Rheumatology joining December 16th #NephJC discussion on “Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis”

Paul Sufka

Rituximab

Image: Rituximab crystal structure. Credit: Wikimedia Commons.

I’m thrilled to announce that the online rheumatology community has been asked to join the next #NephJC, which will be held Tuesday, December 16 from 9-10 PM EST / 8-9 PM CST.

We’ll be discussing the recent NEJM article Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis (PMID: 25372085)

For my rheumatology colleagues that are not familiar, #NephJC is a thriving nephrology journal club on Twitter and NephJC.com. If you’re relatively new to Twitter and using hashtags, but would like to participate, the simplest way would be to follow the instructions on their site.

I’m excited to see what we’re able to learn from our nephrology colleagues, and hope us rheumatologists have much to share as well.

Background on establishment of the use of rituximab for ANCA-associated vasculitis

Until recently, the only standard therapy for treatment of ANCA-associated vasculitis had been induction with cyclophosphamide plus glucocorticoids. In 2010, the RAVE and RITUXVAS trials respectively established rituximab as non-inferior therapy for the induction of systemic and renal ANCA-associated vasculitis, with similar adverse events.

The RAVE trial compared rituximab to oral cyclophosphamide, and had a primary outcome of complete remission and tapering of glucocorticoids at 6 months, with results as follows:

  • Rituximab group: 63/99 patients (64%)
  • Cyclophosphamide group: 52/98 patients (53%)

Despite a trend toward improved outcomes in the rituximab group, the RAVE study was powered as a non-inferiority trial, and the differences between the groups were not statistically significant (p=0.09, 95% CI -3.2 to 24.3).

Upon achievement of remission in the RAVE trial, patients on cyclophosphamide were switched to azathioprine, whereas patients treated with rituximab were not given maintenance immunosuppression. Further analysis of the RAVE trial further supported effectiveness of rituximab for the induction of ANCA-associated vasculitis (discussed on episode 17 of The Rheumatology Podcast), however longer term follow up at 12 and 18 months showed the following remission rates:

  • Rituximab: 48% at 12 months, 39% at 18 months.
  • Cyclophosphamide/azathioprine: 39% at 12 months, 33% at 18 months.

Again, despite the numerical trend, this data was only able to support rituximab as non-inferior to cyclophosphamide. Additional analysis showed that in patients with relapsing disease, rituximab was superior at 6 months (p=0.01) and 12 months (p=0.009), but this effect did not extend out to 18 months (p=0.06).

The difficulty of frequent relapse in ANCA-associated vasculitis

Clearly, maintenance of remission for patients with ANCA-associated vasculitis remains a challenge and patients continue to relapse frequently despite current management strategies. Prior studies looking at remission rates with maintenance immunosuppression show significant relapse rates:

NephJC-Table3-NEJM2008-Pagnoux

From NEJM 2008;359:2790-803.

What is the role of rituximab in maintenance therapy for ANCA-associated vasculitis?

Until now, only retrospective data has suggested that rituximab might be useful as a maintenance strategy for ANCA-associated vasculitis. This question was addressed in our current journal club article:

NepjJC-NEJM-article-header

Study design

Patients

This study recruited patients aged 18-75 with newly diagnosed ANCA-associated vasculitis who were in complete remission after treatment with glucocorticoids plus pulsed cyclophosphamide. Disease activity was measured using BVAS, a standard vasculitis activity measure. Patients who previously received rituximab were excluded.

Treatment protocol

Induction of remission in both groups was:

  • Prednisone starting at 1 mg/kg with gradual taper, with some patients initiated with pulse methylprednisolone 500-1000 mg for 1-3 days.
  • Pulse cyclophosphamide 0.6 g/m² on days 0, 14, and 28, followed by 0.7 g/m² every 3 weeks for 3-6 additional pulses until remission was attained.

After 4-6 months, patients were randomly assigned 1:1 to either:

  • Rituximab 500 mg on days 0 and 14, then at months 6, 12, and 18.
  • Azathioprine 2 mg/kg for 12 months, 1.5 mg/kg for 6 months, then 1 mg/kg for 4 months.

