Combined use of cyclophosphamide (CYC) and glucocorticoids (GCS) has been the standard of care for remission induction for ANCA-associated vasculitis (AAV) for decades. Uncontrolled studies suggest rituximab (RTX) may be effective for AAV, and its use may avoid some of the toxicities associated with CYC therapy. This trial compares the efficacy of RTX to that of CYC for AAV.
A multicenter, randomized, double-blind, placebo-controlled trial was conducted to determine if treatment with RTX (375 mg/m2 i.v. weekly x 4) was not inferior to CYC (2 mg/kg/d p.o.) for inducing remission in severe AAV. Once remission was achieved, CYC was replaced by azathioprine between months 3-6. All patients received the same GCS treatment protocol: 1-3 g i.v. methylprednisolone followed by prednisone 1 mg/kg/d p.o. reduced to 40 mg/d by month 1, and then tapered and discontinued completely by month 6. The primary endpoint was disease remission in the absence of prednisone therapy at month 6. Remission was defined as a Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG) of 0.
Nine centers enrolled a total of 197 patients with severe Wegener’s granulomatosis or microscopic polyangiitis (3:1), all positive for PR3-ANCA or MPO-ANCA (2:1). The mean BVAS/WG at enrollment was 8.4 (range 3-19). Disease severity, organ involvement, proportion of newly diagnosed disease (49%), AAV type, and ANCA type were similar in both treatment arms. All results reported refer to the initial 6 months of study participation for each patient. Eighty-four (85%) of the 99 patients in the RTX arm and 81 (83%) of the 98 in the CYC arm completed 6 months of follow-up. Sixty-three (64%) of the patients assigned to RTX achieved the primary outcome, compared with 52 (55%) in the CYC arm (P=0.21). Seventy patients (71%) in the RTX arm achieved a BVAS/WG of 0 and a prednisone dose < 10 mg/day at six months, compared with 61 patients (62%) in the CYC arm (P=0.22). No differences were observed between the groups in the rates of disease flares. The rates of protocol-defined selected adverse events were similar between the RTX and CYC groups (0.06 versus 0.08; P=0.29), but fewer patients in the RTX group experienced one or more of these events (19 vs 32 patients; P=0.03). There was no difference in treatment response within the subgroups with major renal involvement (n=99) or alveolar hemorrhage (n=50).
RTX is not inferior to CYC for the induction of remission in severe AAV. These results provide strong support for the use of RTX as an alternative to CYC in AAV.
Disclosure: J. H. Stone, None; P. A. Merkel, Genentech, Inc., 9 ; P. Seo, None; R. Spiera, None; C. A. Langford, None; G. S. Hoffman, None; C. G. M. Kallenberg, None; E. W. St. Clair, Genentech and Biogen IDEC Inc., 2, Biogen Idec, 5 ; B. J. Fessler, None; N. Tchao, None; L. Ding, None; L. V. Webber, None; D. Ikle, None; D. Weitzenkamp, None; W. Wu, None; P. Brunetta, Genentech,Inc, 3 ; L. Seismundo, None; F. C. Fervenza, Genentech , 2 ; K. A. Keogh, None; E. Y. Kissin, None; K. S. Mieras, None; P. A. Monach, None; T. Peikert, None; C. Stegeman, None; S. R. Ytterberg, None; U. Specks, None; T. RAVE-ITN Research Group, None.