Rituximab versus cyclophosphamide for ANCA-associated vasculitis

Abstract

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.)

Figure 1. Randomization and Inclusion in the Analysis at 6 Months

Patients were randomly assigned, in a 1:1 ratio, to the treatment and control groups. The study groups were balanced with respect to ANCA type. The majority of patients (84 patients in the rituximab group and 81 patients in the control group) completed 6 months of the treatment to which they were assigned. The remainder had one or more events that led to withdrawal from the study. Data related to the primary analysis were available for all patients. Five patients who withdrew voluntarily from the trial (1 patient in the rituximab group and 4 patients in the control group) were regarded as having had a treatment failure with respect to the primary end point.

Figure 2. Treatment Effect According to Prednisone Dose at 6 Months

Point estimates and 95.1% confidence intervals are shown for the treatment effect, defined as the difference in rates of complete remission between the treatment groups. The criterion for the noninferiority of rituximab was a difference in remission rates of 20 percentage points, and the criterion for superiority was a difference of 0 percentage points. For both complete remission with 0 mg of prednisone per day and complete remission with less than 10 mg per day, the difference in remission rates was above 20 percentage points, meaning that the criterion for the noninferiority of rituximab was met (P<0.001 for both comparisons).

Figure 3. Peripheral-Blood B-Cell Counts

Panel A shows the peripheral-blood B-cell counts in the rituximab and control groups according to antineutrophil cytoplasmic antibody (ANCA) type. The counts in most patients who received rituximab decreased to less than 10 CD19+ cells per cubic millimeter after two infusions and remained at that level until 6 months. B-cell counts decreased more slowly in the control group than in the rituximab group and remained detectable, at low levels. MPO-ANCA denotes ANCA directed against myeloperoxidase, and PR3-ANCA ANCA directed against proteinase 3. Panel B shows box plots of log₂-transformed values for CD19+ B cells at six time points, according to treatment group. The horizontal line within each box indicates the median value; the bottom and top lines of the box depict the 25th and 75th quartiles, respectively; and the whiskers show the upper and lower values at 1.5 times the interquartile range. The open circles represent values outside this range and are considered outliers. Values equaling 0 were converted to the lowest nonzero value of 0.06 before log₂ transformation.