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Original research
Identifying the preferable rheumatoid arthritis subgroups for intervention with the anti-RANKL antibody denosumab to reduce progression of joint destruction
  1. Yoshiya Tanaka1,
  2. Satoshi Soen2,
  3. Naoki Ishiguro3,
  4. Hisashi Yamanaka4,
  5. Toshiyuki Yoneda5,
  6. Sakae Tanaka6,
  7. Takeshi Ohira7,
  8. Takaya Nitta7,
  9. Naoki Okubo8,
  10. Harry Genant9,
  11. Desirée van der Heijde10 and
  12. Tsutomu Takeuchi11
  1. 1 First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
  2. 2 Department of Orthopaedic Surgery and Rheumatology, Kindai University Nara Hospital, Ikoma, Japan
  3. 3 Department of Orthopaedics, Nagoya University Graduate School of Medicine, Aichi, Japan
  4. 4 Director of Rheumatology, Sanno Medical Center, Tokyo, Japan
  5. 5 Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan
  6. 6 Department of Orthopaedic Surgery, The University of Tokyo, Tokyo, Japan
  7. 7 Clinical Development Department, Daiichi Sankyo Co Ltd, Tokyo, Japan
  8. 8 Data Intelligence Department, Daiichi Sankyo Co Ltd, Tokyo, Japan
  9. 9 Departments of Radiology, University of California San Francisco, California, USA
  10. 10 Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
  11. 11 Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  1. Correspondence to Yoshiya Tanaka; tanaka{at}


Objectives To clarify which rheumatoid arthritis (RA) patients benefit most from the anti-receptor activator of nuclear factor-κB ligand antibody denosumab to reduce the progression of joint destruction.

Methods We pooled patient data from the 12-month, double-blind, placebo-controlled DRIVE (phase II) and DESIRABLE (phase III) studies. In DRIVE, concomitant treatment was limited to methotrexate, salazosulfapyridine and bucillamine. In DESIRABLE, patients could receive any disease-modifying antirheumatic drug. RA patients were randomised to denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or placebo. Efficacy was assessed by van der Heijde-modified total Sharp score (mTSS), bone erosion score (ES) and joint space narrowing score (JSNS). Change in mTSS was assessed in subgroups stratified by risk factors for radiographic damage if the interaction factor was significant.

Results The pooled analysis included 909 patients. Denosumab reduced worsening of mTSS (mean (SD)) at 12 months in the Q6M (0.88 (3.30), p=0.0024) and Q3M (0.66 (2.16), p=0.0002) groups versus placebo (1.50 (3.73)). This reduction in mTSS progression was due to the change in ES (Q6M, 0.44 (1.89), p=0.0006; Q3M, 0.20 (0.86), p<0.0001) versus placebo (0.98 (2.54)); no effect was observed on JSNS. Anti-cyclic citrullinated peptide (CCP) antibodies, glucocorticoid use and baseline ES showed a significant interaction. Denosumab was particularly effective in patients who were anti-CCP antibody positive (p<0.05). Changes in mTSS versus placebo were observed in all denosumab dose groups, regardless of glucocorticoid use and baseline ES.

Conclusions Denosumab broadly reduced the progression of joint destruction in RA patients with risk factors for radiographic damage such as especially anti-CCP antibody positivity.

  • Rheumatoid Arthritis
  • DMARDs (biologic)
  • Treatment

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  • Contributors YT, SS, NI, HY and TT provided substantial contributions to the study conception and design. TY diagnosed the oral adverse events. ST diagnosed the atypical femoral fracture events. TO and TN were involved in the design and conduct of the study and in collecting data. NO was involved in the design of the study and data analysis. DvdH supervised scoring of the radiographs. All authors interpreted the data. All authors discussed and agreed on the content of the manuscript before submission.

  • Funding This study was funded by Daiichi Sankyo Co., Ltd.

