BACKGROUND Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

Background The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is unknown. Methods In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months. Results A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide–azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. Conclusions In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

Objective. To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG).Methods. Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting ‫؍‬ 1 point) or major (e.g., alveolar hemorrhage ‫؍‬ 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG.Results. We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r ‫؍‬ 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (withincase) correlation coefficients in the 2 simulation exercises was r ‫؍‬ 0.93 for the BVAS/WG and r ‫؍‬ 0.88 for the PGA in the first and r ‫؍‬ 0.91 for the BVAS/WG and r ‫؍‬ 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r ‫؍‬ 0.73 (95% confidence interval 0.43-0.83).Conclusion. The BVAS/WG is a valid, diseasespecific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good interand intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.The investigation of new therapies for the treatment of systemic vasculitis and the organization of

The 1990 ACR classification criteria function poorly in the diagnosis of specific vasculitides.

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Objective. To analyze damage occurring in patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET) and to correlate that damage with disease activity, adverse events, and quality of life.Methods. The Vasculitis Damage Index (VDI) was applied to all 180 patients at trial entry and every 6 months throughout the trial. Items of damage were analyzed by presumed etiology (i.e., secondary to WG, to therapy, or both) and time of occurrence. Spearman's rank correlation coefficients were calculated between VDI scores and the Birmingham Vasculitis Activity Score for WG (BVAS/WG), frequency of flares, number of adverse events, and the patients' quality-of-life assessments.Results. The mean VDI score was 1.3 at the study enrollment and 1.8 at the end of the trial. This increase was due to damage that occurred despite (or because of) therapy, including visual impairment, hearing loss, nasal blockade, pulmonary fibrosis, hypertension, renal insufficiency, peripheral neuropathy, gonadal failure, and diabetes mellitus. Only 11% of the enrolled patients had not sustained a single VDI item after 1 year of enrollment. When adjusted for baseline VDI, the baseline BVAS/WG correlated moderately well with the VDI score at 1 year (r ‫؍‬ 0.20, P ‫؍‬ 0.015). Increases in adjusted VDI scores also correlated with the number of adverse events, particularly among patients with limited WG (P ‫؍‬ 0.06).Conclusion. Damage from both active disease and its treatment remain important problems for patients with WG. Despite the dramatic improvements in patient survival achieved over the last several decades, only a few patients with WG emerge from a period of active disease without sustaining some damage from the disease itself, its treatment, or both.

Objective. Etanercept is a soluble fusion protein designed to inhibit tumor necrosis factor (TNF). During the Wegener's Granulomatosis Etanercept Trial (WGET), a placebo-controlled trial of etanercept given in addition to standard therapy for remission induction and maintenance, more solid malignancies were observed in the etanercept group than in the group treated with standard therapy alone. This study was undertaken to further explore the potential association between anti-TNF therapy and the development of malignancy in these patients.Methods. One hundred eighty patients with active WG were enrolled and followed up for a median of 27 months. At enrollment, disease characteristics, treatment history, specific medical history items, and information about previous WG treatments and risk factors for malignancy were recorded. During the trial, the occurrence of malignancies and other adverse events was recorded prospectively.Results. All 6 solid malignancies observed during the WGET occurred in the etanercept group (P ‫؍‬ 0.01 versus placebo group); based on a comparison of ageand sex-specific incidence rates, 1.92 solid malignancies would have been expected in this group. The solid malignancies included 2 cases of mucinous adenocarcinoma of the colon, 1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and 1 recurrent liposarcoma. There were no differences between the 2 treatment groups in sex distribution, disease severity, personal or family history of cancer, or tobacco and alcohol use. The etanercept group was older at baseline and less likely to be newly diagnosed with WG at the time of randomization. Patients who developed solid tumors were older than patients who did not. All etanercept-treated patients who developed solid tumors were also treated with cyclophosphamide during the trial. However, there were no differences between the groups in the amount of cyclophosphamide received during the trial or the percentage who had received cyclophosphamide before enrollment. There were also no differences in the mean duration of daily cyclophosphamide therapy or the maximum daily cyclophosphamide dosage before enrollment.Conclusion.

The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.