Page 72 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

48 David S. Younger

include hemorrhagic cystitis, bladder cancer, bone marrow suppression and the risk of fatal
infection and gonadal toxicity. Bladder toxicity may be reduced by administration of the drug
in a single daily oral morning dose followed by hydration; and administration of the drug
intravenously as pulse therapy, adjusting the dose to renal function. Intravenous
cyclophosphamide, which can be administered as pulses therapy based on body surface area,
is as effective as and less toxic than oral cyclophosphamide.

Rituximab is a chimeric monoclonal anti-CD20 antibody that selectively depletes B-cells,
but not plasma cells. The Rituximab Versus Cyclophosphamide in ANCA-Associated
Vasculitis (RITUXVAS) [218] demonstrated non-superiority of rituximab to standard
intravenous cyclophosphamide for severe AAV with high sustained remission rates in both
groups. Rituximab-based therapy was not associated with reductions in early adverse events.
The Rituximab in ANCA-Associated Vasculitis (RAVE) Study [69] found that rituximab was
not inferior to daily cyclophosphamide treatment for induction of remission in severe AAV
and possibly superior in relapsing disease.

The bioavailable agents with activity against TNF-? which include etanercept and
infliximab have been well studied in AAV and other systemic vasculitides. In animal models,
inhibition of TNF-? markedly decreases the development of bactericidal granulomas during
Bacille de Calmette et Guérin (BCG) infection. Moreover, CD4+ T-cells from patients with
GPA are associated with HLA-DR+ CD4+ T cells that exhibit an unbalanced Th1-type
cytokine pattern and elevated levels of TNF-? [219]. Serum levels of TNF-? receptor
correlate with disease activity and TNF-?-positive cells infiltrate renal lesions [220].
Treatment with the dimeric soluble TNF receptor etanercept was not effective for the
maintenance of remission in patients with GPA and durable remissions were achieved in only
a minority of patients, with a high rate of treatment-related complications including the
development of solid cancers in six patients in the etanercept group as compared with none in
the control group [221]. A pilot study of the anti-TNF-a antibody infliximab [145] were well
tolerated during short-term followup and successfully induced prompt symptomatic responses
in those with systemic vasculitis not responding to conventional treatments. Seven patients
with GPA, two with RV, and one with CV of mean duration of 9, 21.5 and 17 years
respectively, so treated had no major side effects.

Oral methotrexate at the dose of 20 to 25 mg/week with prednisolone was as effective as
oral cyclophosphamide 2 mg/kg/day with prednisolone that was tapered and withdrawn over
12 months in the initial treatment of early non-severe AAV [222], however the methotrexate
regimen was less effective for induction of remission in those with extensive disease and
pulmonary involvement and associated with more relapses than cyclophosphamide after
termination of treatment. The high relapse rates in both treatment groups supported the
practice of continuing immunosuppressive treatment beyond 12 months. The adverse effects
of methotrexate in that study [222] included infection, leukopenia, hypertension, liver
dysfunction, nausea and vomiting.

The purine analog azathioprine, which metabolizes to the cytotoxic derivative 6-
mercaptopurine, exerts favorable action in vasculitis by the inhibition of T-cell activation and
T-cell-dependent antibody-mediated responses. Azathioprine is generally considered a safe
alternative although less effective agent to prednisone and cyclophosphamide in virtually all
forms of vasculitis. However, there are three drawbacks to its use. First, idiosyncratic side
effects, most often gastrointestinal and flu-like, occur in approximately 10% of patients and

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