  • Competing interests YT has received speaking fees and/or honoraria from Daiichi Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers Squibb, Takeda, Mitsubishi Tanabe, Novartis, Eisai, Janssen and Teijin; and has received research grants from Asahi Kasei Pharma, Mitsubishi Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers Squibb, UCB, Daiichi Sankyo, Eisai and Ono. SS has received grant/research support from Chugai and Daiichi Sankyo; and has served on speakers’ bureaus for Asahi Kasei Pharma, Astellas, Daiichi Sankyo, Takeda, Chugai, Eisai, Pfizer, Eli Lilly and Ono. NI has received grant/research support from AbbVie GK, Asahi Kasei Corp, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kaken, Medical Corporation Sanjikai, Medical Corporation Toukoukai, Mitsubishi Tanabe, Otsuka, Pfizer and Pfizer Japan, Takeda, Taisho Pharma and Zimmer Biomet GK; speakers’ bureau fees from Astellas, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Pfizer and Taisho Pharma; and consulting fees or other remuneration from Ono. HY has received grant/research support from Astellas, AbbVie, Bristol-Myers Squibb, Kaken, UCB, Ono, Ayumi, Eisai, Daiichi Sankyo, Nippon Boehringer Ingelheim, Novartis, Taisho Pharma, Takeda, Mitsubishi Tanabe, Chugai, Teijin, Torii, Nippon Shinyaku, Pfizer and YL Biologics; and speakers’ bureau fees from Pfizer, YL biologics, Takeda, Teijin and Bristol-Myers Squibb. TY has received Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT #17H04377); and has acted as a consultant for Daiichi Sankyo. ST has received grant/research support from KYOCERA Corp and Asahi Kasei Corp; consulting fees from Amgen Astellas BioPharma K.K., KYOCERA Corp, Daiichi Sankyo and Pfizer; and speakers’ bureau fees from Asahi Kasei Corp, Astellas, Ayumi, Eisai, Ono, Daiichi Sankyo, Taisho Pharma, Mitsubishi Tanabe, Chugai, Teijin, Eli Lilly, Hisamitsu, Pfizer and Bristol–Myers Squibb. TO, TN and NO report full-time employment at Daiichi Sankyo. HG has received consulting fees or other remuneration from Daiichi Sankyo, Pfizer, Amgen, Bioclinica, Eli Lilly, Janssen, Servier, Novartis, Takeda, Merck, Biomarin, Clementia, Agnovos and Regeneron. DvdH has acted as a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Bristol–Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eisai, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB and is an employee of Imaging Rheumatology BV. TT has received grant/research support from Astellas, Chugai, Daiichi Sankyo, Takeda, AbbVie GK, Asahi Kasei Pharma, Mitsubishi Tanabe, Pfizer, Eisai, Nippon Kayaku, Novartis and Ayumi; speakers’ bureau fees from AbbVie GK, Bristol-Myers Squibb, Chugai, Mitsubishi Tanabe, Pfizer, Astellas, Daiichi Sankyo, Eisai, Sanofi, Teijin, Takeda and Novartis; and consulting fees from AstraZeneca, Eli Lilly, Novartis, Mitsubishi Tanabe, AbbVie GK, Nippon Kayaku, Janssen, Astellas, Taiho, Chugai, Taisho Pharma, GlaxoSmithKline and UCB.

  • Patient consent for publication Not required.

  • Ethical approval The study was approved by the institutional review boards (DRIVE study: Rheumatology, Hokkaido Medical Center for Rheumatic Diseases Ethics Committee and DESIRABLE study: Sunagawa City Medical Center Ethics Committee) of all participating sites and was conducted in accordance with the principles of the Declaration of Helsinki. This trial has been registered with JapicCTI-101 263 (DRIVE study) and, number NCT01973569 (DESIRABLE).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement De-identified individual participant data and applicable supporting clinical trial documents (protocol, statistical analysis plan and clinical study report) may be available upon request, to qualified scientific and medical researchers for the purpose of conducting legitimate research, by applying to URL: Details on data sharing criteria and the procedure for requesting access can be found at this URL:

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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