Antineutrophil cytoplasmic antibodies reacting with the pro form of proteinase 3 and disease activity in patients with Wegener's granulomatosis and microscopic polyangiitis

Objective. Antineutrophil cytoplasmic antibodies (ANCA) directed against pr oteinase 3 (PR3) are diagnostic markers for the small vessel vasculitides W egener's granulomatosis (WG) and microscopic polyangiitis (MPA). Correlatio n of disease activity with PR3 ANCA levels, as determined by standard metho ds, is not apparent in every patient. PR3 ANCA react with yet to be identif ied conformational epitopes. We have identified PR3 ANCA subsets that react differentially with mature recombinant PR3 (rPR3; lacking the N-terminal a ctivation dipeptide) and the pro form of this enzyme (pro-rPR3). The presen t study was performed to determine the association of these PR3 ANCA subset s with disease activity. Methods. Sera from 61 PR3 ANCA-positive patients with WG or MPA were assaye d by capture enzyme-linked immunosorbent assay using pro-rPR3 and rPR3 as t arget antigens, and were correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). Results. Median levels of PR3 ANCA reacting with pro-rPR3 were higher durin g active (n = 32) than during inactive (n = 29) disease (P = 0.016). Reacti vity with mature rPR3 was not significantly different (P = 0.71). Serial fo llowup in individual patients also indicated better correlation of PR3 ANCA reactivity with pro-rPR3 than with mature rPR3. Conclusion. PR3 ANCA subsets reactive with epitopes accessible on pro-PR3 c orrelate better with disease activity than do subsets reactive with epitope s accessible only on mature PR3. This observation may explain why ANCA leve ls determined with current standard methods are suboptimal for monitoring d isease activity. It raises new questions about the primary target of the PR 3 ANCA immune response in patients with small vessel vasculitis.