c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis.

Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.

Co-trimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement.

BACKGROUND: Bacterial and viral respiratory tract infections may trigger relapses in patients with PR3-positive vasculitis. Data have suggested that treatment with co-trimoxazole may be beneficial, because this antibiotic could act by eliminating the offending microbe and thereby stopping the initiating stimulus. GOAL AND METHODS: Prospective, randomized, placebo-controlled study of the efficacy of co-trimoxazole given 960 mg thrice weekly for 18 months in preventing relapses in patients with Wegener's granulomatosis (WG) in remission, after treatment with cyclophosphamide and prednisolone was conducted. Relapses and infections were assessed with predefined criteria based on clinical, laboratory, serological, microbiological, and histopathological findings. Sixteen patients were assigned to receive co-trimoxazole and 15 to receive placebo. RESULTS: Seventy five percent of the patients in the co-trimoxazole group remained in remission at 18 months and 55% of those in the placebo group. A proportional hazard regression analysis identified a positive PR3-ANCA test at the start of treatment, chronic nasal crusting, and Staphylococus aureus infection as risk factors for relapse. Furthermore, the analysis identified treatment with co-trimoxazole as an independent factor associated with prolonged disease-free interval. CONCLUSION: Treatment with co-trimoxazole reduces the incidence of relapses in patients with Wegener's granulomatosis in remission.

Successful therapeutic use of rituximab in refractory Wegener's granulomatosis after renal transplantation.

Wegener's granulomatosis is a significant cause of end-stage renal disease requiring renal replacement therapy. Treatment of relapses is often difficult as immunosuppressive therapy can be limited by various factors including graft survival in renal transplantation. Rituximab is a novel therapeutic approach in those conditions. We present the case of a 42 year-old Caucasian woman who had been diagnosed with Wegener's granulomatosis 15 years ago. Predominantly affected organs were kidneys and pituitary gland. Five years later she reached end-stage renal failure and received a renal transplant soon after. She suffered from continuous relapses involving pulmonary hemorrhage and treatment became increasingly difficult. Symptoms resolved soon after single administration of low dose rituximab.

[Survival and relapses assessment in patients with Wegener's granulomatosis and predominant renal involvement]. / Ocena czasu prezycia i ryzyka nawrotów u pacjentów z ziarniniakowatoscia Wegenera z dominujqcym zajqciem nerek.

INTRODUCTION: Wegener's granulomatosis (WG) is a potentially fatal condition with remissions and high relapses rates. OBJECTIVES: Assessment of survival and relapses in a population based cohort of patients with WG with predominant renal involvement. PATIENTS AND METHODS: A prospective cohort study including 60 patients--median age of 42 years with different dynamics and clinical presentation. Patients were divided into 3 groups (group 1, group 2 and group 3 respectively, and subgroups: 3.1, 3.2, 3.3): group 1--WG patients without renal involvement, group 2--WG patients with abnormalities in urinary sediment, group 3.1--WG patients with chronic renal failure, group 3.2--WG patients with diffuse alveloar hemorrhage (DAH) and rapid progressive glomerulonephritis (RPGN), and group 3.3--WG patients with RPGN. The clinical analysis has been conducted using the disease extent index (DEl) only and Birmingham Vasculitis Activity Score-Wegener's granulomatosis (BVAS-WG) disease activity questionnaire. Logistic regression analysis and the Wilcoxon test were used. Survival time and death risk were assessed using the Kaplan-Meier estimator and Cox proportional hazard model. RESULTS: Eighty-eight percent of patients survived the first year follow-up since the diagnosis, while 84% of patients remained alive after the second year of observation. Life expectancy was 67.1 +/- 4.4 months. During the first year of observation 9.8% of patients died, after 2 years death hazard amounted to 3.7% per year, and after 4 years 2.6% per year (p < 0.05). Death risk was 1.3-fold higher in group 2 and 3.3-fold higher in group 3 compared to group 1 (p > 0.05). Mortality in patients from group 3.1 was 6-fold lower than in patients from group 3.2 (p < 0.03) and in group 3.3 was more than 4-fold lower than in patients from group 3.2 (p < 0.04). Relapse risk after first the year of follow-up was 20% per year and minimally changed after 3 years of observation, then decreased to 6% after 5 years. Relapse hazard ratio in group 2 was significantly lower in comparison with group 1 (HR1/3.6, p < 0.04). CONCLUSIONS: We found significant differences in survival and relapses in various subpopulationsof WG patients.

