Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a heterogeneous group of rare diseases characterised by necrotising inflammation of the small blood vessels and the presence of ANCA with specificity for proteinase-3 or myeloperoxidase. Genetic susceptibility along with malignancy, drug exposure, and environmental exposures to infectious agents and silica are involved in disease progression. To date, growing evidence has revealed that ANCA specificity defines homogeneous groups of patients more effectively than clinical diagnosis, since proteinase-3 ANCA and myeloperoxidase-ANCA are linked with different genetic backgrounds and epidemiologies. This review presents current and updated knowledge on the central aetiopathogenic role of genetic associations and environmental exposures in AAV; discusses the main mechanisms of ANCA immunogenesis; and highlights the value of ANCA specificity for future classification criteria.

Renal involvement with rapidly progressive glomerulonephritis is a common manifestation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides characterised by end-stage renal disease and high mortality rates in untreated and late referral patients. Long-term renal survival has improved dramatically since the addition of cyclophosphamide and, more recently, rituximab in association with corticosteroids to remission induction therapeutic regimens. However, renal prognosis remains unfavourable for many patients and mortality is still significantly higher than in the general population. In this review, the open challenges to be addressed to optimise remission induction therapy, especially in patients with advanced kidney failure, are analysed. This concerns the first-line therapy (cyclophosphamide or rituximab) based on different parameters (estimated glomerular filtration rate at baseline, new or relapsed disease, ANCA specificity, tissue injury, and safety) and the role of plasma exchange. Furthermore, the paper discusses future perspectives on induction remission therapy by reporting recent advances in new targeted therapies, with particular reference to avacopan, an orally administered selective C5a receptor inhibitor.