RITUXVAS

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Jones RB, et al. "Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis". The New England Journal of Medicine. 2010. 363(3):211-232.
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Clinical Question

Among patients with newly-diagnosed, severe ANCA-associated renal vasculitis, is rituximab superior to cyclophosphamide in 12 month remission rates or severe adverse events?

Bottom Line

Among patients with newly diagnosed, severe ANCA-associated renal vasculitis, rituximab had similar efficacy for 12-month remission and similar adverse events to cyclophosphamide. This trial's analytical strategy did not include a non-inferiority analysis and was instead simply a superiority study. Rituximab was not superior to cyclophosphamide.

Major Points

Before the release of the anti-CD20, B-cell depleting drug rituximab, cyclophosphamide and glucocorticoids were the mainstay of vasculitis treatment, particularly in granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and severe systemic necrotizing vasculitis.[1][2] (Of note, the seminal work of the use of cyclophosphamide in vasculitis was performed by a young Dr. Tony Fauci.) As a cytotoxic chemotherapeutic agent, cyclophosphamide is associated with multiple short- and long-term complications, including "conventional" chemotherapy side effects (e.g., nausea/vomiting, hair loss, myelosuppression) and later risk of malignancies.[3][4] Rituximab is generally better tolerated than cyclophosphamide, and the 2010 RAVE trial established non-inferiority of rituximab when compared to cyclophosphamide in new or severely-recurrent vasculitis.[5] Both arms use pulse-dose corticosteroids.

Published simultaneously with RAVE, the 2010 RITUXVAS study enrolled individuals with ANCA-associated renal vasculitis, a group that was generally excluded from RAVE. RITUXVAS was also limited to individuals with new disease, unlike RAVE. RITUXVAS randomized 34 participants in a 3:1 fashion to rituximab or cyclophosphamide, both groups receiving pulse-dose corticosteroids. There was no difference in 1-year sustained remission & severe adverse events between rituximab (76% & 42%) or cyclophosphamide (82% & 36%). Of note, the rituximab arm did include 2 weeks of cyclophosphamide infusion, but the overall dose was far lower than that administered in the other arm.

RITUXVAS did not include a non-inferiority analysis, so there was no statistical comparison for rituximab vs. cyclophosphamide for non-inferiority, only superiority. While it's clear that rituximab is not superior to cyclophosphamide for 12-month remissions or lower serious adverse events, it's reasonable to consider the efficacy and safety of the two agents to be similar. Together, RAVE and RITUXVAS provide evidence for the use of rituximab in ANCA-vasculitis.

Guidelines

ACR & Vasculitis Foundation ANCA-Vasculitis Treatment (2021, adapted)[6]

  • Conditionally recommend rituximab over cyclophosphamide for induction among adults with active, severe disease (very low to moderate LOE).

Design

  • Prospective, randomized, open-label parallel-design
  • N=44
    • Rituximab (n=33)
    • Cyclophosphamide (n=11)
  • Setting: 8 centers in Europe and Australia
  • Enrollment: 2006-2007
  • Follow-up: 12 months
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Remission at 12 months
    • Serious Adverse Events

Population

Eligibility criteria is described in depth on page 10 of the Supplemental Appendix.[7]

Inclusion Criteria

  • All three of the following:
    • New GPA or MPA or Renal-limited vasculitis (RLV)
    • Renal involvement by biopsy (necrotizing glomerulonephritis), RBC casts, or hematuria
    • ANCA positive: PR3, MPO, cANCA, or pANCA

Exclusion Criteria

  • Prior treatment with cyclophosphamide
  • Presence of other rheumatological disease: SLE, EPA, HSP, rheumatoid vasculitis, cryoglobulinemia, anti-GBM disease
  • HBVe Ag, HCV Ab, or HIV positivity
  • Prior malignancy
  • Pregnancy, breastfeeding, inadequate contraception
  • Allergy to protocol agent
  • Recent live vaccine

Baseline Characteristics

From the Rituximab group except where specified.

  • Demographics: Age 68, 52% male sex
  • Diagnosis:
    • GPA 55% vs. 36% in cyclophosphamide group
    • MPA 36% vs 36% in cyclophosphamide group
    • RLV 9% vs. 37% in cyclophosphamide group
  • P3 and MPO biding u/mL: 53 vs. 70 in cyclophosphamide group
  • ANCA pattern
    • cANCA: 61% vs. 45% in cyclophosphamide group
    • pANCA: 39% vs. 55% in cyclophosphamide group
  • GFR: 20 vs 12 in cyclophosphamide group
  • Number organs involved (median): 3 vs. 2
  • BVAS 19
  • CRP mg/dL: 28
  • ESR mm/hr: 52
  • Dialysis at randomization: 24% vs. 9% in cyclophosphamide group
  • Median IV methylprednisolone dose in grams: 1
  • Use of plasma exchange: 24% vs 37% in cyclophosphamide group

Interventions

  • Pre-randomization: Plasma exchange or up to 2g IV methylprednisolone
  • Randomization to a group:
    • Rituximab - at 375 mg/m[8] weekly for 4 weeks plus IV cyclophosphamide 15 mg/kg on weeks 1 and 3
      • Progressive disease at within 6 months may receive one additional cyclophosphamide infusion
    • Cyclophosphamide - at 15 mg/kg q2wks x6 weeks followed by 15 mg/kg q3wks x9 weeks, (total 6-10 doses) followed by azathioprine therapy
  • Both groups received concurrent methylprednisolone 1 g IV followed by 1 mg/kg PO prednisolone reduced to 5 mg/d at 6 months

Outcomes

Presented as Rituximab vs. Cyclophosphamide.

Primary Outcome

Sustained remission at 12 months
76% vs. 82% (p=0.68)
Serious Adverse Events
Defined as Grade 3-5 NCI Common Terminology Criteria v3 events.
42% vs. 36% (p=0.77)
Deaths: 18% vs 18% (p=1.00)

Secondary Outcomes

B-cell depletion
82% vs 75%
Prednisolone tapered to 5 mg by 9 months
96% vs 89%
12 month weight adjusted prednisolone dose
0.071 mg/kg vs 0.082 mg/kg
Remission (BVAS = 0 for 2 months)
91% vs 91%
Median BVAS change at 3 months
-19 vs - 18
Median eGFR change at 12 months
19 vs 15
Relapse rate
15% vs 10%


Criticisms

  • Incomplete reporting of baseline demographics (eg, race/ethnicity)
  • Study sample was based on a 33% effect size to reach 80% power, this assumed 95% remission rate with rituximab, as was seen in pilot studies.[9]
  • The protocol was not a direct comparison of lone-rituximab or lone-cyclophosphamide treatment as both groups received at least some cyclophosphamide. There were also other drugs in the protocol, such as steroids and azathioprine (in the cyclophosphamide group).

Funding

  • Multiple public funding agencies
  • La Roche
  • Authors with financial conflicts

Further Reading