SNOWMASS, COLO. — The future of therapeutics in at least one form of severe vasculitis appears to lie in the biologic agents, in light of rituximab's impressive showing in the RAVE trial, Dr. Leonard H. Calabrese observed at a symposium sponsored by the American College of Rheumatology.
RAVE (Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis) was an eagerly awaited, randomized trial presented last fall at the annual meeting of the American College of Rheumatology. It demonstrated that rituximab (Rituxan) was as effective as—and safer than—standard-of-care cyclophosphamide at inducing remission in patients with severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis.
Moreover, in a prespecified subgroup analysis, patients who entered RAVE with a severe flare of their vasculitis rather than with new-onset disease had a statistically and clinically greater remission rate with rituximab than with cyclophosphamide. “This is a very important study that marks a major shift in thinking,” said Dr. Calabreseof the Cleveland Clinic Foundation.
Indeed, in recent decades the emphasis has been on developing strategies to fine-tune cyclophosphamide therapy to minimize its serious toxicities.
The most popular of these strategies is step-down therapy—specifically, 3 months of cyclophosphamide as induction therapy, followed by maintenance treatment with a nonalkylator (most commonly methotrexate, although azathioprine, mycophenolate mofetil, leflunomide, and intravenous immunoglobulin have also been studied).
For non–life-threatening, early, systemic disease, the NORAM (Non-Renal Vasculitis Alternative Treatment With Methotrexate) trial demonstrated that it was reasonable to do away with cyclophosphamide altogether, and to use methotrexate for induction as an alternative (Arthritis Rheum. 2005;52:2461–9).
However, in severe ANCA-associated vasculitis with impaired vital organ function, cyclophosphamide has remained the workhorse—that is, until RAVE.
RAVE was a National Institute of Allergy and Infectious Diseases–sponsored, 197-patient, randomized trial involving assignment to B-cell depletion via four once-weekly infusions of rituximab (375 mg/m
RAVE study chair Dr. Ulrich Specks, who was in the audience for the ACR Snowmass symposium, rose to emphasize that in the 101 RAVE participants with baseline severe flares, the 6-month remission rate was 67% with rituximab, which was statistically superior to the 42% rate in the cyclophosphamide arm.
“So for the treatment of severe flares of the disease, rituximab is probably going to be the standard of care as we move forward. It will spare patients from prolonged cyclophosphamide exposure,” said Dr. Specks of the Mayo Clinic in Rochester, Minn. Key remaining questions—such as how best to reinfuse rituximab when B cells eventually return—are being addressed in an ongoing follow-up study.
Rituximab may not be the only biologic response modifier with a bright future in ANCA-associated vasculitis.
Dr. Calabrese said that although he, like most rheumatologists, has opted out of the use of anti–tumor necrosis factor–alpha therapies altogether in light of the negative Wegener's Granulomatosis Etanercept Trial (N. Engl. J. Med. 2005;352:351–61), he wonders whether etanercept (Enbrel) was the right drug. The anti-TNF agents don't all act in the same way, and most of the anecdotal reports of treatment success have involved infliximab (Remicade), not etanercept, he noted.
Dr. Peter A. Merkel, director of the vasculitis center at Boston University, conceded that it's possible a different anti-TNF agent would have done better, but these large National Institutes of Health trials take years to complete, and the research momentum has shifted away from the older biologics. Now underway, for example, is a clinical trial in Wegener's granulomatosis of abatacept (Orencia), a fusion protein that inhibits costimulation of T cells and is approved for the treatment of rheumatoid arthritis.
Disclosures: Dr. Calabrese disclosed that he serves as a consultant to Amgen Inc., Centocor Inc., Genentech Inc., Sanofi-Aventis, UCB, and Wyeth.