European therapeutic trials in ANCA-associated systemic vasculitis: disease scoring, consensus regimens and proposed clinical trials EUROPEAN COMMUNITY STUDY GROUP ON CLINICAL TRIALS IN SYSTEMIC VASCULITIS ECSYSVASTRIAL (BMHl-Cr93-1078)

Abstract

In previous phases of this project, proteinase 3 (PR3) and myeloperoxidase (MPO), the main antigenic target molecules of antineutrophil cytopiasmic antibodies, were isolated and applied in standardized ELISAs.In this study, standardized ELISAs with three PR3 preparations (from Copenhagen (CO), Raisdorf (RS) and Leiden (LF)) and one MPO preparation (from Copenhagen), were evaluated in a large retro-and prospective clitiical study.New patients (n=174) with primary systemic vasculitis (Wegener's granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive glomerulonephritis, classical PAN and Churg-Strauss Syndrome) were included. Retrospectively, another 190 patients were evaluated. Furthermore control sera were obtained from patients with other forms of vasculitis, glomerulonephritis or granulomatous diseases (disease controls, n = 184) and healthy donors (healthy controls, n = 728). All patients were categorized by a system based on clinical and histoiogical data. Patients were followed up for at least 1 year after diagnosis in order to evaluate a possible correlation between ANCA levels and disease activity.The sensitivity of the anti-PR3 assays for histologically proven WG was between 59% and 69% in new patients, with a sensitivity of 22% for the anti-MPO assay. Similar figures were found for patients with clinically suspected WG. This was comparable with the results of the IIF test. In MPA and IRPGN a larger percentage of patients had anti-MPO antibodies than in WG. Only a few patients with PAN and CSS were investigated, and most of these were negative in the ELISAs.The specificity ofthe assays for disease controls was 89-91% for the anti-PR3 assays and 95% for the anti-MPO assay. In the healthy controls the specificity was 98-99%. The specificity of the IIF test was 97% for a cANCA pattern and 81 % for a pANCA pattern in disease controls. The combination of cANCA with anti-PR3 and pANCA with anti-MPO both had a specificity of 99%.Further details will be presented during the meeting, in addition to the results of a follow-up study with correlation ofdisease activity and ANCA level. From this study we can conclude that ELISAs using purified PR3 or MPO are not more sensitive than the IIF test. However, the anti-MPO assay is more specific for systemic vascuitis as compared to disease controls with related diseases. Furthermore, the combination of the IIF test with antigen-specific ELISAs is very specific for the diagnosis Wegetier's granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive gtomerulonephritis.

Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody–associated vasculitis

“…Of the patients in whom remission was achieved during the treatment period, 32 of 46 in the MTX group (69.5%) had a relapse, as compared to 20 of 43 in the CYC group (46.5%). Time to relapse from remission was longer in the CYC group than in the MTX group (P ϭ 0.023), as shown in Figure 4 (median 13 months [range [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] in the MTX group, and 15 months [range [4][5][6][7][8][9][10][11][12][13][14][15][16][17] in the CYC group) (hazard ratio for MTX versus CYC 1.85 [95% CI 1.06-3.25]). In the MTX group there were 14 major and 18 minor relapses; of the latter, 3 were followed by major relapses.…”

“…After informed consent was obtained, patients were randomized at entry to receive either the "consensus standard regimen" of CYC plus prednisolone for 12 months or the "best alternative regimen" consisting of MTX plus prednisolone (5). All drugs were tapered and withdrawn by 12 months, while followup continued to 18 months from entry.…”

“…At the time this trial was designed, the predominantly used treatment for induction of remission in AASV consisted of daily oral cyclophosphamide (CYC) plus corticosteroids (5). This empirical treatment leads to remission in ϳ90% of patients (6)(7)(8).…”

“…However, it is associated with considerable long-term morbidity and even mortality (7,8). The aims of the European Vasculitis Study Group (EUVAS) are to standardize treatment, to subgroup patients at presentation according to disease stage, and to test alternative, safer treatments via randomized controlled trials (5,9). Single-center experience (10) has suggested that WG with normal or only moderately impaired renal function (creatinine Ͻ150 moles/liter) and without life-threatening disease manifestations ("early systemic disease") can be successfully treated with weekly methotrexate (MTX).…”

Treatment of polyarteritis nodosa and microscopic polyangiitis

“…Other criteria, such as the Birmingham Vasculitis Activity Score (14), can also be used to determine the intensity of treatment and are being tested in prospective trials proposed by the European Community Systemic Vasculitis Trial (EUVAS) group (15).…”