Week 19 – RAVE

“Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis”

by the Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network (RAVE-ITN) Research Group

N Engl J Med. 2010 Jul 15;363(3):221-32. [free full text]

ANCA-associated vasculitides, such as granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and microscopic polyangiitis (MPA) are often rapidly progressive and highly morbid. Mortality in untreated generalized GPA can be as high as 90% at 2 years (PMID 1739240). Since the early 1980s, cyclophosphamide (CYC) with corticosteroids has been the best treatment option for induction of disease remission in GPA and MPA. Unfortunately, the immediate and delayed adverse effect profile of CYC can be burdensome. The role of B lymphocytes in the pathogenesis of these diseases has been increasingly appreciated over the past 20 years, and this association inspired uncontrolled treatment studies with the anti-CD20 agent rituximab that demonstrated promising preliminary results. Thus the RAVE trial was performed to compare rituximab to cyclophosphamide, the standard of care.

ANCA-positive patients with “severe” GPA or MPA and a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 3+.

notable exclusion: patients intubated due to alveolar hemorrhage, patients with Cr > 4.0

rituximab 375mg/m2 IV weekly x4 + daily placebo-CYC + pulse-dose corticosteroids with oral maintenance and then taper

placebo-rituximab infusion weekly x4 + daily CYC + pulse-dose corticosteroids with oral maintenance and then taper

primary end point = clinical remission, defined as a BVAS/WG of 0 and successful completion of prednisone taper

primary outcome = noninferiority of rituximab relative to CYC in reaching 1º end point

authors specified non-inferiority margin as a -20 percentage point difference in remission rate

subgroup analyses (pre-specified) = type of ANCA-associated vasculitis, type of ANCA, “newly-diagnosed disease,” relapsing disease, alveolar hemorrhage, and severe renal disease

secondary outcomes: rate of disease flares, BVAS/WG of 0 during treatment with prednisone at a dose of less than 10mg/day, cumulative glucocorticoid dose, rates of adverse events, SF-36 scores

197 patients were randomized, and baseline characteristics were similar among the two groups (e.g. GPA vs. MPA, relapsed disease, etc.). 75% of patients had GPA. 64% of the patients in the rituximab group reached remission, while 53% of the control patients did. This 11 percentage point difference among the treatment groups was consistent with non-inferiority (p < 0.001). However, although more rituximab patients reached the primary endpoint, the difference between the two groups was statistically insignificant, and thus superiority of rituximab could not be established (95% CI -3.2 – 24.3 percentage points difference, p = 0.09). Subgroup analysis was notable only for superiority of rituximab in relapsed patients (67% remission rate vs. 42% in controls, p=0.01). Rates of adverse events and treatment discontinuation were similar among the two groups.

Rituximab + steroids is as effective as cyclophosphamide + steroids in inducing remission in severe GPA and MPA.

This study initiated a major paradigm shift in the standard of care of ANCA-associated vasculitis. The following year, the FDA approved rituximab + steroids as the first-ever treatment regimen approved for GPA and MPA.  It spurred numerous follow up trials, and to this day expert opinion is split over whether CYC or rituximab should be the initial immunosuppressive therapy in GPA/MPA with “organ-threatening or life-threatening disease” (UpToDate).

The study’s double-blind, double-dummy RCT design is strong. However, a large shortcoming of this trial was that 101 patients (51%) already had relapsing disease at the time of inclusion in the study, which implies that they had likely already failed treatment with standard-of-care CYC. Thus both the superiority of rituximab in this subgroup and its noninferiority overall is much less impressive. Overall, the follow up duration of 6 months is relatively short compared to the extended timeframe of these relapsing diseases and the potentially late-appearing adverse effects of their treatments (e.g. therapy-induced malignancy). Finally, the authors do not justify why they chose the relatively-generous margin of -20 percentage points as their inferiority margin (in this case rituximab-induced remission could be 34% while CYC-induced could be 53% and rituximab would still be considered non-inferior). Non-inferiority trials are increasingly common, and careful attention needs to be paid to their methodologies. (See this 2017 NEJM review and http://www.rds-sc.nihr.ac.uk/study-design/quantitative-studies/clinical-trials/non-inferiority-trials/ for more details.)

Further Reading/References:
1. “Wegener granulomatosis: an analysis of 158 patients” (1992)
2. RAVE at ClinicalTrials.gov
3. “Challenges in the Design and Interpretation of Noninferiority Trials,” NEJM (2017)
4. “Clinical Trials – Non-inferiority Trials”
5. UpToDate,“Initial Immunosuppressive Therapy in Granulomatosis with Polyangiitis and Microscopic Polyangiitis
6. Wiki Journal Club
7. 2 Minute Medicine

Summary by Duncan F. Moore, MD