Treatment of ANCA – Associated Vasculitis

Abstract

ANCA – associated vasculitis (AAV) encompass Wegener granulomatosus (WG), Churg Strauss syndrome (CSS) and Microscopic Polyangiitis (MPA). Granuloma formation characterizes both WG and CSS, while necrotising inflammation of middle to small arteries, pauci-immune glomerulonephritis and production of ANCA typify all three of them. Common clinical and laboratory features point towards common pathogenetic mechanisms and thus therapeutic approach have evolved over the years from treatment of individual members of the group to unified treatment strategies. It is the presentation of the disease rather than a particular AAV that guides treatment decisions. Clinical subtypes of AAV according to the extend and the severity of the disease, have been proposed by the European Vasculitis Study (EUVAS) Group (Jayne & Rasmussen 1997) (Table 1): AAV can be presented as localized, early systemic, generalized, severe or refractory disease. This classification currently serves as the basis for the assignment of different treatment regimens. Forty years ago AAV was a rapidly fatal disease. One-year survival was estimated to be less than 20%, mainly due to pulmonary and/or renal failure and steroids-related infection (Hoffman et al. 1992). The introduction of oral cyclophosphamide (CyP) during the ‘70s radically changed the prognosis of AAV. Recent data from the EUVAS Group trials show that survival at 1-year is currently almost 90%. CyP in combination with prednisone remain today the cornerstone of treatment of AAV. However, several issues have emerged: a) there are still patients that either die early in the course of the disease or display progressive disease refractory to conventional treatment, b) relapses are frequent, affecting approximately 50% of patients with AAV during extended follow-up, c) the burden of drugrelated toxicity is high, as serious adverse events affect approximately 40% of the patients. In addition to glucocorticoids toxicity, CyP can acutely lead to cytopenias, hemorrhagic cystitis and infections along with late complications including gonadal insufficiency and infertility, myelodysplasias and bladder cancer. In an effort to minimize CyP toxicity as well as to find regimens that could replace CyP in cases of non-responding, refractory, or relapsing disease, several treatment options have been considered. During the last 20 years and despite the rarity of AAV, several multicenter, multi-national randomized control trials (RCTs) were conducted largely due to the combined efforts of EUVAS Group and the VCRC (Vasculitis Clinical Research Consortium), which have altered our treatment practice as it will be discussed below. Treatment of AAV consists of an initial phase aiming at rapid induction of remission and a second phase where maintenance of remission is sought.