REVIEW www.nature.com/clinicalpractice/rheum Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides Cees GM Kallenberg*, Peter Heeringa and Coen A Stegeman INTRODUCTION The idiopathic, or primary, vasculitides (Box 1) comprise a spectrum of diseases characterized by inflammation of blood vessels. Classification, according to a committee of the American College of Rheumatology, 1 is based on the size of vessels predominantly involved, histopathologic findings, and clinical symptoms. Definitions for the various vasculitides have been proposed by the Chapel Hill consensus conference. 2 The vasculitides differ not only in clinical and patho- logic presentation, but also in their presumed pathogenesis. The large-vessel vasculitides are supposedly caused by cell-mediated immune reactions to poorly defined (auto) antigens. 3 Immune complexes are involved in some of the small-vessel vasculitides. In Henoch–Schönlein purpura, IgA-containing immune deposits are observed in the target organs—in particular, the skin and kidneys. Cryoglobulinemic vascu- litis, frequently associated with hepatitis C virus infection, is caused by deposition of type II cryoglobulins within small vessels, particularly in postcapillary venules in the skin. Biopsy samples from purpuric skin lesions in cuta- neous leukocytoclastic angiitis frequently show leukocytoclastic vasculitis and deposition of IgM, IgG, and complement in dermal vessels. Vasculitic lesions that are caused by Wegener’s granulomatosis, microscopic polyangiitis, and Churg–Strauss syndrome, however, frequently lack immune deposits (particularly in the kidneys) 4 although deposits have been detected by electron microscopy in over half of renal biopsy samples. 5 These vasculitides are collectively designated as pauci-immune necrotizing vasculitides. The pauci-immune vasculitides are character- ized by the presence of autoantibodies against neutrophil cytoplasmic constituents, known as antineutrophil cytoplasmic autoantibodies (ANCA); 6 neutrophils are the main effector cells in the lesions of patients with Wegener’s granulo- matosis or microscopic polyangiitis. This article discusses new insights into the pathogenesis Wegener’s granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener’s granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener’s granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener’s granulomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress. KEYWORDS ANCA-associated vasculitis, MPO-ANCA, pathogenesis, PR3-ANCA, Wegener’s granulomatosis CGM Kallenberg is a Full Professor in the Department of Rheumatology and Clinical Immunology, P Heeringa is an Associate Professor in the Department of Pathology and Laboratory Medicine, and CA Stegeman is an Associate Professor in the Department of Nephrology, all at the University of Groningen, Groningen, The Netherlands. Correspondence *Department of Rheumatology and Clinical Immunology, University Medical Center Groningen and University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands c.g.m.kallenberg@int.umcg.nl Received 17 March 2006 Accepted 16 October 2006 www.nature.com/clinicalpractice doi:10.1038/ncprheum0355 REVIEW CRITERIA PubMed and MEDLINE were searched from January 1983 (the first description of ANCA) until February 2006 for papers published in English-language journals. The following keywords were used: “ANCA”, “proteinase 3/PR3-ANCA”, “myeloperoxidase/MPO-ANCA”, “ANCA-associated vasculitis”, “Wegener’s granulomatosis”, “microscopic polyangiitis”, “Churg–Strauss syndrome”, “pathogenesis”, and “treatment”. SUMMARY DECEMBER 2006 VOL 2 NO 12 NATURE CLINICAL PRACTICE RHEUMATOLOGY 661 Nature Publishing Group ©2006