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Skopis et al. Vessel Plus 2020;4:30 I http://dx.doi.org/10.20517/2574-1209.2020.42 Page 3 of 14

RTX did not have an increased risk of adverse events as compared to CYC. Additionally, at month 18
in the RAVE trial and at month 12 in the RITUXVAS trial, RTX alone was shown to be as efficacious in
preventing disease relapse as CYC followed by azathioprine (AZA) maintenance therapy [9,10] . The RAVE
[9]
trial also found that RTX had a better safety profile than CYC . This was a cornerstone discovery in that,
an induction therapy as effective as CYC (especially in severe relapsing disease) had yet to be discovered
with the added benefit that RTX had a better safety profile. Despite these promising discoveries for
induction therapy, maintenance of AAV remission still poses a significant challenge to physicians. This has
prompted further research into alternative maintenance therapies.

Remission maintenance therapies in ANCA associated vasculitis
Cyclophosphamide, an alkylating agent, has been used as the gold standard of induction therapy in AAV
for many years. Given its significant toxicity, however, it is not an ideal agent to use in maintaining disease
remission in AAV, as long-term exposure significantly increases the risk of adverse effects including
hemorrhagic cystitis and bladder cancer. Therefore, research of alternate remission maintenance strategies
has been aimed at maintaining disease remission with less toxic immunosuppressants after initial induction
therapy with cyclophosphamide.

In 2003, a randomized trial comparing AZA versus CYC in maintaining disease remission in ANCA-
associated vasculitis was conducted. The study included patients who had recently been diagnosed with
generalized vasculitis that were also found to have renal involvement (with a serum creatinine of 5.7 mg/dL
or less). All patients received CYC and glucocorticoids for induction of disease remission. After
achieving remission, patients were randomly assigned to receive CYC (1.5 mg/kg) or AZA (2 mg/kg/day)
maintenance therapy while both groups continued receiving prednisolone. These patients were followed
for 18 months. Relapse rates in both groups were roughly the same (11 patients in the AZA group and 10
patients in the CYC group). The study thus concluded that administering AZA after induction therapy with
CYC was effective in maintaining disease remission and that AZA could be used as a feasible and less toxic
[11]
maintenance therapy than CYC for patients with ANCA-associated vasculitis .

Methotrexate has also been researched for use as a maintenance therapy in AAV. In 2017, a single center,
open-label randomized trial studied the use of MTX vs. CYC for maintenance therapy in AAV. The
study enrolled patients with MPA, GPA or EGPA and administered induction therapy with CYC before
randomizing these patients to receive maintenance therapy with CYC or MTX for 12 months. The patients
were monitored for relapses for 12 months after receiving induction therapy. The study found that the
frequency of relapses and adverse events was the same between two groups. Methotrexate was thus
[12]
designated a safe and effective alternate option for maintenance therapy in AAV after CYC induction .
Further studies sought to investigate the use of AZA vs. MTX in maintenance of disease remission in
ANCA-associated vasculitis. The Wegner Granulomatosis-Entretien (WEGENT) trial, an open label,
multicenter study, investigated patients with a diagnosis of MPA or GPA who had been given induction
therapy with CYC and glucocorticoids and were then randomized 1:1 to receive maintenance AZA
(2 mg/kg/day) or MTX (0.3 mg/kg/day increased incrementally to 25 mg/week) for 12 months. The
patients were followed for 29 plus or minus 13 months and monitored for relapses. The results showed that
similar relapse rates and numbers of adverse events occurred in both the AZA and MTX groups, indicating
that the two drugs have similar efficacies in terms of maintenance of disease remission and, similar safety
[13]
profiles in terms of adverse events .
The above data demonstrates that while AZA and MTX are alternate options for maintenance therapy in
patients with AAV after CYC induction and, that they do decrease the overall amount of exposure to CYC,
they are still associated with a high risk of relapse and adverse events, with neither of these medications