- We've come a long way in the management of ANCA-associated vasculitis. It wasn't too long ago when this condition was almost universally fatal. With the advent of immunosuppressive therapies, especially cyclophosphamide, the mortality of ANCA-associated vasculitis (AAV) has significantly decreased.
- Cyclophosphamide (CYC) requires special mention; it can be considered as the single agent that turned the course of AAV. As an induction agent, CYC has had a remarkable effect at initiating remission in AAV. Trials such as EUVAS have shown that lower doses of CYC can be used to help maintain remission. The only problem: CYC has a significant toxic profile that is dependent on the cumulative dose to which one is exposed.
- When CYCAZAREM was published, patients with AAV now had a new maintenance drug that could be used: azathioprine (AZA). AZA was shown to have equally effective rates of continued remission as CYC, but with significantly lower side effects. Indeed many patients today are placed on AZA as maintenance therapy.
- Many scientists began to wonder if a milder form of therapy could be used for induction, as AZA was discovered to be effective for maintenance. Enter RITUXIVAS and RAVE as the next trials in the story of AAV (youtu.be/h9D2kRMY8YE). Both trials looked at using a milder induction agent (rituximab) rather than CYC. Both showed no inferiority of rituximab as induction therapy against CYC.
- In total, EUVAS, CYCAZAREM, RAVE and RITUXIVAS have revolutionized the way we treat AAV. MAINRITSAN is a natural extension of the ground-breaking work that the previous trials have laid down. The basic premise is to determine if rituximab (shown to be an equally effective but milder induction agent) would have the same effect as maintenance therapy as the AZA (the current standard).
- In the MAINRITSAN trial, AAV patients (n = 115) who were treated with CYC for induction (not rituximab) were randomized to:
- 1) rituximab 500 mg IV at day 0, day 14, and then months 6, 12, 18 and then no therapy from month 19 to 28, or
- 2) AZA at 2 mg/kg/d x 12 months with a downward titration of 1.5 mg/kg/d x 6 months to 1.0 mg/kg/d x 4 months and then no therapy for the remaining 6 months (to end at month 28); in all phases the patients received low dose prednisone (5 mg/d).
- The patients who were included in the study had to have achieved a BVAS score of 0 after completing induction therapy with CYC.
- The primary endpoint was the percentage of patients with a major relapse (BVAS > 0 + one major organ affected) at month 28 post-induction.
- The results were all in favor of rituximab. The hazard ratio of a major relapse was 6.61 (95% CI 1.56..27.96). The wide confidence interval is probably because of the low sample size (only 115 patients randomized).
- shown above is the probability of remaining free of a major relapse in either maintenance arm
- Based on the absolute risk reduction of 23%, the NNT to avoid 1 major relapse in the rituximab group was 4 (95% CI 3..9).
- The side effect profile of chronic rituximab infusions was very similar to AZA. Only one patient developed Pneumocystis jiroveci (formerly known as Pneumocystis carinii) -- prompting the authors to suggest that TMP/SMX prophylaxis may be necessary.
- MAINRITSAN has a number of excellent features that make its results extremely useful:
- 1) the trial was a randomized, non-placebo-controlled trial; the authors chose the correct comparator to use in the control arm. Using placebo as the control would have tilted the results in favor of rituximab, since we know that AAV patients who receive CYC as induction therapy need to be maintained on some therapy chronically to avoid relapses. This trial pits rituximab against the standard of care, making the results more reliable.
- 2) the trial was designed as a superiority trial; Most trials, including RITUXIVAS, were non-inferiority trials, in which the burden of showing an effect is less strict and easier to achieve than the burden associated with a superiority trial. The stricter, tougher burden of proof placed on the rituximab arm makes the results impressive.