RAVE

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Stone JH, et al. "Rituximab versus cyclophosphamide for ANCA-associated vasculitis". The New England Journal of Medicine. 2010. 363(3):221-232.
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Clinical Question

In patients with severe ANCA-associated vasculitis, how does rituximab compare to cyclophosphamide for induction of remission when combined with glucocorticoids?

Bottom Line

Rituximab is non-inferior to cyclophosphamide in inducing remission of severe ANCA-associated vasculitis when combined with glucocorticoids.

Major Points

The ANCA-associated vasculitides (eg, granulomatosis with polyangiitis or GPA, and microscopic polyangiitis or MPA) affect small- and medium-caliber vessels and are associated with pulmonary and renal injury. The efficacy of cyclophosphamide in combination with glucocorticoids was first demonstrated by Fauci and colleagues in the late 1970s and early 1980s[1][2] and has been the mainstay of therapy since. The role of the newer anti-CD20 monoclonal antibody rituximab was unclear.

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial randomized 197 patients with severe ANCA-associated vasculitis to either cyclophosphamide or rituximab in addition to glucocorticoids tapered to symptoms. At 6 months, rituximab was non-inferior to cyclophosphamide in induction of remission and ability of patients to remain off of glucocorticoids. The related RITUXVAS[3] (2010) trial, which also compared rituximab and cyclophosphamide but explicitly in patients with renal vasculitis, showed similar results to RAVE, with non-inferior efficacy and no difference in the rates of adverse events between treatment groups.

Guidelines

The FDA has subsequently approved rituximab with glucocorticoids for treatment of GPA and MPA. No large organizations have released recommendations regarding rituximab in GPA and MPA, although an independent research group has recommended its use in newly diagnosed patients (grade 1b).[4]

Design

  • Multicenter, randomized, double-blind, double-dummy, noninferiority trial
  • N=197 patients with severe ANCA-associated vasculitis
    • Rituximab (n=99)
    • Cyclophosphamide (n=98)
  • Setting: Nine centers
  • Enrollment: 2004-2208
  • Follow-up: 6 months
  • Analysis: Non-inferiority
  • Primary outcome: Remission of disease without the use of prednisone at six months

Population

Inclusion Criteria

  • GPA or MPA
  • Positive serum assay for PR3-ANCA or MPO-ANCA
  • New diagnosis at time of screening or presenting with a severe disease flare
  • Birmingham Vasculitis Activity Score for WG (BVAS/WG)[5] of ≥3
  • Severe disease requiring treatment with cyclophosphamide
  • Patient to be otherwise considered for treatment with cyclophosphamide and glucocorticoids

Exclusion Criteria

  • Churg-Strauss syndrome or anti-GBM disease
  • Limited disease which would not otherwise be treated by cyclophosphamide
  • Alveolar hemorrhage requiring intubation
  • Creatinine ≥4.0 mg/dL from current episode's renal disease activity
  • WBC <4,000/mm3 or platelets <120,000/mm3
  • Liver function tests >2.5x ULN
  • Allergy to monoclonal antibodies or murine proteins
  • Infection
  • Previous deep space infection
  • HBV, HCV, or HIV infection
  • Liver disease
  • Malignancy in <5 year other than SCC, BCC, or CIS after curative treatment
  • Live vaccine in prior 4 weeks
  • Cyclophosphamide in previous 4 months
  • Glucocorticoids for >14 days previously
  • Previous adverse effects from standard therapy
  • Previous treatment with rituximab or alemtuzumab
  • Treatment with plasma exchange in prior 3 months

Baseline Characteristics

From the rituximab group.

