ANCA - associated vasculitides (AAV)

Last edited 10/2020 and last reviewed 09/2022

• antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of uncommon diseases characterised by inflammatory cell infiltration and necrosis of blood vessel walls
  • severity of vasculitis is related to the size, site and number of vessels affected.

The association between ANCA and vasculitis was first described in 1982, in a short report describing the clinical course of eight patients diagnosed with a segmental
necrotising glomerulonephritis.

The discovery of perinuclear and cytoplasmic patterns on indirect immunofluorescence (P-ANCA and C-ANCA) and the main specificities myeloperoxidase and proteinase 3 were recognised in the 1980s.

The AAV comprise:

• granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis), over 90% are c-ANCA positive
• microscopic polyangiitis (MPA) and
• eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg-Strauss syndrome).

GPA, MPA and EGPA have respective annual incidence rates of 2.1–14.4, 2.4–10.1 and 0.5–3.7 per million in Europe, and the prevalence of AAV is estimated at to be 46–184 per million (2)

• are more common in those aged over 60 years and slightly more common in men
• 5-year survival rates for GPA, MPA and EGPA are estimated to be 74–91%, 45–76% and 60–97%, respectively.

Classification of systemic vasculitis remains confusing and controversial because the aetiology is usually unknown and there is considerable overlap in the clinical expression of the different vasculitic syndromes

• Classification generally reflects dominant vessel size and ANCA status
  
  
  • large vessel - giant cell arteritis, Takayasu
    
    
  • medium vessel - polyarteritis nodosa, Kawasaki
    
    
  • small vessel
    • ANCA associated - GPA (Wegener), MPA, EGPA (Churg-Strauss)
    • Immune complex - cryoglobulinaemic, IgA (HSP), HUV, Anti-IgM
      
      
  • variable vessel - Behcet, Cogan
    
    
  • key:
    • EGPA eosinophilic granulomatosis with polyangiitis; GBM glomerular basement membrane; GPA granulomatosis with polyangiitis; HSP Henoch-Schonlein purpura; HUV hypocomplementaemic urticarial vasculitis; IgA immunoglobulin A; MPA microscopic polyangiitis

The AAV form a separate group because they

• (a) often involve small and sometimes medium-sized arteries,
  
  
• (b) are most frequently associated with ANCA,
  
  
• (c) are associated with a high risk of glomerulonephritis, and
  
  
• (d) respond well to immunosuppression with cyclophosphamide
  
  
• aetiology of these diseases is probably unrelated to immune complex formation in contrast to pure small-vessel vasculitis such as IgA vasculitis (Henoch-Schonlein purpura) and cryoglobulinaemic vasculitis.

Management:

• induction treatment for most patients with AAV should be with cyclophosphamide or rituximab and glucocorticoids
• AAV should be considered to be a chronic disease needing longterm immunosuppressive therapy
• rituximab should be considered as an alternative induction agent for those at high risk of infertility and infection
• rituximab can be effective in refractory disease and may have a role where there are contraindications to the use of cyclophosphamide
• mortality remains high, and late death is due to cardiovascular disease, infection (secondary to treatment) and malignancy
• molecules other than anti- TNF agents and rituximab, such as abatacept, mepolizumab (an anti-IL5 antibody) and alemtuzumab (a humanised monoclonal
  anti-CD52 antibody) have been used in refractory cases of AAV (3)
• a systematic review "...found moderate-certainty evidence that in patients with relapsing or refractory EGPA, mepolizumab compared to placebo probably
  decreases disease relapse and low-certainty evidence that mepolizumab may increase the probability of accruing at least 24 weeks of
  disease remission..."

Prognosis

• patients with AAV (ANCA associated vasculitis) are at risk of complications, both from their disease and its treatment
• mortality in the first year is mainly due to active vasculitis or infection, late mortality is due to infection, cardiovascular disease and malignancy; 5-year survival is around 75%
• morbidity accumulates with time because of the consequences of active disease and therapies
• around one-third of patients have five or more items of damage at a mean of 7 years post-diagnosis.

Reference:

• 1) ARC Autumn 2012. Topical Reviews - ANCA-associated vasculitis; 1:1-12.
• 2) Yates A, Watts R. ANCA-associated vasculitis. Clinical Medicine 2017 Vol 17, No 1: 60–4
• 3) Bala MM et al. Anti-cytokine targeted therapies for ANCA-associated vasculitis. Cochrane Database of Systematic Reviews 2020, Issue 9. Art. No.: CD008333.
  DOI: 10.1002/14651858.CD008333.pub2.