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

Authors

  • R. N. Maini,

    Corresponding author
    1. Kennedy Institute of Rheumatology Division, Imperial College, London, UK
    • FMed Sci, Kennedy Institute of Rheumatology Division, Imperial College, London W6 8LH, UK
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    • Dr. Maini has received consulting fees and honoraria (less than $10,000 each) from Roche and Centocor and has received consulting fees (more than $10,000) from Chugai Pharmaceuticals Ltd. Dr. Maini receives royalties from The Kennedy Institute of Rheumatology Trust for an anti–tumor necrosis factor patent. Dr. Maini is a coinventor of the coadministration of tocilizumab and methotrexate, for which a patent is pending. Dr. Maini previously owned stock in Johnson & Johnson, of which Centocor is a subsidiary. Dr. Maini is Non-Executive Director of Domantis and founder of Synovis Ltd. Dr. Taylor has received honoraria (less than $10,000) from Centocor. Dr. Emery has received consulting fees (less than $10,000) from Roche. Dr. Kishimoto holds a patent for tocilizumab.

  • P. C. Taylor,

    1. Kennedy Institute of Rheumatology Division, Imperial College, London, UK
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    • Dr. Maini has received consulting fees and honoraria (less than $10,000 each) from Roche and Centocor and has received consulting fees (more than $10,000) from Chugai Pharmaceuticals Ltd. Dr. Maini receives royalties from The Kennedy Institute of Rheumatology Trust for an anti–tumor necrosis factor patent. Dr. Maini is a coinventor of the coadministration of tocilizumab and methotrexate, for which a patent is pending. Dr. Maini previously owned stock in Johnson & Johnson, of which Centocor is a subsidiary. Dr. Maini is Non-Executive Director of Domantis and founder of Synovis Ltd. Dr. Taylor has received honoraria (less than $10,000) from Centocor. Dr. Emery has received consulting fees (less than $10,000) from Roche. Dr. Kishimoto holds a patent for tocilizumab.

  • J. Szechinski,

    1. University School of Wroclaw, Wroclaw, Poland
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  • K. Pavelka,

    1. Institute of Rheumatology, Prague, Czech Republic
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  • J. Bröll,

    1. Ludwig Boltzmann Institute for Rheumatology and Balneology, Wien-Oberlaa, Austria
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  • G. Balint,

    1. National Institute of Rheumatology and Physiotherapy, Budapest, Hungary
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  • P. Emery,

    1. University of Leeds, Leeds, UK
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    • Dr. Maini has received consulting fees and honoraria (less than $10,000 each) from Roche and Centocor and has received consulting fees (more than $10,000) from Chugai Pharmaceuticals Ltd. Dr. Maini receives royalties from The Kennedy Institute of Rheumatology Trust for an anti–tumor necrosis factor patent. Dr. Maini is a coinventor of the coadministration of tocilizumab and methotrexate, for which a patent is pending. Dr. Maini previously owned stock in Johnson & Johnson, of which Centocor is a subsidiary. Dr. Maini is Non-Executive Director of Domantis and founder of Synovis Ltd. Dr. Taylor has received honoraria (less than $10,000) from Centocor. Dr. Emery has received consulting fees (less than $10,000) from Roche. Dr. Kishimoto holds a patent for tocilizumab.

  • F. Raemen,

    1. AZ Jan Palfijn Hospital, Antwerp, Belgium
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  • J. Petersen,

    1. The Finsen Centre, State University Hospital, Copenhagen, Denmark
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  • J. Smolen,

    1. Medical University of Vienna and Lainz Hospital, Vienna, Austria
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  • D. Thomson,

    1. Chugai Pharma Europe, London, UK
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  • T. Kishimoto

    1. Osaka University, Osaka, Japan
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    • Dr. Maini has received consulting fees and honoraria (less than $10,000 each) from Roche and Centocor and has received consulting fees (more than $10,000) from Chugai Pharmaceuticals Ltd. Dr. Maini receives royalties from The Kennedy Institute of Rheumatology Trust for an anti–tumor necrosis factor patent. Dr. Maini is a coinventor of the coadministration of tocilizumab and methotrexate, for which a patent is pending. Dr. Maini previously owned stock in Johnson & Johnson, of which Centocor is a subsidiary. Dr. Maini is Non-Executive Director of Domantis and founder of Synovis Ltd. Dr. Taylor has received honoraria (less than $10,000) from Centocor. Dr. Emery has received consulting fees (less than $10,000) from Roche. Dr. Kishimoto holds a patent for tocilizumab.


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.

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