What causes vasculitis?

Causes of Vasculitis

Vasculitis is primarily caused by immune-mediated inflammation of blood vessel walls, which can be triggered by infections, genetic factors, environmental exposures, autoimmune responses, or medications, resulting in vessel damage and subsequent tissue ischemia. 1

Primary Causes of Vasculitis

Immune-Mediated Mechanisms

• Autoimmune responses: The immune system mistakenly attacks blood vessel walls through various mechanisms:
  • ANCA (anti-neutrophil cytoplasmic antibodies) binding to and activating neutrophils, causing release of oxygen radicals, lytic enzymes, and inflammatory cytokines 1
  • Immune complex formation and deposition in vessel walls 2
  • Direct antibody adherence to endothelial cells 1

Genetic Factors

• Genetic susceptibility: Several genetic associations have been identified:
  • HLA-DP association with MPO-ANCA-positive EGPA (eosinophilic granulomatosis with polyangiitis) 1
  • Variants in genes involved in mucosal responses and eosinophil biology (GPA33, IL5) in ANCA-negative EGPA 1
  • Susceptibility genes including CTLA4, PTPN22, COL11A2, SERPINA1, and MHC class II gene clusters 1

Environmental Triggers

• Environmental exposures:
  • Silica exposure
  • Organic solvents
  • Farming-related exposures 1

Secondary Causes of Vasculitis

Infectious Agents

• Direct vascular damage by pathogens with tropism for endothelial cells:

  • Bacteria: Staphylococcus aureus (implicated in GPA relapses), Streptococcus, Salmonella, Treponema 1, 3
  • Viruses: Cytomegalovirus, Herpes Simplex Virus 1 and 2 3
  • Rickettsial organisms 3

• Indirect immune-mediated damage:

  • Mycobacterium tuberculosis
  • Mycobacterium leprae
  • Hepatitis B and C viruses
  • HIV 3

• Other infectious triggers:

  • Aspergillosis
  • Mycoplasma pneumoniae
  • Coxsackie-9 virus
  • California encephalitis virus
  • Mumps
  • Paramyxovirus
  • Borrelia burgdorferi (Lyme disease)
  • Cat-scratch disease
  • Brucellosis
  • Neurocystercercosis 1

Associated Conditions

• Autoimmune diseases:

  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sjögren's syndrome 4, 5

• Medications and drugs:

  • Various pharmaceutical agents
  • Cocaine and its adulterant levamisole 1

• Malignancies:

  • Various cancers can trigger vasculitic syndromes 2, 4

Pathophysiological Classification

Vasculitis can be classified based on the size of affected vessels:

1. Large vessel vasculitis:

   • Giant cell arteritis (Takayasu's disease)
   • Behçet's syndrome
   • Relapsing polychondritis 1

2. Medium vessel vasculitis:

   • Polyarteritis nodosa
   • Temporal arteritis
   • Kawasaki disease 1

3. Small vessel vasculitis:

   • ANCA-associated: GPA, EGPA, microscopic polyangiitis
   • Immune complex-mediated: Henoch-Schönlein purpura (IgA vasculitis) 1, 2

Clinical Pearls and Pitfalls

• Important caveat: Not all individuals with vasculitis show clinical or laboratory signs of inflammation, and classic angiographic findings (arterial beading, alternating constriction/dilation) are nonspecific 1

• Diagnostic challenge: Primary CNS vasculitis can present with normal inflammatory markers (ESR, CRP) despite active disease 1

• ANCA status matters: In EGPA, ANCA-positive patients (~40%) more commonly present with glomerulonephritis, peripheral neuropathy, and purpura, while ANCA-negative patients more frequently have cardiac involvement and gastroenteritis 1

• Mimics to consider: Always rule out thrombotic disorders (e.g., anti-phospholipid antibody syndrome) that can present as pseudovasculitis 2

• Staphylococcus aureus connection: S. aureus colonization is found more frequently in GPA patients compared to controls (72% vs 25%) and has been implicated in disease relapses 1

Understanding these diverse causes helps guide appropriate diagnostic workup and treatment strategies for patients with suspected vasculitis, ultimately improving morbidity, mortality, and quality of life outcomes.