Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab.
Journal: 2007/September - Annals of the Rheumatic Diseases
ISSN: 0003-4967
Abstract:
OBJECTIVE
To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA.
METHODS
In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method.
RESULTS
Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively.
CONCLUSIONS
Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
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Ann Rheum Dis 66(9): 1162-1167

Study of active controlled monotherapy used for rheumatoid arthritis, an IL‐6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an <em>x</em> ray reader‐blinded randomised controlled trial of tocilizumab

Norihiro Nishimoto, Jun Hashimoto, Tadamitsu Kishimoto, Osaka University, Osaka, Japan
Nobuyuki Miyasaka, Tokyo Medical &amp; Dental University, Tokyo, Japan
Kazuhiko Yamamoto, University of Tokyo, Tokyo, Japan
Shinichi Kawai, Toho University Omori Medical Center, Tokyo, Japan
Tsutomu Takeuchi, Saitama Medical Center/School, Saitama, Japan
Norikazu Murata, Kyowakai Hospital, Osaka, Japan
Désirée van der Heijde, University Hospital Maastricht, Maastricht, The Netherlands
Correspondence to: Norihiro Nishimoto
MD, Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University 1–3, Yamada‐oka, Suita, Osaka, 565‐0871, Japan; norihiro@fbs.osaka‐u.ac.jp
Norihiro Nishimoto, Jun Hashimoto, Tadamitsu Kishimoto, Osaka University, Osaka, JapanNobuyuki Miyasaka, Tokyo Medical &amp; Dental University, Tokyo, JapanKazuhiko Yamamoto, University of Tokyo, Tokyo, JapanShinichi Kawai, Toho University Omori Medical Center, Tokyo, JapanTsutomu Takeuchi, Saitama Medical Center/School, Saitama, JapanNorikazu Murata, Kyowakai Hospital, Osaka, JapanDésirée van der Heijde, University Hospital Maastricht, Maastricht, The NetherlandsCorrespondence to: Norihiro Nishimoto
MD, Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University 1–3, Yamada‐oka, Suita, Osaka, 565‐0871, Japan; norihiro@fbs.osaka‐u.ac.jp
Accepted 2007 Apr 14.

Abstract

Objective

To evaluate the ability of tocilizumab (a humanised anti‐IL‐6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA.

Methods

In a multi‐centre, x ray reader‐blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease‐modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method.

Results

Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively.

Conclusion

Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by persistent synovitis and destruction of bone and cartilage in multiple joints.1 Although etiological causes are still obscure, constitutive overproduction of interleukin‐6 (IL‐6), a pleiotropic cytokine that regulates the immune response, inflammation, hematopoiesis, and bone metabolism, is thought to play a pathological role in RA.2 Overproduction of IL‐6 augments autoimmune reaction and causes systemic inflammatory manifestations. IL‐6, synergistically with IL‐1β or TNFα, induces the production of vascular endothelial growth factor, a potent inducer of angiogenesis necessary to oxygenate the hyperplastic synovial tissues in the affected joints.3 IL‐6 in the presence of soluble IL‐6 receptor induces osteoclast differentiation and can be responsible for joint destruction and osteoporosis associated with RA.45 In fact, elevated IL‐6 levels are observed in serum and synovial fluid in RA patients678910 and correlate with disease activity and radiological joint damage.511121314 IL‐6 levels also correlate with levels of matrix metalloproteinase 3,15 which degrades the proteoglycan of cartilage and also predicts radiological progression.151617

Tocilizumab, a humanised anti‐IL‐6 receptor (IL‐6R) monoclonal antibody,18 has been shown to improve the symptoms of RA in previous clinical trials.19202122 However, there is no study to date that investigates the potential of tocilizumab in inhibiting joint damage and improving disability, which are also important therapeutic endpoints.

To investigate whether tocilizumab monotherapy provides radiographic and clinical benefits to active RA patients, we conducted a multi‐centre, x ray reader‐blinded, randomised, controlled study.

Acknowledgements

The authors wish to thank the members of MRA clinical study group for the treatment and Takahiro Kakehi BSc, Tatsuya Horiguchi BSc, and Paul Langman PhD for their valuable assistance with the design and analysis of the study and preparation of this manuscript. This work was supported by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.

Acknowledgements

Footnotes

Competing interests: NN has served as a consultant to and/or received honoraria from Chugai Pharmaceutical, the manufacture of tocilizumab. TK holds a patent for tocilizumab. The other authors have no competing interests.

Footnotes

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