History of antineutrophil cytoplasmic autoantibodies : Milestones in rheumatology.

Abstract

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are autoimmune inflammatory small-vessel disorders with potentially life-threatening organ manifestations. Recent disease definitions and classification criteria allow distinction between granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and non-granulomatous microscopic polyangiitis (MPA). The discovery of ANCA-autoantibodies directed against proteolytic enzymes of neutrophil granules-has enabled earlier diagnosis of AAV and paved the way to stage-adapted treatments. ANCA testing initially relied on different immunofluorescence patterns, i.e., cytoplasmic ANCA (C-ANCA) vs. perinuclear ANCA (P-ANCA), in ethanol-fixed neutrophils. This is nowadays outperformed by well-standardized immunoassays against the ANCA target antigens proteinase3 (PR3) and myeloperoxidase (MPO) for the diagnosis of small-vessel vasculitides. The discovery of ANCA has contributed substantially to unravelling the pathogenesis of AAV, which comprises neutrophil degranulation, NETosis with concurrently amplified ANCA antigen presentation, and intra- and transmural vascular inflammation involving the alternative complement system in susceptible individuals. There is agenetic disposition concerning certain HLA alleles and polymorphisms of the proteinase3 gene. Furthermore, epigenetic modifications impact on disease activity and relapse. During follow-up, the ANCA titer is not areliable mirror of disease activity; however, PR3-ANCA positivity is associated with agreater likelihood of relapse and abetter treatment response to rituximab as compared to cyclophosphamide/azathioprine. Within the past 60years, the discovery of ANCA has revolutionized the ability to diagnose, understand, classify, and treat AAV in atargeted manner.