Prolonged treatment with low-dose intravenous pulse cyclophosphamide may reduce rate of relapse in ANCA-associated vasculitis.

BACKGROUND: Cyclophosphamide has transformed the outcome of ANCA-associated vasculitis, but it is highly toxic. Recent studies have suggested that pulsed intravenous cyclophosphamide (pCyc) is an effective alternative with less complications, but may lead to an increased rate of relapse. However, these studies used relatively short courses of treatment with cyclophosphamide. In this study we used a prolonged course of low-dose intravenous cyclophosphamide for 18-24 months for ANCA-associated vasculitis, evaluated the effectiveness of pCyc and analysed the outcome of a prolonged treatment on the rate of relapse. METHODS: A retrospective analysis of all the patients treated with pCyc from 1995 to 2002 was performed. RESULTS: Thirty-seven patients were followed for an average of 38 months. Thirty-four of 37 patients (91.9%) achieved complete remission at 3 months. Eight (21%) episodes of relapse occurred in 7 patients. The cyclophosphamide was well tolerated with a low rate of infections (18.9%) and 1 death (2.7%) due to sepsis whilst on cyclophosphamide. CONCLUSION: In this study, pCyc was effective in achieving rapid remission and had a low complication rate. If prolonged, this treatment may reduce the rate of relapse.

Control of a relapse and induction of long-term remission of Wegener's granulomatosis by cyclosporine.

We report a case of severe Wegener's granulomatosis that caused end-stage renal failure and recurrent flares of sinusitis and pulmonary manifestations. To avoid the cumulative toxicity of iterative treatments with cyclophosphamide pulses and glucocorticoids, treatment with cyclosporine as a single agent was instituted in the early phase of the third relapse, before any pulmonary involvement. Cyclosporine enabled rapid control of the disease and induced a complete remission of more than 30 months.

Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group.

BACKGROUND: Respiratory tract infections may trigger relapses in patients with Wegener's granulomatosis in remission. Uncontrolled data have suggested that treatment with trimethoprim-sulfamethoxazole (co-trimoxazole) may be beneficial. METHODS: We conducted a prospective, randomized, placebo-controlled study of the efficacy of co-trimoxazole (800 mg of sulfamethoxazole and 160 mg of trimethoprim) given twice daily for 24 months in preventing relapses in patients with Wegener's granulomatosis in remission during or after treatment with cyclophosphamide and prednisolone. Relapses and infections were assessed with predefined criteria based on clinical, laboratory, and histopathological findings. Patients were evaluated at least once every three months for signs of disease activity, compliance with the treatment regimen, side effects of the therapy, and evidence of infections. Titers of serum antineutrophil cytoplasmic antibodies were measured serially. RESULTS: Forty-one patients were assigned to receive co-trimoxazole, and 40 to receive placebo. In 8 of the 41 patients in the co-trimoxazole group (20 percent), the drug had to be stopped because of side effects. According to life-table analysis, 82 percent of the patients remained in remission at 24 months, as compared with 60 percent of the patients in the placebo group (relative risk of relapse, 0.40; 95 percent confidence interval, 0.17 to 0.98). There were fewer respiratory tract infections (P = 0.005) and non-respiratory tract infections (P = 0.05) in the co-trimoxazole group than in the placebo group. There were no significant differences in antineutrophil cytoplasmic antibody titers at any time. Proportional-hazards regression analysis identified treatment with co-trimoxazole as an independent factor associated with prolonged disease-free survival and a positive antineutrophil cytoplasmic antibody test at the start of treatment as a risk factor for relapse. CONCLUSIONS: Treatment with co-trimoxazole reduces the incidence of relapses in patients with Wegener's granulomatosis in remission.

Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre.

58 patients with biopsy-proven Wegener's granulomatosis (WG) were prospectively screened for clinical evidence of the disease 3-monthly, with antineutrophil cytoplasmic antibody (ANCA) measurements every month. Over 24 months, ANCA rose in 20 patients, 9 of whom were randomly assigned to receive combined 9 and 3 month courses of cyclophosphamide and prednisolone, respectively, at the time of ANCA rise; and 11 patients who were untreated except if there was a clinical relapse. 6 of 11 untreated patients relapsed within 3 months of ANCA rise. 3 of the remaining 5 patients relapsed after 3 months. There were no early or late relapses in patients randomised to treatment. Patients receiving no treatment at the time of ANCA rise took more cyclophosphamide and prednisolone than patients who were treated. Side-effects did not significantly differ between the two groups.