title: Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial.
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.
  
  
  CONCLUSIONS
  Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.
authors.affiliation: Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Suita-City, Osaka, Japan. norihiro@fbs.osaka-u.ac.jp
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishimoto
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yoshizaki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawai
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Jun
authors.initials: J
authors.lastname: Hashimoto
authors.forename: Junichi
authors.initials: J
authors.lastname: Azuma
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: 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
chemical_list: D000906:Antibodies; D018501:Antirheumatic Agents; D019947:Receptors, Interleukin-6