Rituximab versus cyclophosphamide for ANCA-associated vasculitis with renal involvement

Abstract

Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) × 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.

Keywords: ANCA; GN; vasculitis.

Figure 1.

Kaplan–Meier plots for the risk of disease relapse after achieving complete remission. The time to first disease relapse after achieving complete remission by treatment (RTX versus CYC/AZA) is shown. Subjects are censored at termination, 18 months postrandomization, or the time of treatment change by blinded crossover, best medical judgment, or open-label RTX treatment. Only subjects achieving complete remission are included in this analysis, which is defined as achieving a BVAS/WG score=0 while not on prednisone. The P value is from a log-rank test and compares the survival curves of the treatment arms.

Figure 2.

eGFR at baseline and 6, 12, and 18 months postrandomization. Estimates for the mean and SEM in eGFR (milliliters per minute per 1.73 m²) at baseline and 6, 12, and 18 months postrandomization for each treatment arm (RTX versus CYC/AZA) are shown. GFR is estimated using the MDRD method. The results are obtained from a random regression model with fixed effects for treatment assignment, time, type of diagnosis, ANCA status at baseline, an indicator of new diagnosis versus relapsing disease at baseline, and random effects for treatment group intercepts and linear trends over time. All data through month 18, termination, or treatment change by blinded crossover, best medical judgment, or open-label RTX treatment, whichever is earliest, are included in the model.

Figure 3.

eGFR over time by treatment group and baseline eGFR. eGFR over time per subject stratified by the baseline eGFR for each treatment arm (RTX versus CYC/AZA) is shown. eGFR for subjects having a baseline eGFR (top panels)>60, (middle panels) between 30 and 60, and (bottom panels) <30 ml/min per 1.73 m². All data through month 18, termination, or treatment change by blinded crossover, best medical judgment, or open-label RTX treatment, whichever is earliest, are included. Where no baseline value exists, the screening value is included and set to study day 0.