PRAGUE—A single four-week course of rituximab was as effective as 18 months of standard therapy with daily oral cyclophosphamide (CyP) and azathioprine (AZA) for induction and maintenance of remission in patients with severe anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). For either treatment, the number, rate, and severity of adverse events did not differ.

Cees Kallenberg, MD, PhD, Professor of Clinical Immunology at University Medical Center Groningen in Groningen, Netherlands presented these late-breaking clinical trial results from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial at the 48th Congress of the European Renal Association-European Dialysis and Transplant Association. The trial compared the efficacy of rituximab and cyclophosphamide for induction of remission of severe AAV.

Eligible patients had active or severe AAV—either Wegener’s granulomatosis (WG) or microscopic polyangiitis (MPA). At least half of the patients enrolled were to have WG, a Birmingham vasculitis activity score specific for Wegener’s granulomatosis (BVAS/WG) of 3 or higher, a clinical situation requiring cyclophosphamide, and ANCA-positivity at screening.

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Participants could not require mechanical ventilation or have a serum creatinine level above 4 mg/dL. They could not have used CyP in the previous four months or have had a history of toxicity or unresponsiveness to CyP. Subject could not have been treated previously with rituximab.

All 200 enrolled patients initially received 1-3 g of IV methylprednisolone. They were then randomly assigned to rituximab infusions (375 mg/m2 weekly for four weeks) and CyP-placebo for six months and AZA-placebo for 12 more months, or to CyP (2 mg/kg orally daily for three to six months) and rituximab-placebo infusions. For patients in the latter group achieving remission, CyP was replaced by AZA from months 3-6 and continued on this drug for the remainder of the 18 months.

All patients received prednisone 1 mg/kg/day, tapered over 5.5 months. Upon induction regimen failure, patients were crossed-over to the other treatment. If remission was lost while patients were taking AZA, they were treated with open-label rituximab. In each group, two-thirds of the patients were positive for antibodies against proteinase 3 (PR3), one third for antibodies against myeloperoxidase (MPO), one quarter had MPA, and three quarters had WG. The 99 subjects in the rituximab arm and the 98 in the CyP arm were well matched for BVAS/WG score and other baseline characteristics.

Equal efficacy for remissions

The primary outcome measure was complete remission at 6 months, as defined by a BVAS/WG score of 0 and no need for corticosteroids. All patients were followed for at least 18 months. Data were presented according to intention-to-treat.

“B cells were undetectable after two infusions of rituximab and stayed undetectable during six months,” Dr. Kallenberg reported. The B cell count in the CyP arm was also significantly diminished out to six months. The study revealed no difference between patients with MPO-ANCA or PR3-ANCA.

At six months, 63.6% of patients on rituximab and 53.1% receiving CyP had achieved remission. “So the primary endpoint was reached, which means that rituximab is not inferior to cyclophosphamide for induction of remission,” Dr. Kallenberg said.

In subgroup analyses, 60.4% to 64.% of newly diagnosed patients experienced a remission across the two groups, but rituximab was associated with significantly better responses among patients with a severe flare (66.7% vs. 42.0%).

Maintenance of remission was fairly durable in both arms at 12 and 18 months. Most failures occurred because of disease flares or the use of prednisone, most often for conditions other than AAV. The groups did not differ in terms of either severe or limited disease flares at either time point.

Severe flares occurred in the presence of detectable peripheral blood B lymphocytes, Dr. Kallenberg said. In two of 16 cases of flare, B cell concentrations were still low and not completely reconstituted.

Overall and serious adverse event rates were similar between the groups. Two deaths occurred in each treatment arm. Grade 3 infections occurred in 16% to 18% of the patients.

Dr. Kallenberg concluded that “one course of four weekly infusions of rituximab without any maintenance treatments is as effective as 18 months treatment of standard therapy with daily oral cyclophosphamide followed by azathioprine.”