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

proving to be safer or more efficacious than the other. This fact prompted further investigation into safer,
more efficient remission maintenance therapies such as RTX.

RITUXIMAB IN ANCA ASSOCIATED VASCULITIS
Rituximab is a monoclonal antibody consisting of both human and murine components that specifically
[14]
targets the B cell CD20 antigen, thus causing removal of B cells from the peripheral circulation . This
is important because B cells have been implicated in the pathogenesis of AAV via their production of
ANCAs, activation of the alternative complement pathway, and initiation of inflammatory cascades that
induce severe necrotizing vascular inflammation. The ANCA autoimmune response is driven by inhibited
suppression of T cells and B cells, and by release of B-cell stimulating factors by activated neutrophils
[15]
which act to slow the apoptosis of B cells, thus enhancing their proliferation . Due to the fact that the
pathogenesis of AAV is rooted in B cell mediated autoimmunity, it stands to reason that RTX would be
of significant therapeutic benefit given its ability to target autoreactive B cells and deplete them from the
circulation. As such, RTX provides a promising treatment option for induction and maintenance therapy in
AAV because it targets the direct pathogenesis of the disease.

MAINTENANCE THERAPY WITH RITUXIMAB IN AAV
With the advent of promising research demonstrating RTX as a safe and effective induction therapy,
investigators set their sights on this drug as a possible maintenance therapy for patients with AAV.
Rituximab showed promise as a maintenance therapy for AAV in early case reports and retrospective
reviews. In 2001, the use of RTX was described in a man with a history of chronic, relapsing GPA who did
not tolerate treatment of disease relapse with CYC due to bone marrow toxicity, which caused significant
anemia. Additional immunosuppressive treatments such as AZA and mycophenolate mofetil (MMF)
were attempted, however, the patient did not respond to these treatments and had continued relapses with
worsening renal failure and a meningeal flare of GPA. The decision was made to initiate therapy with RTX
on a compassionate basis given the patient had been refractory to all conventional treatments and MTX
2
was contraindicated. Subsequently, the patient received 4 infusions of 375 mg/m of RTX and high dose
glucocorticoids. The patient entered complete remission after treatment with RTX and it was observed that
his cytoplasmic ANCA (cANCA) and B lymphocyte levels had completely disappeared. At 11 months after
treatment, the patient’s cANCA and B lymphocytes reappeared, yet he did not have any signs or symptoms
of disease relapse; he was preemptively treated with RTX at that time and remained in complete remission
[16]
at 18-month follow up [Table 1].
In 2005, a case series reviewed 9 patients with a history of GPA or MPA who had either been resistant to
treatment with CYC or, had experienced recurrent relapses after cessation of CYC therapy. Two of the
patients were myeloperoxidase (MPO) - ANCA positive and 7 were proteinase-3 (PR-3) ANCA positive.
These patients were treated with RTX infusions in addition to conventional immunosuppressants (AZA,
MMF, or a short course of CYC) in order to prevent the formation of antibodies to RTX. Three patients
were treated twice with a once per week infusion and four patients were treated four times with a once
per week infusion. Eight out of the 9 patients in the study exhibited a complete response to RTX therapy
with one patient having a partial response. Responses included improvement of chest x-ray (four patients),
cessation of lower extremity gangrene (one patient), improvement of peripheral neuropathy (one patient),
[17]
remission of renal vasculitis (two patients), and improvement in severe musculoskeletal pain (one patient)
[Table 1].

A retrospective study of 8 patients with a history of relapsing or refractory GPA who received RTX
infusions in conjunction with ongoing immunosuppressive therapy was conducted in 2007. This
study investigated the efficacy of RTX in patients with GPA who had either failed treatment with prior