creatinine >4 mg/dl or >354 μmol/l) 1
• Consider combining rituximab with 2 pulses of cyclophosphamide (15 mg/kg at weeks 0 and 2) for severe disease presentations 1, 3

Alternative Induction Agents

• Mycophenolate mofetil (2000 mg/day in divided doses) may be considered for non-severe disease in MPO-ANCA positive patients, but avoid in PR3-ANCA positive patients due to significantly increased relapse risk 1, 3
• Methotrexate with glucocorticoids can be used for AAV without kidney involvement, but is associated with higher relapse rates and damage accrual compared to cyclophosphamide 1

Adjunctive Therapies

Plasma Exchange

• Consider plasma exchange for patients with serum creatinine ≥500 μmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis 1
• Can also be considered for severe diffuse alveolar hemorrhage 1
• However, the PEXIVAS trial failed to show reduction in death or ESKD when added to immunosuppressive therapy (28.4% vs 31.0%, HR 0.86) 1

Avacopan

• C5a receptor antagonist may be considered as glucocorticoid-sparing alternative in combination with rituximab or cyclophosphamide, particularly for patients at high risk of glucocorticoid toxicity 3

Prophylaxis

• All patients receiving cyclophosphamide must receive Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim/sulfamethoxazole (800/160 mg on alternate days or 400/80 mg daily) 1, 3
• Administer MESNA with cyclophosphamide to prevent hemorrhagic cystitis 3

Maintenance Therapy

After achieving remission, all patients should receive maintenance immunosuppressive therapy to prevent relapse 1

Preferred Maintenance Regimen

• Rituximab is the preferred maintenance agent, particularly after rituximab induction 1
• Dosing: 500 mg intravenous every 6 months for 18 months to 4 years following induction 1, 3
• The MAINRITSAN trial demonstrated rituximab maintenance after cyclophosphamide induction was superior to azathioprine for preventing relapses 1
• Extending rituximab maintenance beyond 18 months reduces relapse rates compared to placebo 1

Alternative Maintenance Options

• Azathioprine (1.5-2 mg/kg/day) combined with low-dose glucocorticoids is an acceptable alternative when rituximab is not available or contraindicated 1, 3
• Methotrexate or mycophenolate mofetil can be considered as alternatives 1
• Maintenance therapy should be continued for at least 18 months to 4 years following induction of remission 1
• Longer maintenance (4 years vs 2 years) with azathioprine reduces relapse rates, particularly in PR3-ANCA positive patients who remain ANCA-positive 1

Risk-Stratified Duration

Tailor maintenance duration based on relapse risk factors:

• High-risk features include PR3-ANCA positivity, cardiovascular involvement, lung involvement, and persistent ANCA positivity after induction 1
• MPO-ANCA positive patients with kidney failure on dialysis and no extrarenal symptoms may not require long-term maintenance if monitored intensively 1

Treatment of Relapse

Major Relapse (Organ-Threatening or Life-Threatening)

• Treat as new disease with glucocorticoids combined with either cyclophosphamide OR rituximab 1
• Rituximab is preferred for relapsing disease based on superior response rates in patients with prior relapses 1, 5, 4
• For non-severe active disease, glucocorticoids alone may be sufficient as first-line therapy 5

Refractory Disease

• Switch from cyclophosphamide to rituximab or vice versa 1
• Refer to expert centers for evaluation and potential enrollment in clinical trials 1

Monitoring During Treatment

Essential Monitoring Parameters

• Structured clinical assessment using validated scoring systems (e.g., BVAS) to define remission as absence of vasculitis manifestations 1
• Regular monitoring of kidney function, urinalysis with proteinuria quantification, inflammatory markers (C-reactive protein), and ANCA levels 1
• Test serum immunoglobulin levels (IgA, IgG, IgM) prior to each rituximab course and in patients with recurrent infections, as hypogammaglobulinemia occurs in 27-58% of patients 1, 2
• Complete blood count, renal function, and urinalysis at regular intervals 3
• Investigate persistent unexplained hematuria in patients with prior cyclophosphamide exposure due to bladder cancer risk 1

ANCA Monitoring Caveats

• Structured clinical assessment rather than ANCA testing should inform treatment decisions 1
• However, persistence of ANCA positivity, rising ANCA levels, or conversion from negative to positive may predict future relapse and should be considered when making treatment decisions 1
• ANCA titers and B cell counts are poor predictors of disease relapse or quiescence in the first 6 months 4

Long-Term Management

• Periodic assessment of cardiovascular risk is essential, as mortality remains 2.6-fold higher than the general population 1
• Assess extent and ongoing impact of comorbidities after remission-induction phase 1
• Provide clear verbal explanation of disease nature, treatment options, side effects, and prognosis 1
• Long-term follow-up with rapid access to specialist services is necessary, as complications can develop years after treatment discontinuation 1

Common Pitfalls to Avoid

• Do not use mycophenolate mofetil in PR3-ANCA positive patients for induction, as the MYCYC trial showed significantly increased relapse risk 1, 3
• Do not rely solely on ANCA titers to guide treatment changes—clinical assessment is paramount 1
• Do not discontinue maintenance therapy prematurely—minimum 18 months is required, with longer duration for high-risk patients 1
• Do not use standard high-dose glucocorticoid regimens when reduced-dose protocols are equally effective with fewer infections 1, 3
• Do not forget Pneumocystis prophylaxis with cyclophosphamide—this is mandatory 1, 3