Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody

A multicenter, double-blind, placebo-controlled trial

Norihiro Nishimoto, Kazuyuki Yoshizaki, Nobuyuki Miyasaka, Kazuhiko Yamamoto, Shinichi Kawai, Tsutomu Takeuchi, Jun Hashimoto, Junichi Azuma, Tadamitsu Kishimoto

Research output: Contribution to journalArticle

632 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1761-1769
Number of pages9
JournalArthritis and Rheumatism
Volume50
Issue number6
DOIs
Publication statusPublished - 2004 Jun
Externally publishedYes

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Interleukin-6 Receptors
Rheumatoid Arthritis
Placebos
Antibodies
Interleukin-6
Antinuclear Antibodies
Therapeutics
Body Weight
Hematopoiesis
Rheumatology
Leukocyte Count
Anti-Idiotypic Antibodies
Cholesterol
Cytokines
Inflammation
Safety
Liver
Incidence

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody : A multicenter, double-blind, placebo-controlled trial. / Nishimoto, Norihiro; Yoshizaki, Kazuyuki; Miyasaka, Nobuyuki; Yamamoto, Kazuhiko; Kawai, Shinichi; Takeuchi, Tsutomu; Hashimoto, Jun; Azuma, Junichi; Kishimoto, Tadamitsu.

In: Arthritis and Rheumatism, Vol. 50, No. 6, 06.2004, p. 1761-1769.

Research output: Contribution to journalArticle

Nishimoto, N, Yoshizaki, K, Miyasaka, N, Yamamoto, K, Kawai, S, Takeuchi, T, Hashimoto, J, Azuma, J & Kishimoto, T 2004, 'Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: A multicenter, double-blind, placebo-controlled trial', Arthritis and Rheumatism, vol. 50, no. 6, pp. 1761-1769. https://doi.org/10.1002/art.20303
Nishimoto, Norihiro ; Yoshizaki, Kazuyuki ; Miyasaka, Nobuyuki ; Yamamoto, Kazuhiko ; Kawai, Shinichi ; Takeuchi, Tsutomu ; Hashimoto, Jun ; Azuma, Junichi ; Kishimoto, Tadamitsu. / Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody : A multicenter, double-blind, placebo-controlled trial. In: Arthritis and Rheumatism. 2004 ; Vol. 50, No. 6. pp. 1761-1769.
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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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T2 - A multicenter, double-blind, placebo-controlled trial

AU - Nishimoto, Norihiro

AU - Yoshizaki, Kazuyuki

AU - Miyasaka, Nobuyuki

AU - Yamamoto, Kazuhiko

AU - Kawai, Shinichi

AU - Takeuchi, Tsutomu

AU - Hashimoto, Jun

AU - Azuma, Junichi

AU - Kishimoto, Tadamitsu

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N2 - 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.

AB - 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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