What is the pathophysiology of systemic vasculitis?

Pathophysiology of Systemic Vasculitis

Systemic vasculitis is characterized by inflammation and damage to blood vessel walls, involving complex immune mechanisms including ANCA-mediated neutrophil activation, granulomatous inflammation, and tissue destruction, which leads to organ dysfunction and potentially life-threatening complications. 1, 2

Key Pathophysiological Mechanisms

ANCA-Associated Vasculitis (AAV)

• Autoantibody Production: Production of anti-neutrophil cytoplasmic antibodies (ANCA), primarily targeting:

  • Proteinase 3 (PR3-ANCA) - associated with granulomatosis with polyangiitis (GPA)
  • Myeloperoxidase (MPO-ANCA) - associated with microscopic polyangiitis (MPA) 1, 2

• Neutrophil Activation: ANCA binds to neutrophils causing:

  • Degranulation and release of reactive oxygen species
  • Neutrophil extracellular trap (NET) formation
  • Endothelial cell damage 1

• Vascular Inflammation: Characterized by:

  • Pauci-immune pattern (little or no immune complex deposition)
  • Necrotizing inflammation of vessel walls
  • Segmental lesions affecting small vessels (arterioles, capillaries, venules) 1

Granulomatous Inflammation

• Particularly prominent in GPA and eosinophilic granulomatosis with polyangiitis (EGPA)
• Formation of granulomas with:
  • Activated T cells
  • Macrophages
  • Multinucleated giant cells
  • Tissue eosinophilia (in EGPA) 1

Disease Classification by Vessel Size

Small Vessel Vasculitis

• Pauci-immune vasculitis:
  • GPA, MPA, EGPA
  • Characterized by ANCA positivity in most cases
  • Necrotizing glomerulonephritis is common 1

Medium Vessel Vasculitis

• Polyarteritis nodosa:
  • Segmental inflammation of muscular arteries
  • Microaneurysm formation
  • Typically ANCA-negative 2

Large Vessel Vasculitis

• Giant cell arteritis and Takayasu arteritis:
  • Granulomatous inflammation of aorta and major branches
  • Cell-mediated immune responses predominate
  • T-cell activation and macrophage recruitment 2

Organ-Specific Manifestations

Renal Involvement

• Pauci-immune focal and segmental necrotizing and crescentic glomerulonephritis
• Presents with:
  • Microscopic hematuria with dysmorphic red blood cells
  • Red cell casts
  • Moderate proteinuria (1-3 g/day)
  • Rapidly declining glomerular filtration rate 1

Pulmonary Involvement

• Diffuse alveolar hemorrhage in 10% of AAV patients
• Granulomatous inflammation in lungs (GPA)
• Eosinophilic infiltration (EGPA) 1

Disease Activity States

The pathophysiology manifests in different clinical states:

Activity State	Pathophysiological Basis
Remission	Absence of active inflammation
Response	Partial reduction in inflammatory activity
Relapse	Recurrence of inflammatory process
Refractory disease	Persistent inflammation despite standard therapy
Low-activity disease	Minimal ongoing inflammation [1]

Biomarkers and Disease Monitoring

• ANCA titers: May correlate with disease activity but clinical assessment remains primary
• Inflammatory markers: ESR, CRP reflect systemic inflammation
• Tissue damage markers: Reflect cumulative organ damage from active disease 2

Treatment Targets in the Pathophysiological Process

• Induction therapy: Targets active inflammation to achieve remission
• Maintenance therapy: Prevents reactivation of inflammatory pathways
• Refractory disease management: Addresses persistent inflammation through alternative pathways 1, 2

Understanding the pathophysiology of systemic vasculitis is crucial for appropriate classification, diagnosis, and treatment selection to minimize mortality and morbidity in these complex diseases.