A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

NTINEUTROPHIL CYTOPLASmic antibodies (ANCAs) are frequently found in patients with Wegener granulomatosis and microscopic polyangiitis. Together, Wegener granulomatosis and microscopic polyangiitis are considered ANCA-associated vasculitis (AAV) due to their similarity in clinical and histological features, prognosis, and treatment. Standard therapy for patients with AAV consists of induction of remission with cyclophosphamide and glucocorticoids, followed by remission maintenance with azathioprine or methotrexate and a tapering course of glucocorticoids. 1,2 Relapses of AAV occur in 50% of patients within 5 years of diagnosis, and treatment toxicity is common. 3,4 Safe and effective therapies to maintain remission of AAV are a priority. For editorial comment see p 2413.

Abstract. Tumor necrosis factor ␣ (TNF␣) plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. TNF␣ blockade is a potential therapy for these disorders. Methods: An open-label, multi-center, prospective clinical trial in two subgroups was performed. Study I examined acute disease, either first presentation or relapse (Birmingham Vasculitis Activity Score [BVAS] Ն 10; n ϭ 16); study II examined persistent disease (BVAS Ն 4; n ϭ 16). Patients received infliximab (5 mg/kg) at 0, 2, 6, and 10 wk. Concomitant therapy in study I included prednisolone and cyclophosphamide. Study II patients continued their existing treatment regimens, with prednisolone tapered according to clinical status. Results: Mean age was 52.4 yr, 53% of the patients were female, and follow-up was 16.8 mo. Twenty-eight patients (88%) achieved remission (14 per study group). BVAS decreased from 12.3 (confidence interval [CI] ϭ 10.5 to 14.0) at entry to 0.3 (CI ϭ 0.2 to 0.9) at wk 14 (P Ͻ 0.001). C-reactive protein (mg/L) decreased from 29.4 (CI ϭ 16.8 to 42.0) at entry to 7.0 (CI ϭ 3.3 to 10.9) by wk 14 (P ϭ 0.001). Mean prednisolone dose (mg/d) in study II decreased from 23.8 (CI ϭ 15.0 to 32.5) at entry to 8.8 (CI ϭ 5.9 to 11.7) at wk 14 (P ϭ 0.002). There were two deaths and seven serious infections. Relapse occurred in five patients (three in study II) after a mean of 27 wk. Conclusion: TNF␣ blockade with infliximab was effective at inducing remission in 88% of patients with antibody-associated systemic vasculitis and permitted reduction in steroid doses. Severe infections were seen in 21% of patients, and despite continued infliximab, 20% of initial responders experienced disease flares. Infliximab is a promising new therapy for vasculitis both as a component of initial therapy and in the management of refractory disease. These results need confirmation in larger randomized trials.The primary systemic necrotizing vasculitides are a group of life-threatening diseases that, untreated, have an 85% 2-yr mortality. The best defined and most studied subgroup of these diseases are the anti-neutrophil cytoplasmic antibody (ANCA)-related small vessel vasculitides (AASV), which are characterized by a pauci-immune microscopic vasculitis and focal, necrotizing glomerulonephritis (1).The introduction of steroids and cyclophosphamide results in disease remission in 80% of patients by 3 mo and in 95% by 6 mo (15). However, there is considerable morbidity related to current regimens, on which at least 25% of patients experience severe drug-related adverse effects. Furthermore, 50% of patients experience disease relapse, resulting in accumulating damage from disease scars and treatment (2,3,16). The addition of plasma exchange or pulsed methylprednisolone improves rates of renal recovery but increases the risk of side effects. There is a clear need to achieve more effective remission induction and to reduce therapy-related toxicity in AASV.Evidence suggests that tumor necrosis factor ␣ (TNF␣) plays...

Glomerular-derived proteins may activate tubular cells to express the macrophage-directed chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Macrophages at interstitial sites have a central role in directing renal scarring. We have prospectively assessed the relationship between albuminuria, urinary MCP-1/CCL2, interstitial macrophage infiltration, in situ damage, and clinical outcomes in a large group of patients with chronic kidney disease. We studied 215 patients and quantified albumin-creatinine ratio (ACR), urinary MCP-1/CCL2, interstitial macrophage numbers, and in situ damage. ACR correlated with urinary MCP-1/CCL2 (correlation 0.499; P<0.001), interstitial macrophage numbers (correlation 0.481; P<0.001), and index of chronic damage (correlation 0.363; P<0.001). Macrophage numbers closely correlated with in situ damage (correlation 0.755; P<0.001). By multivariate analysis ACR, urinary MCP-1/CCL2, and interstitial macrophage numbers were interdependent. By Kaplan-Meier survival analysis albuminuria, urinary MCP-1/CCL2, interstitial macrophages, and chronic damage predict the outcome. ACR, macrophage numbers, chronic damage, and creatinine independently predicted renal survival. The association of ACR with other variables was strongest in patients with less advanced disease states. There is a close association between albuminuria, urinary MCP-1/CCL2, and interstitial macrophage infiltration with in situ damage and clinical outcomes. These findings support the hypothesis that albuminuria triggers tubular MCP-1/CCL2 expression with subsequent macrophage infiltration. These processes may represent the dominant pathway for the progression of renal injury before the establishment of advanced renal scarring.