In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.

Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine Ͼ500 mol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine Ͼ500 mol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n ϭ 70) or 3000 mg of intravenous methylprednisolone (n ϭ 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P ϭ 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.

Anti-neutrophil cytoplasmic antibodies (ANCA) are widely used as diagnostic markers for Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and idiopathic rapidly progressive glomerulonephritis (iRPGN). The objective of this study was to evaluate the diagnostic value of ANCA measurement by the indirect immunofluorescence (IIF) test, and by anti-PR3 and anti-MPO ELISA performed in different locations, in patients with idiopathic small vessel vasculitis. Fourteen centers participated in a standardization study of ANCA assays, and entered a total number of 169 newly diagnosed and 189 historical patients with idiopathic systemic vasculitis or iRPGN. Patients were classified according to a pre-defined diagnostic classification system. Results were compared with those of 184 disease controls and 740 healthy controls. The IIF test was performed according to standard methodology; ELISAs had been standardized among the participants in a previous phase of the study. The sensitivities of assays in patients were as follows. The sensitivity in WG was: cANCA 64%, pANCA 21%, anti-PR3 66%, anti-MPO 24%. In MPA the sensitivity was: cANCA 23%, pANCA 58%, anti-PR3 26%, anti-MPO 58%. Sensitivity in iRPGN was: cANCA 36%, pANCA 45%, anti-PR3 50%, anti-MPO 64%. The specificity of assays (related to disease controls) was: cANCA 95%, pANCA 81%, anti-PR3 87%, anti-MPO 91%. When the results of the IIF test were combined with those of the ELISAs (cANCA/anti-PR3 positive, pANCA/anti-MPO positive), the diagnostic specificity increased to 99%. The sensitivity of the combination of cANCA + anti-PR3 or pANCA + anti-MPO for WG, MPA or iRPGN was 73%, 67% and 82%, respectively. From this study we conclude that the value of the IIF test for ANCA detection can be greatly increased by the addition of a well standardized antigen-specific ELISA. In a significant number of patients with idiopathic small vessel vasculitis, however, the ANCA test results (either in IIF or ELISA) are negative.

No abstract

This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients with ANCA-associated vasculitis and severe renal involvement (serum creatinine >500 mol/L). One hundred patients who were enrolled in an international, randomized, clinical trial to compare plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed prospectively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic and nine clinical parameters were determined as candidate predictors of renal outcome. The end points were renal function at the time of diagnosis (GFR 0 ) and 12 mo after diagnosis (GFR 12 ), dialysis at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of GFR 0 were age (r ‫؍‬ ؊0.40, P ‫؍‬ 0.04), arteriosclerosis (r ‫؍‬ ؊0.53, P ‫؍‬ 0.01), segmental crescents (r ‫؍‬ 0.35, P ‫؍‬ 0.07), and eosinophilic infiltrate (r ‫؍‬ ؊0.41, P ‫؍‬ 0.04). Prognostic indicators for GFR 12 were age (r ‫؍‬ ؊0.32, P ‫؍‬ 0.01), normal glomeruli (r ‫؍‬ 0.24, P ‫؍‬ 0.04), tubular atrophy (r ‫؍‬ ؊0.28, P ‫؍‬ 0.02), intraepithelial infiltrate (r ‫؍‬ ؊0.26, P ‫؍‬ 0.03), and GFR 0 (r ‫؍‬ 0.29, P ‫؍‬ 0.01). Fibrous crescents (r ‫؍‬ 0.22, P ‫؍‬ 0.03) were predictive of dialysis at entry. Normal glomeruli (r ‫؍‬ ؊0.30, P ‫؍‬ 0.01) and treatment arm (r ‫؍‬ ؊0.28, P ‫؍‬ 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both chronic and acute tubulointerstitial lesions predicted GFR 12 in severe ANCA-associated glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after 12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who were dialysis dependent at presentation were analyzed separately (r ‫؍‬ ؊0.36, P ‫؍‬ 0.01). Normal glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo, indicating that the unaffected part of the kidney is vital in determining renal outcome.

It is important that physicians are aware of this clinical association and the presence of ILD should be considered in all patients with ANCA-associated vasculitis, especially those with MPO-ANCA. The possibility that patients with ILD may subsequently develop features of systemic vasculitis should also be remembered.

SummaryBackgroundMembranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of patients with declining renal function is not available. We aimed to assess whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function.MethodsThis randomised controlled trial was undertaken in 37 renal units across the UK. We recruited patients (18–75 years) with biopsy-proven idiopathic membranous nephropathy, a plasma creatinine concentration of less than 300 μmol/L, and at least a 20% decline in excretory renal function measured in the 2 years before study entry, based on at least three measurements over a period of 3 months or longer. Patients were randomly assigned (1:1:1) by a random number table to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. The primary outcome was a further 20% decline in renal function from baseline, analysed by intention to treat. The trial is registered as an International Standard Randomised Controlled Trial, number 99959692.FindingsWe randomly assigned 108 patients, 33 of whom received prednisolone and chlorambucil, 37 ciclosporin, and 38 supportive therapy alone. Two patients (one who received ciclosporin and one who received supportive therapy) were ineligible, so were not included in the intention-to-treat analysis, and 45 patients deviated from protocol before study end, mostly as a result of minor dose adjustments. Follow up was until primary endpoint or for minimum of 3 years if primary endpoint was not reached. Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 [58%] of 33 patients reached endpoint vs 31 [84%] of 37, hazard ratio [HR] 0·44 [95% CI 0·24–0·78]; p=0·0042); risk did not differ between the ciclosporin (29 [81%] of 36) and supportive treatment only groups (HR 1·17 [0·70–1·95]; p=0·54), but did differ significantly across all three groups (p=0·003). Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care only group (56 events vs 24 events; p=0·048).InterpretationFor the subset of patients with idiopathic membranous nephropathy and deteriorating excretory renal function, 6 months' therapy with prednisolone and chlorambucil is the treatment approach best supported by our evidence. Ciclosporin should be avoided in this subset.FundingMedical Research Council, Novartis, Renal Association, Kidney Research UK.

Anti-neutrophil cytoplasmic antibodies (ANCA) have been identified as a diagnostic marker in primary systemic vasculitis, and immunofluorescence assays identify two patterns of binding: cytoplasmic (C-ANCA and perinuclear (P-ANCA). We have examined retrospectively the use of such assays in long-term monitoring of disease activity, in order to determine the relationship between presence of ANCA and relapse, and to assess their suitability as a guide to therapy. Seventy patients were studied over a period of 50 months, using clinical and laboratory criteria for the diagnosis of relapse and the internationally standardised immunofluorescence assay for detection of ANCA. In 19 patients C- or P-ANCA were detectable throughout the study period; six of these (with C-ANCA) relapsed. In 18 patients ANCA were undetectable during long-term follow-up; none of these patients relapsed. In 33 patients C- or P-ANCA were intermittently present; nine of these relapsed and all had C-ANCA detectable at the time of relapse. In six of the nine cases, relapse was accompanied or closely preceded by reappearance of C-ANCA. We conclude that continuing presence and reappearance of ANCA may identify patients who are at risk of relapse and who are most likely to benefit from long-term immunosuppressive therapy.