Summary
Despite a significant improvement in outcome with the use of glucocorticoids and cyclophosphamide, relapse remains a major problem in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
B lymphocytes play a central role in the pathogenesis of ANCA-associated vasculitis (AAV), and rituximab has been shown to be effective in inducing remission.
However, the optimal maintenance strategy, particularly in patients with a history of relapse, remains unclear.

The RITAZAREM study investigated whether rituximab is superior to treatment with azathioprine for maintaining remission in relapsing AAV after induction with rituximab and glucocorticoids.
In addition, it should be shown whether higher doses of rituximab compared to previous studies such as MAINRITSAN (half cumulative RTX dose) could reduce the risk of relapse beyond the maintenance phase.

The study consisted of three phases: In the initiation phase (months 1-4), rituximab and prednisone/prednisolone were administered; in the maintenance phase (months 4-24), patients who achieved remission were randomized to receive either repeated doses of rituximab (1000mg i.v. every 4 weeks until month 20) or azathioprine (2mg/kg bw/day with reduction after 24 months) over a period of at least 36 months.
In the follow-up phase, patients were followed up for 24-48 months for minor and major relapses.
Randomization was based on ANCA type, severity of relapse and glucocorticoid induction regimen.

Rituximab proved to be superior to azathioprine in the prevention of major and minor relapses both in the maintenance phase and in the follow-up phase.
The hazard ratio for relapse was 0.41, which is in favor of rituximab.
Neither the glucocorticoid.
Neither the induction regimen (high vs low dose) nor the ANCA subtype influenced the risk of relapse.
Despite a higher rituximab dose regimen compared to previous studies, relapses still occurred during treatment and there was still an increased risk of relapse after discontinuation of rituximab.
There were no differences between the groups with regard to hypogammaglobulinemia and infections.

In summary, the RITAZAREM study supports rituximab as the standard of care for maintenance treatment of relapsing AAV and showed superiority over azathioprine.
However, the persistent risk of relapse and the risk of side effects with prolonged rituximab therapy emphasize the need for new therapeutic options in AAV.

References
[1] Rona M. Smith et al.
Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomized controlled trial.
Ann Rheum Dis.
2023 Jul;82(7):937-944.
doi: 10.1136/ard-2022-223559.
Epub 2023 Mar 23.

Written by
Dr. med. Andrea D. Gloor
Clinical Immunology
University Hospital Basel
May 2023