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


CONCLUSIONS
Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.
Nishimoto
Norihiro
N
Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Suita-City, Osaka, Japan. norihiro@fbs.osaka-u.ac.jp
Yoshizaki
Kazuyuki
K
Miyasaka
Nobuyuki
N
Yamamoto
Kazuhiko
K
Kawai
Shinichi
S
Takeuchi
Tsutomu
T
Hashimoto
Jun
J
Azuma
Junichi
J
Kishimoto
Tadamitsu
T
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000008:administration & dosage* / Q000009:adverse effects; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D016896:Treatment Outcome
D000906:Antibodies; D018501:Antirheumatic Agents; D019947:Receptors, Interleukin-6