Treatment of rheumatoid arthritis with humanized anti–interleukin-6 receptor antibody: A multicenter, double-blind, placebo-controlled trial

Authors

  • Norihiro Nishimoto,

    Corresponding author
    1. Osaka University, Osaka, Japan
    • Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University 1-3, Yamada-Oka, Suita-City, Osaka 565-0871, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Kazuyuki Yoshizaki,

    1. Osaka University, Osaka, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Nobuyuki Miyasaka,

    1. Tokyo Medical and Dental University, Tokyo, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Kazuhiko Yamamoto,

    1. University of Tokyo, Tokyo, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Shinichi Kawai,

    1. St. Marianna University School of Medicine, Kanagawa, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Tsutomu Takeuchi,

    1. Saitama Medical Center/School, Saitama, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Jun Hashimoto,

    1. Osaka University, Osaka, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Junichi Azuma,

    1. Osaka University, Osaka, Japan
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    • Drs. Nishimoto, Yoshizaki, Miyasaka, Yamamoto, Kawai, Takeuchi, Hashimoto, and Azuma have served as consultants to and/or received honoraria from Chugai Pharmaceutical, the manufacturer of MRA.

  • Tadamitsu Kishimoto

    1. Osaka University, Osaka, Japan
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Abstract

Objective

Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti–IL-6 receptor antibody, MRA, in patients with RA.

Methods

In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.

Results

Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients.

Conclusion

Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

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