Pathogenesis and management of ANCA-associated vasculitis

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) represent a group of three heterogeneous syndromes: granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome). They share a primary necrotizing small vessel vasculitis with propensity to involve the kidneys and the respiratory tract. The majority of patients with these syndromes have ANCA detectable in the serum at the time of diagnosis. Two types of ANCA are of clinical significance: C-ANCA reacting with the neutrophil enzyme proteinase 3 (PR3-ANCA) occur in over 80 % of patients with GPA and P-ANCA reacting with myeloperoxidase (MPO-ANCA) occur in less than 10 % of patients with GPA but in the majority of patients with MPA. MPO-ANCA is also the predominant type of ANCA encountered in patients with EGPA, where PR3-ANCA is the exception. The pathogenesis is not fully understood, but there is mounting evidence for a genetic predisposition, environmental triggers including infections, and ANCA all playing significant roles in the development of the syndromes. The outcome of untreated AAV with renal involvement is usually fatal. Treatment with the combination of glucocorticosteroids and cyclophosphamide (CYC) has turned these syndromes into manageable chronically relapsing disorders. Not all patients respond satisfactorily to CYC, and even for those who do, the subsequent relapse rate is high. Up to half of the patients who achieve remission relapse within the first 3-5 years. The need for retreatment exposes patients to significant long-term toxicities of glucocorticoids and less toxic alternatives have been sought. Rituximab has recently emerged as an alternative for CYC and currently represents the only FDA-approved treatment for remission induction in patients with severe AAV. This chapter reviews recent advances in the pathogenesis and treatment of AAV.