Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate.

Abstract

OBJECTIVE:

To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).

METHODS:

The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.

RESULTS:

A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.

CONCLUSION:

These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

• Authors: R N Maini, P C Taylor, J Szechinski, K Pavelka, J Bröll, G Balint, P Emery, F Raemen, J Petersen, J Smolen, D Thomson, T Kishimoto, CHARISMA Study Group
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 54 Issue 9 Pg. 2817-29 (Sep 2006) ISSN: 0004-3591 [Print] United States
• PMID: 16947782 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents
• Receptors, Interleukin-6
• tocilizumab
• Methotrexate

Topics

• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antirheumatic Agents (therapeutic use)
• Arthritis, Rheumatoid (drug therapy, physiopathology)
• Dose-Response Relationship, Drug
• Europe
• Female
• Humans
• Male
• Methotrexate (therapeutic use)
• Middle Aged
• Pain (epidemiology)
• Patient Selection
• Receptors, Interleukin-6 (antagonists & inhibitors)
• Safety
• Treatment Failure
• Treatment Outcome