In both groups, prednisone was further tapered to approximately 5 mg/day for at least 18 months, after which prednisone could be further tapered at investigator discretion.

End points

“The primary end point was the percentage of patients with major relapse (reappearance or worsening of disease with a BVAS >0 and involvement of at least one major organ, a life-threatening manifestation, or both) at month 28.”

Secondary end points: Rates of minor relapse, adverse events, mortality.

Statistics

Under the hypothesis that rituximab would decrease major relapses by 25% at month 28, assuming 5% exclusion or dropout, to have 80% statistical power and a 2-sided alpha risk of 0.05, 118 patients had to be enrolled in the trial.

Results

115 patients were enrolled (87 with GPA, 23 with MPA, and 5 with renal-limited ANCA-associated vasculitis). 58 received azathioprine and 57 received rituximab. Patient demographics were not significantly different in either group. 80% of patients had newly diagnosed disease, and 20% had relapsing disease.

Primary end point

At month 28, major relapse rates in each group were:

  • Azathioprine 17/58 patients (29%)
  • Rituximab 3/57 patients (5%)

Which was statistically significant, with hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002.

To put it another way, in the authors words, “hence, to avoid one major relapse, 4 patients (95% CI, 3 to 9) had to be treated with systematic rituximab infusions rather than with azathioprine.“

NephJC-NEJM-Fig2a

Secondary end points

  • Minor relapses were not statistically different between each group, with 9/58 (16%) in the azathioprine group and 6/57 in the rituximab group (11%) (p=0.43).
  • Rates of infection were similar in both groups, with 8/58 (14%) in the azathioprine group and 11/57 (19%) in the rituximab group.
  • There were two deaths in the azathioprine group, one with vasculitis involvement of the aortic valve who had a major relapse and received pulse steroids but died of E. coli bacteremia. The second patient had developed pancreatic cancer.

Author’s discussion

The authors concluded that “in the present study, rituximab was superior to azathioprine at maintaining remission of ANCA-associated vasculitis; this was especially true for granulomatosis with polyangiitis, which was the condition seen in most of the study population.”

“Our data also show that successive 500-mg infusions of rituximab, given every 6 months up to month 18 after remission, were not associated with more frequent severe adverse events than azathioprine.”

Interestingly, the authors note that the 6-month interval between rituximab infusions was chosen based on expected B-cell reconstitution and relapses after a median of 1 year.

They also state that a single 500 mg rituximab dose was chosen because patients were already in remission (i.e. B-cell deplete) and in hopes of decreasing risk of infection.

Study limitations:

  • Unblinded.
  • Unable to generalize to all patient types with ANCA-associated vasculitis since most had PR3-ANCA/GPA.
  • Leaving prednisone tapering up to discretion of investigators after 18-months (although authors note that only 2/20 relapsed patients had stopped prednisone).
  • Azathioprine maintenance until month 22, with a gradual taper (although 8 relapses occurred in the first 12 months at a dose of 2 mg/kg, and only 2 relapses occurred between months 12 and 22).

Another important point from the authors is that “several major relapses (7 of 17 in the azathioprine group and 2 of 3 in the rituximab group) occurred after treatment with the trial maintenance drugs was stopped.”

My thoughts

Having personally used rituximab in the clinical setting for both remission-induction and treatment of relapse for ANCA-associated vasculitis, and knowing that B-cells play a significant role in disease activity, I was not surprised that rituximab would be an effective therapy. This being said, I certainly did not expect a NNT of only 4 patients. I was also impressed were able to achieve these results using only single 500 mg doses of rituximab every 6 months, which may be important not only for potential decreased infectious risks, but may have financial implications as well.

One concerning observation in this study is that after stopping maintenance therapy in either group led to several major relapses. I have often wondered if we can ever safely stop all immunosuppressive therapy in these patients, and if so, how to identify which patients this can be safely achieved.

[Update 12/12/2014: Added slideshow version of the Storify below by @nephondemand. This gives additional background on management of ANCA-associated vasculitis and the trial covered in this journal club.]