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Page 2 of 14 Skopis et al. Vessel Plus 2020;4:30 I http://dx.doi.org/10.20517/2574-1209.2020.42

INTRODUCTION
Anti-neutrophil cytoplasmic antibody associated (ANCA) vasculitis is characterized by infiltration of
[1]
neutrophils into small blood vessel walls, resulting in autoinflammation and necrosis . Microscopic
polyangiitis (MPA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis
(EGPA), and renal-limited ANCA-associated vasculitis are considered the main ANCA associated
vasculitides (AAV). Granulomatosis with polyangiitis and MPA present similarly and have significant
disease overlap, therefore, they are often considered together in terms of management. Eosinophilic
GPA is a process defined by eosinophilic pneumonia and its manifestations are dictated by eosinophilic
inflammation; treatment strategies for this disease are therefore focused on this distinct aspect of its
pathogenesis and differ from the treatment of the other ANCA associated vasculitides.

These rare diseases mostly affect individuals over the age of 50 and can progress to life threatening,
fulminant multisystem disease with complications such as diffuse alveolar hemorrhage (DAH) and
necrotizing glomerulonephritis causing respiratory failure and renal failure, leading to significant mortality
[2]
rates . Furthermore, despite significant treatment advances in remission induction, preventing disease
relapse and successfully maintaining disease remission continues to provide a significant challenge to
physicians. Anti-neutrophil cytoplasmic antibody associated vasculitides therefore must be viewed as
chronic diseases with complex treatment strategies that require long term immunosuppression.

Given the rarity of these diseases and the complexity of their treatment, significant efforts have been made
over the years to investigate safe, effective induction and maintenance therapies for these patients. Prior to
these significant advancements, AAV ran a fulminant and fatal course with rapidly progressive multisystem
disease and an extremely high mortality rate. Eighty-two percent of patients with untreated GPA would die
[3]
in 1 year and 90% would die in 2 years . Initially, induction therapy with glucocorticoids was attempted
and improved survival rates to 1 year, however, this strategy was associated with a multitude of side effects
[4]
and a high rate of disease relapse .

In the early 1970s and 1980s, promising evidence of cyclophosphamide (CYC) use in conjunction with
glucocorticoids for induction therapy surfaced. A paramount study in 1985 revealed that 93% of patients
with GPA followed over a 21-year period who received induction therapy with CYC and glucocorticoids
achieved disease remission . Unfortunately, however, the cytotoxic side effects of long-term CYC use
[3]
became apparent including leukopenia, hemorrhagic cystitis, infertility and 31-fold increased risk of
[4]
bladder cancer . Despite being an effective agent in inducing disease remission in AAV, the cytotoxicity
of CYC provided long term harm to patients and thus, was not an ideal agent for maintaining disease
remission. Further research was needed to discover new treatment modalities that would deliver less
harmful side effects.

Multiple studies explored alternate induction therapies for AAV, most notably the CYCLOPS trial in
2009 (comparing IV pulse doses of CYC vs. daily oral CYC and prednisolone as induction therapy) , the
[5]
[6]
MORAM trial (exploring efficacy of methotrexate (MTX) in inducing remission vs. CYC and prednisolone) ,
and the MEPEX and PEXIVAS trials which studied the use of plasma exchange vs. glucocorticoid therapy
for patients with AAV and sought to determine whether plasma exchange resulted in any significant
difference in renal recovery, progression to ESRD or, overall incidence of death in patients with ANCA
[7,8]
associated vasculitis . Although promising, these alternate therapies did not prove to be any more
efficacious than CYC while still having high relapse rates and significant drug toxicities.

Two randomized controlled trials exploring induction therapy with RTX vs. CYC (RAVE and RITUXVAS
trials) found that induction therapy with RTX (administered alone in the RAVE trial and co-administered
with CYC in the RITUXVAS trial) was non-inferior to CYC alone in inducing disease remission and that