ANCA-Associated Vasculitis

Wegener's granulomatosis and microscopic polyangitis vasculitides are associated with anti-neutrophil cytoplasmic antibodies (ANCA). These auto-antibodies lead to the activation and increased adhesiveness of neutrophils to endothelial cells. These accumulating adhering neutrophils initiate an inflammatory cascade in the small blood vessels by secreting proinflammatory cytokines and chemoattractants. Activation of the complement pathway occurs with production of complement 5a (C5a), one of the most potent pro-inflammatory mediators of the complement system. C5a, through binding to its receptor C5aR, induces expression of adhesion molecules and chemotactic migration of neutrophils, eosinophils, basophils and monocytes. It also mediates inflammatory reactions by causing smooth muscle contraction, increasing vascular permeability, inducing basophil and mast cell degranulation and inducing release of lysosomal proteases and oxidative free radicals.

If left untreated, ANCA-associated vasculitides (AAV) may lead to renal and pulmonary failure and are often fatal. AAV is currently treated with intravenous pulses of cyclophosphamide and high-dose systemic corticosteroids. Little advance in the treatment of these diseases has been made since the 1970's when these treatments were first introduced. Cyclophosphamide is a toxic alkylating agent. Systemic corticosteroid use is associated with increased risk of infection, osteoporosis, etc. Azathioprine, methotrexate, or mycophenolate mofetil maintenance therapy are also used, but there is clearly still a substantial unmet medical need in treatment of patients with AAV.

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