Monday, December 9, 2013

Rituximab for ANCA Associated Vasculitis (AAV): Contender for top 10 of 2013

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.

A few points to consider:

·         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 disease.

·         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. 

Verdict: A knowledge gap may still exist for patients 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.

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