What is the pathophysiology and treatment of Anti-Neutrophil Cytoplasmic Antibody (ANCA) vasculitis?

Pathophysiology of ANCA-Associated Vasculitis

ANCA-associated vasculitis (AAV) is characterized by autoantibodies targeting neutrophil cytoplasmic antigens, primarily proteinase-3 (PR3) and myeloperoxidase (MPO), which trigger neutrophil activation, leading to small vessel inflammation and tissue damage.

Pathophysiological Mechanisms

Autoimmune Basis

• ANCA antibodies bind to and activate neutrophils, causing release of oxygen radicals, lytic enzymes, and inflammatory cytokines 1
• Activated neutrophils damage endothelial cells through direct adherence and killing, leading to vasculitis 1
• Epigenetic dysregulation appears to be the basis for increased MPO and PR3 neutrophil gene expression in ANCA disease 2

Neutrophil Activation Cascade

1. ANCA binds to neutrophil surface-expressed antigens (PR3 or MPO)
2. Binding triggers neutrophil degranulation and release of toxic substances
3. Neutrophil extracellular traps (NETs) may be involved in initiating the autoimmune response 3, 2
4. Complement activation (particularly C5a) through the alternative pathway contributes to pathogenesis 2

Genetic Factors

• Strong association with HLA-DP and genes encoding alpha1 antitrypsin (SERPINA1) and proteinase 3 (PRTN3) 1
• Susceptibility genes include CTLA4, PTPN22, COL11A2, and MHC class II gene cluster 1

Environmental Triggers

• Staphylococcus aureus nasal colonization is found more frequently in GPA patients (72%) compared to CRS patients (28%) and controls (25%) 1
• S. aureus has been strongly implicated as a causative agent, especially in disease relapses 1
• Molecular mimicry and infections may play a role through molecular mimicry 2

Classification of ANCA-Associated Vasculitis

Main Types

1. Granulomatosis with Polyangiitis (GPA)

   • Previously known as Wegener's Granulomatosis
   • Characterized by necrotizing granulomatous lesions and systemic vasculitis
   • Strongly associated with PR3-ANCA (c-ANCA) 1
   • Common manifestations: nasal crusting, stuffiness, epistaxis, scleritis, respiratory tract involvement 1

2. Microscopic Polyangiitis (MPA)

   • Characterized by vasculitis without granulomatous inflammation
   • Associated with MPO-ANCA (p-ANCA) 1
   • Common manifestations: rapidly progressive glomerulonephritis and alveolar hemorrhage 1

3. Eosinophilic Granulomatosis with Polyangiitis (EGPA)

   • Characterized by eosinophilic tissue infiltration and vasculitis
   • Only 40% of patients produce detectable ANCA 1
   • Common manifestations: asthma, peripheral eosinophilia, and peripheral neuropathy 1

Clinical Manifestations

Organ Involvement

• Kidney: Pauci-immune focal and segmental necrotizing and crescentic glomerulonephritis 1

  • Microscopic hematuria with dysmorphic red blood cells and red cell casts
  • Moderate proteinuria (1-3 g/day)
  • Rapidly declining glomerular filtration rate

• Respiratory: Upper and lower respiratory tract involvement 1

  • Pulmonary hemorrhage affects 10% of AAV patients and increases mortality risk 1
  • Nasal crusting, stuffiness, and epistaxis in GPA 1

• Other systems: Skin, eyes, and nervous system involvement 1

Diagnostic Approach

Laboratory Testing

• ANCA testing: Both PR3-ANCA and MPO-ANCA using high-quality antigen-specific assays 4
• Complete blood count with differential
• Comprehensive metabolic panel
• Inflammatory markers (ESR, CRP)
• Urinalysis with microscopic examination 4

Imaging

• Select imaging based on suspected vessel size:
  • Large vessels: CT/CTA, MRI/MRA, or FDG-PET/CT
  • Medium vessels: CTA of affected regions
  • Small vessels: MRI/MRA or FDG-PET/CT 4

Biopsy

• Strongly recommended to establish diagnosis with >70% diagnostic yield when properly targeted 4
• Kidney biopsy may show pauci-immune necrotizing and crescentic glomerulonephritis 1

Treatment Approach

Induction Therapy

• First-line recommendation: Glucocorticoids in combination with rituximab or cyclophosphamide 1
• Rituximab has been shown to be equally effective as cyclophosphamide with similar infection rates 1, 5
• For severe disease: High-dose corticosteroids (prednisone 1 mg/kg/day) plus cyclophosphamide or rituximab 4
  • Cyclophosphamide: Up to 2 mg/kg/day oral or intermittent IV
  • Rituximab: 375 mg/m² IV weekly for 4 doses or 1,000 mg on days 1 and 15 4

Maintenance Therapy

• Options include rituximab, azathioprine, or mycophenolate mofetil with low-dose glucocorticoids 1
• Rituximab maintenance regimens:
  • 500 mg every 6 months for 2 years (MAINRITSAN scheme)
  • 1000 mg after remission induction, and at months 4,8,12, and 16 (RITAZAREM scheme) 1

Management of Relapses

• Patients with relapsing disease should be reinduced, preferably with rituximab 1
• Mycophenolate mofetil may be useful in patients with history of cyclophosphamide toxicity 6

Monitoring and Prognosis

Disease Activity Assessment

• Birmingham Vasculitis Activity Score (BVAS) for measuring disease activity 4
• Vasculitis Damage Index (VDI) for assessing disease damage 4
• Regular monitoring should include:
  • Renal function tests
  • Urinalysis with microscopic examination
  • Inflammatory markers (ESR, CRP)
  • ANCA levels 4

Long-term Outcomes

• Despite newer treatments, AAV patients still have increased mortality compared to the general population 7
• Main causes of death: infections (26%), cardiovascular disease (14%), and malignancies (13%) 7
• Predictors of poor prognosis: advanced age, male sex, low estimated GFR, and low platelet count 7

Important Considerations

• Treatment should not be delayed while waiting for biopsy results in ANCA-positive patients with compatible clinical presentation, especially in rapidly deteriorating patients 4
• A negative ANCA does not exclude vasculitis, particularly in limited forms of disease or following corticosteroid therapy 4
• Persistent hematuria may indicate ongoing disease activity, while return of hematuria after initial resolution may indicate relapse 1