Rituximab for rheumatoid arthritis refractory to anti–tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks

Authors

  • Stanley B. Cohen,

    Corresponding author
    1. Radiant Research, Dallas, Texas
    • Radiant Research, 5939 Harry Hines Boulevard, Suite 441, Dallas, TX 75235
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    • Dr. Cohen has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Scios, and Amgen. Dr. Emery has received honoraria (less than $10,000) from Genentech. Dr. Furie has received honoraria (less than $10,000 each) from Biogen Idec and Genentech. Dr. Keystone has received honoraria (less than $10,000 each) from Amgen, Wyeth, Centocor, Abbott, Schering-Plough, Bristol-Meyers Squibb, Genentech, Biogen Idec, and Roche. Dr. Genovese has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Amgen, Centocor, Abbott, and Bristol-Meyers Squibb. Mr. Cravets and Dr. Totoritis own stock in Biogen Idec. Mr. Shaw owns stock in Roche.

  • Paul Emery,

    1. Leeds General Infirmary, Leeds, UK
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    • Dr. Cohen has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Scios, and Amgen. Dr. Emery has received honoraria (less than $10,000) from Genentech. Dr. Furie has received honoraria (less than $10,000 each) from Biogen Idec and Genentech. Dr. Keystone has received honoraria (less than $10,000 each) from Amgen, Wyeth, Centocor, Abbott, Schering-Plough, Bristol-Meyers Squibb, Genentech, Biogen Idec, and Roche. Dr. Genovese has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Amgen, Centocor, Abbott, and Bristol-Meyers Squibb. Mr. Cravets and Dr. Totoritis own stock in Biogen Idec. Mr. Shaw owns stock in Roche.

  • Maria W. Greenwald,

    1. Desert Medical Advances, Palm Desert, California
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  • Maxime Dougados,

    1. René Descartes University, Paris, France
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  • Richard A. Furie,

    1. North Shore–Long Island Jewish Health System, Lake Success, New York
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    • Dr. Cohen has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Scios, and Amgen. Dr. Emery has received honoraria (less than $10,000) from Genentech. Dr. Furie has received honoraria (less than $10,000 each) from Biogen Idec and Genentech. Dr. Keystone has received honoraria (less than $10,000 each) from Amgen, Wyeth, Centocor, Abbott, Schering-Plough, Bristol-Meyers Squibb, Genentech, Biogen Idec, and Roche. Dr. Genovese has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Amgen, Centocor, Abbott, and Bristol-Meyers Squibb. Mr. Cravets and Dr. Totoritis own stock in Biogen Idec. Mr. Shaw owns stock in Roche.

  • Mark C. Genovese,

    1. Stanford University Medical Center, Stanford, California
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    • Dr. Cohen has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Scios, and Amgen. Dr. Emery has received honoraria (less than $10,000) from Genentech. Dr. Furie has received honoraria (less than $10,000 each) from Biogen Idec and Genentech. Dr. Keystone has received honoraria (less than $10,000 each) from Amgen, Wyeth, Centocor, Abbott, Schering-Plough, Bristol-Meyers Squibb, Genentech, Biogen Idec, and Roche. Dr. Genovese has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Amgen, Centocor, Abbott, and Bristol-Meyers Squibb. Mr. Cravets and Dr. Totoritis own stock in Biogen Idec. Mr. Shaw owns stock in Roche.

  • Edward C. Keystone,

    1. University of Toronto, Toronto, Ontario, Canada
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    • Dr. Cohen has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Scios, and Amgen. Dr. Emery has received honoraria (less than $10,000) from Genentech. Dr. Furie has received honoraria (less than $10,000 each) from Biogen Idec and Genentech. Dr. Keystone has received honoraria (less than $10,000 each) from Amgen, Wyeth, Centocor, Abbott, Schering-Plough, Bristol-Meyers Squibb, Genentech, Biogen Idec, and Roche. Dr. Genovese has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Amgen, Centocor, Abbott, and Bristol-Meyers Squibb. Mr. Cravets and Dr. Totoritis own stock in Biogen Idec. Mr. Shaw owns stock in Roche.

  • James E. Loveless,

    1. Intermountain Orthopedics, Boise, Idaho
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  • Gerd-Rüdiger Burmester,

    1. Charité University Hospital, Berlin, Germany
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  • Matthew W. Cravets,

    1. Biogen Idec, San Diego, California
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    • Dr. Cohen has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Scios, and Amgen. Dr. Emery has received honoraria (less than $10,000) from Genentech. Dr. Furie has received honoraria (less than $10,000 each) from Biogen Idec and Genentech. Dr. Keystone has received honoraria (less than $10,000 each) from Amgen, Wyeth, Centocor, Abbott, Schering-Plough, Bristol-Meyers Squibb, Genentech, Biogen Idec, and Roche. Dr. Genovese has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Amgen, Centocor, Abbott, and Bristol-Meyers Squibb. Mr. Cravets and Dr. Totoritis own stock in Biogen Idec. Mr. Shaw owns stock in Roche.

  • Eva W. Hessey,

    1. Roche Products Ltd., Welwyn Garden City, UK
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  • Timothy Shaw,

    1. Roche Products Ltd., Welwyn Garden City, UK
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  • Mark C. Totoritis

    1. Biogen Idec, San Diego, California
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    • Dr. Cohen has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Scios, and Amgen. Dr. Emery has received honoraria (less than $10,000) from Genentech. Dr. Furie has received honoraria (less than $10,000 each) from Biogen Idec and Genentech. Dr. Keystone has received honoraria (less than $10,000 each) from Amgen, Wyeth, Centocor, Abbott, Schering-Plough, Bristol-Meyers Squibb, Genentech, Biogen Idec, and Roche. Dr. Genovese has received honoraria (less than $10,000 each) from Genentech, Biogen Idec, Amgen, Centocor, Abbott, and Bristol-Meyers Squibb. Mr. Cravets and Dr. Totoritis own stock in Biogen Idec. Mr. Shaw owns stock in Roche.


Abstract

Objective

To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti–tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population.

Methods

We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks.

Results

Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group.

Conclusion

At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.

Ancillary