Efficacy of Rituximab and Plasma Exchange in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Severe Kidney Disease

Abstract

Background: Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX).

Methods: A retrospective cohort study of MPO- or PR3-ANCA-positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m²). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared.

Results: Of 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC (n=161) or RTX (n=64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m² at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], P=0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], P=0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], P=0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], P=0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], P=0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], P=0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], P=0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], P=0.330).

Conclusions: The apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.

Keywords: ANCA; Plasmapheresis; cyclophosphamide; glomerulonephritis; rituximab.

Graphical abstract

Figure 1.

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) flowchart for the selection of patients with severe renal involvement in AAV. Active renal involvement was defined by the presence of (1) active, biopsy-proven, pauci-immune GN; (2) red blood cell casts on urine microscopy; or (3) rise in SCr >30% (or >25% decline in creatinine clearance) attributed to active vasculitis. Severe kidney disease was defined by eGFR<30 ml/min per 1.73 m² at diagnosis of renal disease secondary to AAV. Patients were grouped according to the interventions received for remission-induction (CYC or RTX and with or without PLEX). To assess the efficacy of CYC (n=161) in comparison with RTX (n=64) for remission-induction in patients with AAV and severe renal involvement, we excluded 26 patients treated with other immunosuppressants. In the group of patients that received PLEX (n=51), 37 (72.5%) were treated with CYC and 14 (27.5%) were treated with RTX for remission-induction. EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis.

Figure 2.

Changes in mean eGFR with follow up. Estimates for the mean and SEM of eGFR (ml/min per 1.73 m²) at baseline and at 6, 12, 18, and 24 months after beginning remission-induction therapy for each treatment group are displayed: (A) CYC versus RTX (mean eGFR at baseline, 15.6 versus 17.7 ml/min per 1.73 m²; P=0.050); (B) PLEX versus no PLEX (mean eGFR at baseline, 14.1 versus 16.8 ml/min per 1.73 m²; P=0.035); (C) CYC + PLEX versus RTX + PLEX (mean eGFR at baseline, 12.5 versus 18.5 ml/min per 1.73 m²; P=0.026). GFR was estimated using the Chronic Kidney Disease Epidemiology collaboration formula.

Figure 3.

Remission and combined events after PS matching analysis. Kaplan–Meier plots of remission achieved over 6 months after initiating remission-induction therapy ([A] 60 CYC versus 60 RTX patients, 45 versus 49 events, time to event 4.1 versus 3.5 months, P=0.069), and combined events (ESKD and/or death) at 18 months ([B] 64 CYC versus 64 RTX patients, 16 versus 14 events, time to event 14.3 versus 14.7 months, P=0.698), according to the remission-induction immunosuppression, CYC versus RTX.

Figure 4.

Remission and combined events after PS matching analysis. Kaplan–Meier plots of remission achieved over 6 months after initiating remission-induction therapy ([A] 45 no PLEX versus 45 PLEX patients, 34 versus 30 events, time to event 4.0 versus 4.1 months, P=0.176), and combined events (ESKD and/or death) at 18 months ([B] 45 no PLEX versus 45 PLEX patients, 14 versus 15 events, time to event 13.3 versus 13.0 months, P=0.891), according to the status of treatment or no treatment with PLEX.