Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. Wegener's granulomatosis, microscopic polyangiitis, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis (NCGN) are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against either proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO). This has led some investigators to prefer combining these diseases under the common heading of ANCA-associated vasculitides. However, it is increasingly recognized that there are characteristic differences between patients with anti-PR3 and those with anti-MPO-associated vasculitis. This review focuses on the clinical, histopathologic, and possibly pathophysiologic differences between anti-PR3- and anti-MPO-associated vasculitis. Although there is considerable overlap, the anti-PR3- and anti-MPO-associated vasculitides are each characterized by particular clinical and histopathological findings. Extrarenal organ manifestations and respiratory tract granulomas occur more frequently in patients with anti-PR3 than in those with anti-MPO. Anti-PR3-positive patients with NCGN generally have a more dramatic deterioration of their renal function compared with anti-MPO-positive patients. The term "ANCA-associated vasculitis" is considered as a useful concept in the presence of systemic vasculitis. Likewise, in the presence of vasculitis, the terms "anti-PR3-associated vasculitis" and "anti-MPO-associated vasculitis" are useful concepts.

Results.

SUMMARYT cell-mediated immunity is thought to play an important role in the pathogenesis of WG. In previous studies a minority of WG patients as well as some healthy controls showed in vitro proliferation of their peripheral blood mononuclear cells (PBMC) to PR3, the main autoantigen in WG. The relevant peptides responsible for this in vitro proliferation have not been identified. In order to define immunogenic peptides, PBMC of 13 WG patients in remission and 10 healthy controls were tested for proliferation to linear peptides of PR3 and to whole PR3. Fifty overlapping peptides spanning the whole PR3 sequence were synthesized. Peptides were tested in pools of five peptides and as single peptide. PBMC of two WG patients and one healthy control proliferated to whole PR3 and to peptide pools. In addition, 10 WG patients and eight healthy controls that did not proliferate to whole PR3 did proliferate to pools of PR3 peptides. Although more WG patients tended to react to particular peptide pools, no significant difference was seen between lymphocyte proliferation to PR3 peptides of WG patients and that of healthy controls. The pools of peptides recognized were mainly located at the N-and C-terminus of PR3. No correlation was observed between HLA type and proliferation on particular peptide pools. No proliferation of PBMC was observed to single peptides. In conclusion, T cells of WG patients proliferate in vitro more frequently to PR3 peptides than to the whole PR3 protein. Peptides derived from the signal sequence, the propeptide or peptides located at the C-terminus of PR3 induce highest levels of proliferation. No specific PR3 sequence could be identified that was preferentially recognized by PBMC of WG patients compared with controls.

Patients with anti-myeloperoxidase (MPO)-associated necrotizing crescentic glomerulonephritis (NCGN) may develop chronic renal failure (CRF) leading to end-stage renal disease despite an initially favorable response to treatment. The aim of this study was to determine the prognostic value of clinical, laboratory, and histopathologic features at the time of presentation and during follow-up for the development of CRF in 21 consecutive anti-MPO-positive patients with NCGN. Renal function did not recover in two of five patients who were dialysis-dependent at presentation. The remaining 19 patients all went into remission and were off dialysis at 3 mo after diagnosis. At long-term follow-up, nine of these patients had stable renal function and did not relapse (group A), five patients developed CRF without signs of relapse (group B), and five patients relapsed (group C). At diagnosis, serum creatinine, C-reactive protein, and anti-MPO levels did not differ between groups A, B, and C. Microscopic erythrocyturia resolved in all patients within 4 mo of treatment. BP at presentation and during follow-up did not differ between groups A, B, and C. Proteinuria at diagnosis and in the first 6 mo after diagnosis was higher in patients who developed CRF than in patients with a stable renal function. Anti-MPO levels at 3 mo had decreased compared with anti-MPO levels at diagnosis in groups A and C, whereas anti-MPO levels did not fall significantly in patients who developed CRF. The predictive value of a renal biopsy at diagnosis on long-term renal outcome was limited. In conclusion, a higher degree of proteinuria at diagnosis and during follow-up as well as persistently elevated anti-MPO levels after induction of remission are associated with the development of CRF and are predictive of poor renal outcome in anti-MPO-associated NCGN.

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