Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Extended Follow-up of Treatment with Rituximab Versus Cyclophosphamide for Remission-Induction of ANCA-Associated Vasculitis: Which Subsets Are At Greatest Risk for Flare?
Stone1, John H., Merkel2, Peter A., Seo3, Philip, Spiera4, Robert, Langford5, Carol A., Hoffman5, Gary S., Kallenberg6, Cees GM
Massachusetts General Hospital, Boston, MA
National Institute of Allergy and Infectious Diseases
NIAID, Bethesda, MD
Johns Hopkins University, Baltimore, MD
Mayo Clinic, Rochester, MN
Rho, Chapel Hill, NC
Food & Drug Administration, Bethesda, MD
Genentech, So San Francisco, CA
Duke University Medical Center, Durham, NC
Johns Hopkins University, York, PA
Boston University, Boston, MA
Boston University School of Medicine, Boston, MA
Johns Hopkins Vasculitis Center, Baltimore, MD
Hospital for Special Surgery, New York, NY
Cleveland Clinic, Cleveland, OH
University Medical Center Groningen, Groningen, Netherlands
Duke University Medical Center, Durham
Univ of Alabama-Birmingham, Birmingham, AL
Immune Tolerance Network, Bethesda, MD
Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) for remission-induction in severe ANCA-associated vasculitis (AAV) [microscopic polyangiitis (MPA), granulomatosis with polyangiitis (Wegener's, GPA)] and superior for patients with relapsing disease. Understanding longer-term outcomes, particularly in certain disease subsets, is essential for optimizing AAV treatment. We evaluated the efficacy of one course of RTX compared to CYC followed by AZA over 18 months (M), with assessments of outcomes according to original treatment assignment, ANCA type, AAV type, renal disease, and relapsing disease at baseline.
A randomized, double-blind, placebo-controlled trial tested the hypothesis that RTX (375 mg/m2 iv weekly × 4) was not inferior to CYC (2 mg/kg/d po) for remission-induction at 6 months [N Engl J Med 2010]. CYC was replaced by AZA and RTX by placebo between 36M if remission was achieved. Patients were followed for a minimum of 18M. Remission was defined as a Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG) of 0, and complete remission by BVAS/WG=0 off prednisone. Remission rates were compared for the following subsets using log-rank tests: new diagnosis vs relapsing disease at baseline; MPO- vs PR3-ANCA; MPA vs GPA; and presence vs absence of major renal disease at baseline.
Nine centers enrolled 197 patients with severe GPA or MPA (3:1), all positive for either PR3-ANCA or MPO-ANCA (2:1). At entry, 49% of patients had new disease, 52% had major renal disease. Complete remission was achieved and sustained at 6, 12, and 18M by 64%, 47%, and 39% in the RTX arm, vs 53%, 39%, and 33% in the CYC/AZA arm, respectively (P=0.NS). Disease flares in the two treatment arms did not differ in number/severity. No unexpected safety issues were detected. The Figure shows Kaplan-Meier plots for duration of complete remission for pre-specified disease subsets.
Patients at highest risk for flare had relapsing disease at baseline, no major renal disease, PR3-ANCA positivity, or GPA. Relapsing disease and no major renal disease subsets were enriched with PR3-ANCA-positive patients, who overlapped substantially with a diagnosis of GPA. Among RTX-treated patients who achieved complete remission, flares occurred only after the return of detectable levels of B cells.
A single course of RTX is as effective as 18 months of standard therapy (CYC followed by AZA) for remission induction and maintenance in severe AAV. Patients at increased risk for flares are identifiable by ANCA type, AAV type, absence of major renal disease at baseline, and prior flare history. Additional mechanistic studies may define the immunological events surrounding relapses more precisely.
To cite this abstract, please use the following information:
Stone, John H., Merkel, Peter A., Seo, Philip, Spiera, Robert, Langford, Carol A., Hoffman, Gary S., et al; Extended Follow-up of Treatment with Rituximab Versus Cyclophosphamide for Remission-Induction of ANCA-Associated Vasculitis: Which Subsets Are At Greatest Risk for Flare? [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2432