RITUXIMAB FOR ANCA+ VASCULITIS

October 23, 2009 (Philadelphia, Pennsylvania) — Rituximab is as effective as cyclophosphamide for the treatment of vasculitis and superior to cyclophosphamide for patients experiencing a severe disease flare, according to results of a randomized controlled trial, called RAVE, presented here at American College of Rheumatology 2009.

Cyclophosphamide has been the standard of care for reduction remission for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for many decades, but it is associated with serious toxicities, including neutropenia, infections, genitourinary malignancies, and infertility.

RAVE was a multicenter randomized double-blind placebo-controlled trial comparing rituximab (375 mg/m² intravenous weekly for 4 weeks) with cyclophosphamide (2 mg/kg per day orally). The study met its primary end point of noninferiority, showing that rituximab is as effective as cyclophosphamide.

Although rituximab was not superior to cyclophosphamide in the overall study population, it was superior for the induction of remission in ANCA-associated vasculitis for patients who entered the trial with a severe disease flare, explained Ulrich Specks, MD, from the Mayo Clinic in Rochester, Minnesota, for severe ANCA-associated vasculitis.

"Rituximab is the first proven alternative to cyclophosphamide in severe ANCA-associated vasculitis, and it is effective and well tolerated. This is particularly relevant for patients with severe disease and those of child-bearing age," Dr. Specks stated.

ANCA vasculitis is a systemic autoimmune disease caused by an overreaction of the immune system to many organs of the body. Wegener's granulomatosis, microscopic polyangiitis, and Churg–Strauss syndrome are variants of ANCA-associated vasculitis.

The study assigned 99 patients to rituximab and 98 to cyclophosphamide, with the goal of obtaining complete remission and withdrawing patients from prednisone. Three quarters of the group had Wegener's granulomatosis and one quarter had microscopic polyangiitis.

Disease remission was reported in 63.6% of the rituximab group and 53.1% of the cyclophosphamide group. A reduction in disease activity, measured by a score of 0 on the Birmingham Vasculitis Activity Score for Wegener's granulomatosis, and tapering of prednisone to less than 10 mg/day was observed in 70.7% of the rituximab group and 62.2% of the cyclophosphamide group.

Rituximab obtained almost complete depletion of B-cells, which is thought to be important in controlling this disease. Cyclophosphamide also depleted B-cells, but the effect was less robust, Dr. Specks said.

The difference between the 2 treatment groups was not significant in the newly diagnosed patients (n = 96), but rituximab was superior in achieving complete remission in the 101 patients with severe disease flares at baseline (66.7% vs 42%, representing almost a 25% absolute improvement).

The rate of protocol-defined adverse events was similar between groups (0.06% for rituximab and 0.08% for cyclophosphamide), with no difference in rate of infection. Fewer patients treated with rituximab experienced 1 or more adverse event(s), compared with cyclophosphamide (19.2% vs 32.7; P = .03).

"Strong and Exciting" Data

"These data are strong and exciting," said Robert Terkeltaub, MD, from the VA Medical Center, University of California, San Diego.

"This is good news because oral cyclophosphamide is associated with toxicities that include genitourinary malignancies, loss of fertility, and infection. Many patients have difficulty tolerating long-term cyclophosphamide treatment for ANCA-associated vasculitis. Studies in this patient group have shown that after 10 to 15 years of treatment, the incidence of [genitourinary] transitional cell carcinoma was 10% to 15%, which is startlingly high and unacceptable," Dr. Terkeltaub stated.

He commended the RAVE investigators for a well-designed study. "It's great to know that this alternative therapy works as well, with more rapid B-cell depletion, as cyclophosphamide," he continued. Another plus is that rituximab is already used to treat rheumatoid arthritis, and rheumatologists are comfortable using it.

In Dr. Terkeltaub's opinion, "RAVE showed that rituximab is a significant therapeutic advance in ANCA-associated vasculitis."

Medications were provided by Genentech and Biogenic Idec, and the study received support from the Immune Tolerance Network. Dr. Specks has disclosed no relevant financial relationships. Dr. Terkeltaub reports being a consultant for URL Pharma, Regeneron, Novartis, Takeda, Savient, and Ardea.

American College of Rheumatology (ACR) 2009: Abstract 550. Presented October 18, 2009.