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, non-inferiority trial of rituximab (375 mg/m² of body surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg/kg 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 non-inferiority (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 Institute of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299).

RAVE is a well-conducted landmark study that clearly establishes the efficacy of rituximab (B cell depleting, chimeric, monoclonal antibody that targets CD20 on B cells) as induction therapy in AAV. The control group received what would be regarded as standard induction therapy of cyclophosphamide (2 mg/kg) combined with glucocorticoids. Rituximab was administered as four doses of 375 mg/m²/week. In addition to the demonstrated non-inferiority with cyclophosphamide, rituximab was superior to cyclophosphamide in a prespecified analysis of patients who had relapsing disease at baseline. There was no difference in hospitalization and death in the two groups.

Background: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity.

Objective: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission.

Design: Randomized, controlled trial. Random assignments were computer generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment.

Setting: 42 centers in 12 European countries.

Patients: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease.

Intervention: Pulse cyclophosphamide, 15 mg/kg every 2–3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg/day (73 patients), plus prednisolone.

Measurement: Time to remission (primary outcome): change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes)

Results: Groups did not differ in time to remission (hazard ratio, 1.098 [95 % CI, 0.78–1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1 % vs. 87.7 %). Thirteen patients in the pulse group and six in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11–22.5 g] vs. 8.2 g [interquartile range, 5.95–10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23–0.71]).

Limitations: The study was not powered to detect a difference in relapse rates between the two groups. Duration of follow-up was limited.

Conclusion: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia.

Other significant limitations include the fact the study wasn’t powered to detect differences in relapse between the two groups which is clearly a major issue when trying to evaluate the clinical utility of the study. Indeed, there was a higher number of relapses in the intravenous group and these concerns were borne out by a retrospective analysis of long-term outcomes of 148 patients in the study which showed a significantly lower risk of relapse in the daily oral cyclophosphamide group compared to pulsed cyclophosphamide (HR = 0.50, 95 % CI 0.26–0.93; p = 0.029) although this was not associated in any difference in mortality [5].

Therefore, it is the total dose exposure to cyclophosphamide that seems to be critical rather than the mode or frequency of drug delivery. The higher the total dose exposure, the increased the chance of relapse-free disease, but the price of this is a significantly higher risk of leukopenia.

Objective: Standard therapy for antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) with cyclophosphamide (CYC) and prednisolone is limited by toxicity. This unblinded, prospective, randomized, controlled trial was undertaken to determine whether methotrexate (MTX) could replace CYC in the early treatment of AASV.

Methods: Patients with newly diagnosed AASV, with serum creatinine levels <150 μmol/L and without critical organ manifestations of disease, were randomized to receive either standard oral CYC, 2 mg/kg/day, or oral MTX, 20–25 mg/week; both groups received the same prednisolone regimen. All drug treatments were gradually tapered and withdrawn by 12 months. Follow-up continued to 18 months. The primary end point was the remission rate at 6 months (non-inferiority testing).

Results: One hundred patients were recruited from 26 European centers; 51 patients were randomized to the MTX group and 49 to the CYC group. At 6 months, the remission rate in patients treated with MTX (89.8 %) was not inferior to that in patients treated with CYC (93.5 %) (P = 0.041). In the MTX group, remission was delayed among patients with more extensive disease (P = 0.04) or pulmonary involvement (P = 0.03). Relapse rates at 18 months were 69.5 % in the MTX group and 46.5 % in the CYC group; the median time from remission to relapse was 13 and 15 months, respectively (P = 0.023, log rank test). Two patients from each group died. Adverse events (mean 0.87 episodes/patient) included leukopenia, which was less frequent in the MTX versus the CYC group (P = 0.012), and liver dysfunction, which was more frequent in the MTX group (P = 0.036).

Conclusion: MTX can replace CYC for initial treatment of early AASV. The MTX regimen used in the present study was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment. The high relapse rates in both treatment arms support the practice of continuation of immunosuppressive treatment beyond 12 months.

This unblinded RCT compares the use of methotrexate (15–25 mg/week till month 10) to cyclophosphamide in early AAV (2 mg/kg/day for 3–6 months) with tapering and withdrawal of all immunosuppression (including steroids) by 12 months. In terms of the primary end point of remission at 6 months, there was no significant difference between the two groups with 89.8 % of the methotrexate group and 93.5 % of the cyclophosphamide group achieving remission. However, nephrologists need to be aware of important caveats to the study. Firstly, the study was not blinded and therefore, unblinded BVAS scoring could introduce a significant source of bias. Furthermore, only around 30 % of both groups had microscopic hematuria and the median creatinine at baseline was 0.96 mg/dl indicating that most patients in the study did not have kidney involvement. Furthermore, those with evidence of significant disease as measured by Disease Extent Index had a significantly longer time to remission with methotrexate than with cyclophosphamide as did those with pulmonary involvement. An important aspect of this study is that all immunosuppression was withdrawn at 12 months and such early withdrawal of therapy is not representative of standard, contemporary practice. However, such a design allowed important observations to be made about the risk of relapse after successful induction therapy. Relapse rates were high in both groups – 46.5 % in the cyclophosphamide group vs. 69.5 % in the methotrexate group. Thus, while data from NORAM could justify the use of methotrexate as induction therapy in AAV in those with limited, predominantly non-nephrological disease, perhaps its most important impact has been to highlight the dangers of early withdrawal of immunosuppressive therapy at 12 months.

Background: Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70–90 % of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80–90 % among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens.

Methods: We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg/m² of body surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3–6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events.