BIRMINGHAM, ENGLAND — Pulsed cyclophosphamide is as effective as daily oral administration for patients with systemic vasculitis and is associated with fewer side effects, according to initial results of a study presented at the annual meeting of the British Society for Rheumatology.
Six previous randomized, controlled trials demonstrate the efficacy of cyclophosphamide for induction and maintenance of remission of generalized vasculitis in a majority of patients up to 6 months, Dr. David Carruthers said. However, the optimal dosing regimen remains unknown.
“A common question is: Does the route of cyclophosphamide administration make a difference?” said Dr. Carruthers, a consultant rheumatologist at City Hospital, Birmingham (England).
In unpublished data from the completed CYCLOPS (Daily Oral Versus Pulsed Cyclophosphamide for Renal Vasculitis) study, researchers compared remission rates at 3 and 6 months for 160 patients randomized to intermittent pulse therapy or daily oral therapy.
The rate of remission at 3 months was 70% in the pulse regimen group and 65% in the conventional daily oral regimen group. At 6 months, 92% of the pulse therapy group achieved remission, compared with 86% of the daily oral group.
“This seems to indicate pulse is as effective,” Dr. Carruthers explained. “There was no difference in patient survival either.”
The researchers found a higher rate of infection—including severe and life-threatening leukopenia—with continuous oral therapy, compared with pulse cyclophosphamide, Dr. Carruthers said. Pulse therapy has a potential for higher long-term remission rates, compared with daily therapy, “but that remains to be seen,” he said.
Cyclophosphamide appears to cause equal rates of induction of remission compared with methotrexate in other studies, Dr. Carruthers said, however, methotrexate remission takes longer to achieve.
In addition, there was a 70% relapse rate at 1 year with methotrexate, compared with 45% with continuous oral cyclophosphamide, among 100 participants in the NORAM (Methotrexate Versus Cyclophosphamide for “Early Systemic” Disease) study (Arthritis Rheum. 2005;52:2461-9). “Most relapses occurred when patients were off all therapy, including steroids,” Dr. Carruthers said.
Mean time to relapse was 13.5 months in the NORAM study. Dr. Carruthers said, “It does seem that prolonged therapy is necessary beyond 12 months.”
In response to a question from an audience member on the use of azathioprine for induction of remission, Dr. Carruthers said: “Cyclophosphamide use in a targeted manner is more predictable than use of azathioprine for induction of remission.”
Although Dr. Carruthers recommended cyclophosphamide as initial therapy, he said it might not be necessary for the maintenance phase. “It appears unnecessary to keep patients on cyclophosphamide once remission is achieved. They can be given azathioprine for up to 18 months.” For example, findings from the CYCAZERAM (Cyclophosphamide Versus Azathioprine as Remission Maintenance Therapy for ANCA [antineutrophil cytoplasmic antibody]-associated Vasculitis) study demonstrated no increase in relapse when azathioprine was substituted for cyclophosphamide after remission was achieved (N. Engl. J. Med. 2003;349:36-44).
“Tapering the dose of oral steroids is probably needed for all,” Dr. Carruthers said. “But it is not clear if steroid maintenance is needed after 18 months or not.” A meeting attendee asked if any randomized, controlled trial compared prednisone and cyclophosphamide for remission induction. “No,” Dr. Carruthers said. “The early studies were retrospective reviews. I don't think now we can ethically do studies where we put patients on steroids only versus cyclophosphamide.”
The British Society for Rheumatology, in conjunction with the British Health Professionals in Rheumatology, expects to release guidelines for the management of adults with ANCA-associated vasculitis soon, Dr. Carruthers said. The recommendations will be available on their Web site (www.rheumatology.org.ukwww.vasculitis.org