In a year which gave us the bardoxolone
failure, NEPHRON-D and the CORAL trial to name a few, a study with a positive
result should be celebrated and the RAVE follow-up must be a contender for top
10 nephrology stories of 2013. The original RAVE trial was a multicenter, blinded, RCT
which was published in 2010 (n=197). It demonstrated non-inferiority of rituximab (375 mg/m2/week
for 4 weeks) as compared to oral cyclophosphamide for remission of severe
AAV at 6 months.
Moreover, among patients who had
relapsing disease at baseline, rituximab was superior to conventional
immunosuppression, at least at 6 months. Of note, in the same issue of the NEJM in
2010, the smaller RITUXIVAS study (n=44) compared IV cyclophosphamide for 3-6
months to a rituximab based regime (same dosing as RAVE but including 2 IV
cyclophosphamide pulses) with equivalent remission rates at 1 year.
In both studies, conventional steroid treatment was employed.
The follow-up to RAVE was reported in the NEJM in
August. Patients achieving
a remission with rituximab received only placebo from month 6 through 18 while
the comparison group received continued immunosuppressive therapy comprising
cyclophosphamide followed by azathioprine. Overall
results demonstrated that the rituximab group non-inferior to cyclophosphamide
followed by maintenance therapy with azathioprine for 18 months. Echoing the
original RAVE report, rituximab was superior to conventional immunosuppression
in relapsing patients (>50% of patients at enrollment) at 12 months
(P=0.009). However, at 18 months when most patients in the rituximab group had
reconstituted B cells, the significance was lost (P=0.06). There was no
significant difference between the groups in the numbers of total adverse
events, serious adverse events or the number of discontinuations.
Regarding the relevancy of the results for
nephrologists, it must be noted that only 66% had renal involvement and
creatinine clearance was 54-69mls/min in the 2 groups. The mean increase in
creatinine clearance was similar at approximately 11mls/min in both groups and
response rate was similar between the 2 groups in patients with ‘severe’ renal
Rituximab is often considered a ‘clean’ drug. What
strikes me after reading many studies using rituximab is that the adverse event
rate is usually similar to the comparison group, in this case cyclophosphamide.
A persistent concern with rituximab is whether or not
to re-treat, and if so when, after B cell re-population occurs. In this 18
month follow-up, non-inferiority was maintained at up to 18 months, when most patients in the rituximab group had reconstituted
B cells. However, B cells were detectable in 88% of rituximab patients who relapsed
between 6-18 months.
presenting with a rapidly progressive GN requiring dialysis although the RITUXIVAS trial contained patients with worse renal function, some needing
dialysis, and suggested equivalent early outcomes (but compared to IV
cyclophosphamide). Also, we lack clarity on whether to re-treat and if steroids
are necessary with rituximab. Overall, however, there is robust evidence that a
4 week course of rituximab is non-inferior to cyclophosphamide in the treatment
of (most?) AAV patients.
For my other highlights of the year, see previous blogs regarding
Abatacept as targeted therapy for FSGS and the merits of high-volume online hemodiafiltration versus conventional high-flux dialysis. Don’t forget to vote for your top stories.