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RITUXVAS

Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis

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Year of Publication: 2010

Authors: Rachel B. Jones, Jan Willem Cohen Tervaert, Thomas Hauser, ..., for the European Vasculitis Study Group

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2010;363:211-20

Link: https://doi.org/10.1056/NEJMoa0909169

Clinical Question

Is rituximab-based therapy superior to standard cyclophosphamide therapy for inducing sustained remission in patients with newly diagnosed ANCA-associated renal vasculitis?

Bottom Line

Rituximab was not superior to cyclophosphamide for severe ANCA-associated vasculitis. Both treatments achieved high sustained remission rates but with similar rates of severe adverse events and mortality.

        Major Points
        Open-label randomized trial comparing rituximab versus cyclophosphamide in ANCA-associated renal vasculitis
44 patients randomized 3:1 to rituximab (n=33) versus control (n=11)
Median age 68 years with severe renal involvement (median GFR 18 ml/min/1.73m²)
Primary endpoints were sustained remission at 12 months and severe adverse events
No significant difference in sustained remission (76% vs 82%) or severe adverse events (42% vs 36%)
Mortality was 18% in both groups, predominantly from infections in first 3 months
All patients in rituximab group became ANCA-negative by 6 months

      

Design

Study Type: Open-label, randomized controlled trial

Randomization: 1

Blinding: Unblinded (open-label)

Enrollment Period: June 2006 to June 2007

Follow-up Duration: 12 months

Centers: 8

Countries: United Kingdom, Netherlands, Switzerland, Australia, Sweden, Czech Republic

Sample Size: 44

Analysis: Intention-to-treat analysis using chi-square test, log-rank test, and analysis of covariance. Stata software version 10

Inclusion Criteria

New diagnosis of ANCA-associated vasculitis
ANCA positivity
Renal involvement evidenced by necrotizing glomerulonephritis on biopsy or red-cell casts or hematuria (≥30 red cells per high-power field) on urinalysis

Arms

Field	Rituximab Group	Control
Intervention	Rituximab 375 mg/m² weekly for 4 consecutive weeks, plus intravenous cyclophosphamide 15 mg/kg with first and third rituximab infusions, plus standard glucocorticoid regimen	Intravenous cyclophosphamide for 3-6 months followed by azathioprine, plus standard glucocorticoid regimen
Duration	4 weeks rituximab, 12 months follow-up	3-6 months cyclophosphamide then azathioprine, 12 months follow-up

Outcomes

Outcome	Type	Control	Intervention	P-value
Sustained remission at 12 months (absence of disease activity BVAS=0 for at least 6 months)	Primary	82% (9/11)	76% (25/33)	0.68
Time to remission (median days)	Secondary	94 days	90 days	0.87
Change in GFR 0-12 months (median ml/min)	Secondary	15 ml/min increase	19 ml/min increase	0.14
Relapse at 12 months	Secondary	10% (1/10)	15% (4/27)	0.70
Severe adverse events	Adverse	36% (4/11)	42% (14/33)	0.77
Death	Adverse	18% (2/11)	18% (6/33)	1.00
Serious infections	Adverse	18% (2/11)	18% (6/33)
All infections	Adverse	27% (3/11)	36% (12/33)

Subgroup Analysis

Among 9 patients dependent on dialysis at entry, 6 of 8 rituximab patients had sustained remission (5 no longer required dialysis), while 1 control patient died shortly after study entry

Criticisms

Open-label design without blinding
Small sample size (44 patients) with unequal randomization (3:1)
Short follow-up duration (12 months) limiting assessment of long-term outcomes
Rituximab group received two cyclophosphamide pulses, potentially confounding pure rituximab effect
High mortality rate (18%) limiting evaluation of efficacy in survivors
Inclusion of elderly patients with severe disease may limit generalizability

Funding

Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann–La Roche

Based on: RITUXVAS (The New England Journal of Medicine, 2010)

Authors: Rachel B. Jones, Jan Willem Cohen Tervaert, Thomas Hauser, ..., for the European Vasculitis Study Group

Citation: N Engl J Med 2010;363:211-20

Content summarized and formatted by NeuroTrials.ai.

RITUXVAS

(2010)

Objective

To compare rituximab versus cyclophosphamide as induction therapy in patients with newly diagnosed ANCA-associated vasculitis and renal involvement

Study Summary

• Rituximab-based regimen was not superior to cyclophosphamide for severe ANCA-associated vasculitis
• Sustained remission rates were high in both groups (76% rituximab vs 82% control)
• No reduction in early severe adverse events with rituximab (42% vs 36%)

Intervention

Rituximab 375 mg/m² weekly for 4 weeks plus two cyclophosphamide pulses versus standard intravenous cyclophosphamide for 3-6 months followed by azathioprine

Inclusion Criteria

New diagnosis of ANCA-associated vasculitis, ANCA positivity, renal involvement with necrotizing glomerulonephritis on biopsy or red-cell casts/hematuria

Study Design

Arms: Rituximab group (n=33) vs Control group (n=11)

Patients per Arm: 33 rituximab, 11 control

Outcome

• Primary: Sustained remission at 12 months (76% vs 82%, P=0.68)
• Safety: Severe adverse events (42% vs 36%, P=0.77)
• Mortality: 18% in both groups

Bottom Line

Major Points

Open-label randomized trial comparing rituximab versus cyclophosphamide in ANCA-associated renal vasculitis
44 patients randomized 3:1 to rituximab (n=33) versus control (n=11)
Median age 68 years with severe renal involvement (median GFR 18 ml/min/1.73m²)
Primary endpoints were sustained remission at 12 months and severe adverse events
No significant difference in sustained remission (76% vs 82%) or severe adverse events (42% vs 36%)
Mortality was 18% in both groups, predominantly from infections in first 3 months
All patients in rituximab group became ANCA-negative by 6 months

Study Design

Study Type: Open-label, randomized controlled trial
Randomization: Yes
Blinding: Unblinded (open-label)
Sample Size: 44
Follow-up: 12 months
Centers: 8
Countries: United Kingdom, Netherlands, Switzerland, Australia, Sweden, Czech Republic

Primary Outcome

Definition: Sustained remission at 12 months (absence of disease activity BVAS=0 for at least 6 months)

Control	Intervention	HR/OR	P-value
82% (9/11)	76% (25/33)	- (-33 to 21 percentage points)	0.68

Limitations & Criticisms

Open-label design without blinding
Small sample size (44 patients) with unequal randomization (3:1)
Short follow-up duration (12 months) limiting assessment of long-term outcomes
Rituximab group received two cyclophosphamide pulses, potentially confounding pure rituximab effect
High mortality rate (18%) limiting evaluation of efficacy in survivors
Inclusion of elderly patients with severe disease may limit generalizability

Citation

N Engl J Med 2010;363:211-20

View Original Publication →

RITUXVAS

Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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