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, placebocontrolled 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.

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate

“…Thus, inflammatory actions on nerve endings, including nociceptive fibers, may result in long‐term sensitization, which contributes to chronic pain conditions. Proinflammatory cytokines like tumor necrosis factor (TNF) and interleukin 6 (IL‐6) are both of specific importance in RA pathogenesis, and specific cytokine blockade has been shown beneficial 22, 23. Both TNF and IL‐6 also affect pain thresholds in experimental arthritis 24, 25, as well as long‐term sensitization of joint nociceptors 26.…”

Targeting Interleukin-6 in Rheumatoid Arthritis

“…At that time, tocilizumab was known as MRA. In this multi-centre study conducted in Japan, 164 patients with refractory RA were randomised to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo [43]. MRA was given as monotherapy as all DMARDs were withdrawn prior to the study.…”

Crucial role of the interleukin‐6/interleukin‐17 cytokine axis in the induction of arthritis by glucose‐6‐phosphate isomerase

“…The therapeutic effects of a humanized anti-IL-6R␣ antibody (tocilizumab) on RA have recently been reported (26,27). Patients with severe forms of RA retained high titers of anti-GPI antibodies (7,28,29), although a few control subjects also had these antibodies.…”

“…In our present study, administration of anti-IL-17 mAb or MR16-1 on day 14 (late effector phase) was not able to ameliorate GPI-induced arthritis. However, both the IL-6/IL-17 axis and TNF␣ might play a crucial role in established RA, since both tocilizumab and TNF antagonists have shown marked therapeutic efficacy in humans with established RA (26,27,(31)(32)(33)(34), although administration of MR16-1 or anti-TNF mAb has shown no effect or only a weak effect on fully established CIA in mouse models (35,36). Further ana-lysis is necessary to determine whether GPI-reactive Th17 cells exist in the peripheral blood or joints of patients with RA who have anti-GPI antibodies.…”