Efficacy of remission-induction regimens for ANCA-associated vasculitis.

Abstract

BACKGROUND:

The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is unknown.

METHODS:

In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months.

RESULTS:

A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P=0.01) and at 12 months (P=0.009) but not at 18 months (P=0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events.

CONCLUSIONS:

In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

• Authors: Ulrich Specks, Peter A Merkel, Philip Seo, Robert Spiera, Carol A Langford, Gary S Hoffman, Cees G M Kallenberg, E William St Clair, Barri J Fessler, Linna Ding, Lisa Viviano, Nadia K Tchao, Deborah J Phippard, Adam L Asare, Noha Lim, David Ikle, Brett Jepson, Paul Brunetta, Nancy B Allen, Fernando C Fervenza, Duvuru Geetha, Karina Keogh, Eugene Y Kissin, Paul A Monach, Tobias Peikert, Coen Stegeman, Steven R Ytterberg, Mark Mueller, Lourdes P Sejismundo, Kathleen Mieras, John H Stone, RAVE-ITN Research Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 369 Issue 5 Pg. 417-27 (Aug 01 2013) ISSN: 1533-4406 [Electronic] United States
• PMID: 23902481 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• Glucocorticoids
• Immunologic Factors
• Immunosuppressive Agents
• Rituximab
• Cyclophosphamide
• Azathioprine

Topics

• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis (drug therapy)
• Antibodies, Monoclonal, Murine-Derived (administration & dosage, adverse effects, therapeutic use)
• Azathioprine (adverse effects, therapeutic use)
• B-Lymphocytes
• Cyclophosphamide (adverse effects, therapeutic use)
• Double-Blind Method
• Drug Administration Schedule
• Drug Therapy, Combination
• Glucocorticoids (therapeutic use)
• Humans
• Immunologic Factors (administration & dosage, adverse effects, therapeutic use)
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Kaplan-Meier Estimate
• Recurrence
• Remission Induction
• Rituximab