CHICAGO – A number of questions remain regarding the safety and efficacy of rituximab for severe antineutrophil cytoplasmic antibody–associated vasculitis, according to Dr. Phillip Seo.

For example, it remains unclear how the sickest patients – such as those with ANCA-associated vasculitis (AAV), plus renal or respiratory failure – should be managed, and it also remains to be seen what the true effects of the drop in immunoglobulin levels that are seen after several treatment cycles may be, said Dr. Seo said at a symposium sponsored by the American College of Rheumatology.

Rituximab, a chimeric monoclonal antibody against the protein CD20 that is primarily found on the surface of B cells, was first approved in the United States in 2006 for use in combination with methotrexate for adult rheumatoid arthritis patients who failed to respond adequately to TNF (tumor necrosis factor)–antagonist therapies. On April 19, it received a new U.S. Food and Drug Administration approval for use – along with a corticosteroid – in the treatment of Wegener’s granulomatosis and microscopic polyangiitis.

The new approval for these indications was based on findings from the 6-month remission-induction phase of the randomized, double-blind, multicenter, active-controlled RAVE (Rituximab in ANCA-Associated Vasculitis) trial. The RAVE findings demonstrated that rituximab is not inferior to cyclophosphamide for remission induction at 6 months in patients with these severe forms of ANCA-associated vasculitis. Data from an 18-month maintenance phase have not yet been published.

The remission-induction data are of particular interest for patients who fail to respond to cyclophosphamide, or who aren’t candidates for treatment with the cytotoxic agent, which has been the cornerstone of therapy in these diseases. In very young patients, for example, there may be concerns about future fertility that would preclude the use of cyclophosphamide. In the elderly, there may be concerns about bone marrow suppression, said Dr. Seo, codirector of the vasculitis center at Johns Hopkins University, Baltimore.

Indeed, data from the 1970s from the National Institutes of Health, which established cyclophosphamide as a mainstay of treatment for AAV, showed that about 25% of patients have an incomplete response even after 3-5 years of therapy. Intolerance is also an issue, particularly for those with hemorrhagic cystitis or bone marrow suppression resulting from prior exposures, he said.

The 6-month data from RAVE, which were published in July, provide some hope for such patients; the data showed that outcomes were statistically similar in 197 patients who were randomized to treatment with daily oral prednisone (1 mg/kg per day up to 80 mg/day) and either a "very standard course" of oral cyclophosphamide (2 mg/kg per day for 3-6 months, followed by azathioprine to maintain remission) plus rituximab placebo, or rituximab (375 mg/m² infusions once weekly for 4 weeks) plus cyclophosphamide placebo (N. Engl. J. Med. 2010; 363:221-32), Dr. Seo said.

Not only was rituximab shown to be noninferior to cyclophosphamide for inducing complete remission with steroid taper, but treatment response did not differ significantly by disease type. However, patients with Wegener’s granulomatosis trended toward having a slightly better treatment response, he noted.

Treatment response was, however, significantly better with rituximab among those with severe disease flare at study baseline.

"Those [severe flare] patients do much better when they get rituximab ... and in fact this might highlight an important use for rituximab in the future," he said.

However, because patients with renal or respiratory failure were ineligible for the trial, it remains unclear whether rituximab is a viable option for these patients.

"So, although I think rituximab still might work, there’s not really any data with any of these patients," he said.

Also, long-term treatment may be a concern. Many patients receive multiple courses, and their immunoglobulin levels start to drop after about five cycles of rituximab.

"The data seem to indicate that this doesn’t matter and doesn’t seem to be associated with any increased risk of infection. Yet emotionally, I find that so hard to believe," Dr. Seo said, adding that this "is something I’m going to be watching for in the near future."

A final concern mentioned by Dr. Seo is the risk of progressive multifocal leukoencephalopathy (PML), which used to be a concern mainly in patients with HIV/AIDS or in patients receiving cancer chemotherapy. "Unfortunately we now have to talk about it as well," he said.

The majority of patients with rheumatic illness who develop PML after treatment with rituximab have received multiple courses of immunosuppression leading up to rituximab, and this likely explains the majority of cases, but it doesn’t explain all cases.

"So this is a story that continues to evolve," he said.

Dr. Seo disclosed that he has received consulting fees and other remuneration from Genentech.

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