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Skopis et al. Vessel Plus 2020;4:30 I http://dx.doi.org/10.20517/2574-1209.2020.42 Page 9 of 14

Optimum regimen of rituximab maintenance therapy and reliability of ANCA titers and presence
of CD19+ B lymphocytes as predictors of AAV relapse
In light of the evidence that RTX was superior to AZA in remission maintenance in the MAINRITSAN
trial, investigators then set out to describe the optimum RTX treatment regimen in order to maintain
disease remission in AAV, and to determine whether the reappearance of ANCA autoantibodies, an
increase in ANCA titers from baseline or, the reappearance of CD19+ B lymphocytes at follow up could
provide a reliable marker of the need for reinfusion of RTX in order to prevent disease relapses.

The study was conducted by comparing the relapse rates of patients receiving individually tailored
regimens of RTX infusions which were administered based on the reappearance of CD19+ B lymphocytes,
reappearance of ANCA autoantibodies, or a marked increase in ANCA titers from baseline to the relapse
rates of patients receiving fixed dose regimens of RTX. This trial was titled Maintenance in Remission
using Rituximab in Systemic ANCA-associated Vasculitis-2 (MAINRITSAN2). The study was an open
label, pragmatic, multicenter, randomized controlled trial. Patients were randomized in a 1:1 ratio to
receive tailored RTX infusions or fixed dose regimens. These therapies were given 1 month after achieving
remission with either CYC, MTX, or RTX induction in both groups.

The results of the study showed that 17.3% of the patients in the tailored therapy arm suffered relapse vs.
9.9% of patients in the fixed dose regimen arm. Major relapses occurred in 7.4% of the tailored regimen
arm vs. 3.7% of the fixed dose regimen arm. Patients in the tailored infusion arm received 248 infusions vs.
patients in the fixed dose regimen arm who received 381 infusions. The results of the MAINRITSAN2 trial
demonstrated that individually tailored infusions of RTX based on biomarker activity were associated with
low major relapse and relapse rates which did not differ significantly from the fixed dose regimen group,
and allowed for administration of fewer RTX infusions. The study also demonstrated that reappearance of
ANCA autoantibodies, increasing ANCA titers or, reappearance of CD19+B lymphocytes was not reliable
in predicting AAV relapse, particularly because 4 patients in the study had negative ANCA autoantibodies
[24]
and no circulating B cells at the time of disease relapse [Table 1].

Rituximab maintenance therapy in patients with relapsing AAV
In 2019, further studies were conducted to determine the efficacy of RTX vs. AZA as a maintenance therapy
for patients with a history of relapsing AAV who achieved disease remission with RTX induction. This
trial, known as the Rituximab as Therapy to Induce Remission after Relapse in ANCA-associated Vasculitis
(RITAZAREM) trial, was an international, multi-center, open labeled, randomized controlled trial. Patients
with a history of relapsing AAV were recruited for the study during the time of an active relapse and
received glucocorticoids and RTX as induction therapy. The patients were then randomized to receive
RTX or AZA maintenance in a 1:1 ratio and followed for 36 months, with 61% of patients having suffered
a major relapse at the time of enrollment in the study. At 24 months after treatment, 13% of patients in the
RTX group experienced relapses; of the 13% of relapses in the RTX group, 82% were classified as minor and
18% were classified as major. 38% of patients in the AZA group suffered relapses; of the relapses in the AZA
group, 62% were classified as minor and 38% were classified as major. The adverse event rate in the RTX
group was lower (22%) vs. the AZA group (36%). The RITAZAREM trial successfully demonstrated that
RTX maintenance therapy was superior to AZA in patients with a history of relapsing AAV who achieved
[25]
remission with RTX induction and, that RTX was associated with fewer adverse events [Table 1].

The role of rituximab in maintenance therapy of lung, renal, and other systemic manifestations
of AAV
Anti-neutrophil antibody associated vasculitis is a systemic disease which affects multiple organ systems.
Below are studies outlining RTX as maintenance treatment of the various systemic manifestations of the
disease.