Demographics:

  • Age: 54 years
  • Female: 46%
  • Race/ethnicity:
    • White: 92%
    • Back: 3%
    • Asian: 1%
    • Other: 4%
    • Hispanic or Latino: 6%

Disease-specific:

  • Vasculitis type:
    • GPA: 75%
    • MPA: 24%
    • Indeterminate: 1%
  • New diagnosis: 48%
  • Disease duration with relapse: 6.5 years
  • Previous cyclophosphamide in relapsed disease: 82%

Interventions

  • Patients were randomized in 1:1 fashion to either
    • Rituximab 375 mg/m2 IV weekly for four weeks plus placebo
    • Cyclophosphamide 2 mg/kg with adjustments for renal function plus placebo with the option to switch to azathioprine if remission attained between 3-6 months
  • Both groups received methylprednisolone 1g once, followed by prednisone 1 mg/kg/day with a taper according to symptoms

Outcomes

Comparisons are rituximab vs. cyclophosphamide.

Primary Outcome

Remission of disease and off prednisone at 6 months
64% vs. 53% (P<0.001 for non-inferiority; NS for superiority)
GPA: 63% vs. 50% (P=NS)
MPA: 67% vs. 62% (P=NS)

Secondary Outcomes

Remission of disease and prednisone <10mg daily at 6 months
71% vs. 62% (P=0.10)
Disease flares
Limited: 0.023 vs. 0.027 per patient-month (P=0.81)
Severe: 0.011 vs. 0.018 per patient-month (P=0.30)
Change in Vasculitis Damage Index at 6 months
+1.3 vs. +1.5 (P=0.62)
Quality of life
No difference
ANCA negativity at 6 months
47% vs. 24% (P=0.004)
PR3: 50% vs. 17% (P<0.001)
MPO: 40% vs. 41% (P=0.95)
Treatment discontinuation
14% vs. 17% (P=NS)

Subgroup Analysis

The primary outcome was not affected for ANCA type, new diagnosis of disease, renal function, alveolar hemorrhage, major renal disease, loss of ANCA at 6 months, BVAS/WG, and age.

Relapsing disease at baseline
62% vs. 42% (OR 1.40; 95% CI 1.03-1.91; P=0.01)

Adverse Events

Any adverse event
Total number: 31 vs. 33
Patients with >1: 22% vs. 33%
Death
1% vs. 2%

Criticisms

  • The authors identify that the included patient population (severe disease and ANCA positivity, excluding alveolar hemorrhage requiring intubation and renal failure) limits the generalizability of the results as well as whether retreatment of long-standing ANCA vasculitis with rituximab would be safe or beneficial
  • Selection bias favoring rituximab, in that many participants had recurrent ANCA-associated vasculitis with many having already failed cyclophosphamide therapy; this may represent increased cyclophosphamide metabolism, for example.[6]
  • Short follow-up period of 6 months is insufficient to draw long-term conclusions.[6]
  • Use of glucocorticoids confounds the analysis of efficacy between treatment groups.[7]

Funding

  • National Institute of Allergy and Infectious Disease to the Immune Tolerance Network
  • Genentech and Biogen provided study medications and some funding
  • Mayo Clinic research funded by an award from the National Center for Research Resources (NCRR)
  • Johns Hopkins research funded by an award from the NCRR and career development awards
  • Boston University research funded by NIH, a career development award, and Arthritis Foundation Investigator Award
  • ELISA kits for ANCA provided by Euroimmun

Further Reading

  1. Fauci AS, et al. "Cyclophosphamide therapy of severe systemic necrotizing vasculitis." New England Journal of Medicine.(1979):301:235-238.
  2. Fauci AS, et al. "Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years." Annals of Internal Medicine.(1983):98:76.
  3. Jones, Rachel B., et al. "Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis." New England Journal of Medicine. (2010):363)211-220.
  4. Guerry MJ, et al. "Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis." Rheumatology. 51.4 (2012): 634-643.
  5. Stone JH, et al. "A disease‐specific activity index for Wegener's granulomatosis: Modification of the Birmingham Vasculitis Activity Score." Arthritis & Rheumatism (2001):44:912-920.
  6. 6.0 6.1 NEJM Letters to the Editor
  7. Falk RJ, et al. "Rituximab in ANCA-Associated Disease." N Engl J Med. 2010; 363:285-286