John H. Stone, MD, Massachusetts General Hospital, Boston, Massachusetts, USA, presented the results of the 18-month follow-up from the Rituximab in ANCA-Associated Vasculitis trial [RAVE; ISRCTN28528813; Stone JH et al. N Engl J Med 2010], which found that one course of treatment with rituximab was noninferior to standard course of therapy (cyclophosphamide followed by azathioprine) for remission-induction of severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Patients who were at highest risk for flare had relapsing disease at baseline, proteinase 3(PR3)-ANCA positivity, or granulomatosis with polyangiitis (GPA).

The RAVE trial was a randomized, double-blind, placebo-controlled, noninferiority study. Patients from the original 6-month study were switched from cyclophosphamide to azathioprine or from rituximab to placebo between 3 and 6 months if remission was achieved [Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 and complete remission if BVAS/WG=0 off prednisone] and followed for 18 months. Remission rates were compared for the following subsets using log-rank tests: new diagnosis versus relapsing disease at baseline; myeloperoxidase (MPO)- versus PR3-ANCA; and microscopic polyangiitis (MPA) versus GPA.

After 18 months, more than 60% of patients from the original groups remained in the study. There was no significant difference in the cumulative number of severe or limited disease flares between the rituximab and cyclophosphamide-azathioprine treatment groups. By the end of the study, 39% of patients in the rituximab group versus 33% in the cyclophosphamide-azathioprine group met the definition of complete remission (p=NS). In the rituximab group, 77% of the originally treated patients achieved complete remission versus 71% for cyclophosphamide-azathioprine at any time during the study (p=0.69).

When analyzed by disease subsets, patients who were MPO-ANCA-positive (79%) had significantly (p=0.01) higher remission rates compared with PR3-ANCA-positive patients (72%). Patients with MPA (79%) had significantly higher (p=0.01) remission rates compared with those with GPA (73%). Patients at study entry who were considered to be in relapse (67%) had significantly lower (p=0.01) remission rates compared with those who entered with a new diagnosis (81%). In all disease types, time to disease flare was longer for those patients with higher remission rates. Disease flares in the two treatment arms did not differ in number or severity.

The investigators noted that an increasing rise in ANCA titer or B-cell count was not an accurate predictor of disease flare. B-cell depletion occurred with cyclophosphamide-azathioprine, as well as rituximab, but was more prolonged with cyclophosphamide-azathioprine. Among rituximab-treated patients who achieved complete remission, flares occurred only after reconstitution of detectable B-cells. Dr. Stone noted that although flares occur in the absence of both B-cells and ANCA, as long as B-cells remain depleted and ANCA remains negative, the risk of a severe flare is low.

There were no clinically significant differences in overall or serious adverse events, deaths, infections, or malignancies. In particular, no additional malignancies occurred beyond those reported in the original study.

These results demonstrate that a single course of rituximab is as effective up to 18 months as standard therapy (cyclophosphamide-azathioprine) for remission induction and maintenance in severe ANCA-associated vasculitis. Relapses are more common in those with PR3-ANCA, GPA, and relapsing disease at baseline. Additional mechanistic studies are needed to define the immunological events that surround relapses more precisely.