Dr. Hoffman has received consulting fees, speaking fees, and/or honoraria from Sanofi-Aventis, Roche, and Genentech (less than $10,000 each).
Clinical Outcomes of Remission Induction Therapy for Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis†
Article first published online: 26 AUG 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 9, pages 2441–2449, September 2013
How to Cite
Miloslavsky, E. M., Specks, U., Merkel, P. A., Seo, P., Spiera, R., Langford, C. A., Hoffman, G. S., Kallenberg, C. G. M., St.Clair, E. W., Tchao, N. K., Viviano, L., Ding, L., Sejismundo, L. P., Mieras, K., Iklé, D., Jepson, B., Mueller, M., Brunetta, P., Allen, N. B., Fervenza, F. C., Geetha, D., Keogh, K., Kissin, E. Y., Monach, P. A., Peikert, T., Stegeman, C., Ytterberg, S. R., Stone, J. H. and for the Rituximab in ANCA-Associated Vasculitis–Immune Tolerance Network Research Group (2013), Clinical Outcomes of Remission Induction Therapy for Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Arthritis & Rheumatism, 65: 2441–2449. doi: 10.1002/art.38044
ClinicalTrials.gov identifier: NCT00104299.
- Issue published online: 26 AUG 2013
- Article first published online: 26 AUG 2013
- Accepted manuscript online: 10 JUN 2013 09:09AM EST
- Manuscript Accepted: 30 MAY 2013
- Manuscript Received: 26 DEC 2012
- Immune Tolerance Network. Grant Numbers: NIH contract N01-AI-15416, protocol number ITN021AI
- University of California San Francisco
- NIH (National Institute of Allergy and Infectious Diseases). Grant Numbers: contract N01-AI-15416, protocol number ITN021AI
- Juvenile Diabetes Research Foundation
- Genentech and Biogen Idec provided the study medications and partial funding for the RAVE trial
- Mayo Clinic
- Johns Hopkins University
- Boston University School of Medicine
- NIH (Mayo Clinic: National Center for Research Resources Clinical and Translational Science award). Grant Number: RR-024150-01
- Johns Hopkins University: National Center for Research Resources Clinical and Translational Science. Grant Numbers: RR-025005, K23-AR-052820, K24-AR-049185
- Boston University: National Center for Research Resources Clinical and Translational Science award. Grant Numbers: RR-025771, M01-RR-00533, K24-AR-02224
- Genentech (Clinical Immunology Fellowship)
- Arthritis Foundation (Arthritis Investigator Award)
To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA).
The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other).
Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)–ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare.
Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.