Inhibitory effects of combination therapy of denosumab, anti-RANKL antibody, and biological DMARD on bone and cartilage destruction in patients with rheumatoid arthritis

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26462290
• Research Institution: Nagoya University
• Principal Investigator: 小嶋 俊久 名古屋大学, 医学部附属病院, 講師 (70378032)
• Co-Investigator(Kenkyū-buntansha): 石黒 直樹 名古屋大学, 医学系研究科, 教授 (20212871) ; 高橋 伸典 名古屋大学, 医学部附属病院, 病院講師 (20570196) ; 舟橋 康治 名古屋大学, 医学部附属病院, 病院助教 (80566977) [Withdrawn] ; 浅井 秀司 名古屋大学, 医学部附属病院, 特任助教 (00770893)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: rheumatoid arthritis / biologics / osteoporosis / denosumab / toll like receptor

Outline of Annual Research Achievements

本研究課題は、特に骨吸収に深く関与する分子RANKLに対する抗体denosumabの効果に注目し、関節リウマチ(RA)における骨代謝、およびこれに関わる因子を解明することを目的としている。本年度は１．Denosumab使用患者の観察研究(TBCR-Bone)、2.RA手術患者から検体採取、解析をすすめた。１．について76名の登録患者の12ヶ月までの効果（骨代謝マーカー、骨密度、）、ステロイド併用の影響を検討した。RA治療実臨床下のdenosumabの効果が検証された。骨密度の改善、骨代謝マーカーの抑制が確認された。疾患活動性の影響が示唆された。RA-Bio、ステロイド投与はdenosumabの効果には影響を与えていなかった。本課題にとってRA-Bio自体の効果検証も必須である。本年度は、同時に行っている多施設観察研究(TBCR)により、主として生物学的製剤の治療の長期継続に関わる因子を検討した、1年以上の長期継続のためにはメトトレキサート併用が重要であり、治療の徹底が長期成績にかかわることがわかった。２については、検体採取については25例の患者から同意を得て手術時に、骨軟骨、滑膜、関節液の採取を行い、免疫染色、病理組織評価を行った。重要なWnt signal 阻害であるスクレスチンは炎症性滑膜の表層に発現していた。炎症性滑膜における新規骨粗鬆治療薬スクレロスチン阻害療法の影響を十分検討する必要がある。さらに、検討および関節液での各種サイトカイン、骨、軟骨代謝マーカーの関連を解析中である。

Research Products

• [Int'l Joint Research] Montreal University(Canada)
  • Country Name: Canada
  • Counterpart Institution: Montreal University
• [Journal Article] Hyaluronan Inhibits Tlr-4-Dependent RANKL Expression in Human Rheumatoid Arthritis Synovial Fibroblasts. (2016)
  • Author(s): Watanabe T, Takahashi N, Hirabara S, Ishiguro N, Kojima T.
  • Journal Title: PLoS One Volume: 11（４） Pages: e0153142
  • DOI: 10.1371/journal.pone.0153142
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Respiratory mechanics measured by forced oscillation technique in rheumatoid arthritis-related pulmonary abnormalities: frequency-dependence, heterogeneity and effects of smoking. (2016)
  • Author(s): Sokai R, Ito S, Iwano S, Uchida A, Aso H, Kondo M, Ishiguro N, Kojima T, Hasegawa Y
  • Journal Title: Springerplus Volume: ５ Pages: 335
  • DOI: 10.1186/s40064-016-1952-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Longterm Retention Rate and Risk Factors for Adalimumab Discontinuation Due To Efficacy and Safety in Japanese Patients with Rheumatoid Arthritis: An Observational Cohort Study. (2016)
  • Author(s): Yosuke Hattori, Toshihisa Kojima, Atsushi Kaneko, Daihei Kida, Yuji Hirano, Takayoshi Fujibayashi, Kenya Terabe, Yuichiro Yabe, Hiroyuki Miyake, Takefumi Kato, Hideki Takagi, Masatoshi Hayashi, Takayasu Ito, Yasuhide Kanayama, Takeshi Oguchi, Nobunori Takahashi, Hisato Ishikawa, Koji Funahashi, Naoki Ishiguro
  • Journal Title: The Journal of Rheumatology Volume: 43（８） Pages: 1475-1479
  • DOI: 10.3899/jrheum.151006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hyaluronan Oligosaccharides Induce MMP-1 and -3 via Transcriptional Activation of NF-kappaB and p38 MAPK in Rheumatoid Synovial Fibroblasts. (2016)
  • Author(s): Hanabayashi M, Takahashi N, Sobue Y, Hirabara S, Ishiguro N, Kojima T.
  • Journal Title: PLoS One Volume: 11（８） Pages: e0161875
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Mechanisms of Cartilage destruction in osteoarthritis and rheumatoid arthritis (2017)
  • Author(s): 小嶋俊久
  • Organizer: 日本軟骨代謝学会
  • Place of Presentation: 京都市勧業館みやこめっせ（京都府京都市）
  • Year and Date: 2017-03-03 – 2017-03-04
  • Invited
• [Presentation] 関節リウマチ治療におけるJAK阻害薬 (2016)
  • Author(s): 小嶋俊久
  • Organizer: 日本関節病学会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-11-11 – 2016-11-12
  • Invited
• [Presentation] リウマチ性疾患の疼痛マネージメント (2016)
  • Author(s): 小嶋俊久
  • Organizer: 日本臨床リウマチ学会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-10-29 – 2016-10-30
  • Invited
• [Presentation] The Predictors for Twelve Months Efficacy of Denosumab, an Anti­RANKL Antibody, on Osteoporosis in Rheumatoid Arthritis Patients from Japanese Multicenter Study (TBCR­BONE) (2016)
  • Author(s): Y. Hirano, Y. Kanayama, M. Isono, N. Ishiguro, T. Kojima, on behalf of TBCR-BONE
  • Organizer: ＡＳＢＭＲ
  • Place of Presentation: Atlanta（ＵＳＡ）
  • Year and Date: 2016-09-16 – 2016-09-19
  • Int'l Joint Research
• [Presentation] Influence of glucocorticoids on effect of denosumab on osteoporosis in patients with Japanese rheumatoid arthritis; 12 months of follow­up ~a Multicenter Registry Study~ (2016)
  • Author(s): Y. Kanayama, Y. Hirano, N. Takahashi, S. Asai, N. Ishiguro, T. Kojima, on behalf of TBCR-BONE Study Group
  • Organizer: ＡＳＢＭＲ
  • Place of Presentation: Atlanta（ＵＳＡ）
  • Year and Date: 2016-09-16 – 2016-09-19
  • Int'l Joint Research
• [Presentation] 名古屋大学医学部附属病院でのリウマチ治療におけるチーム医療 (2016)
  • Author(s): 小嶋俊久
  • Organizer: 中部リウマチ学会
  • Place of Presentation: ザ・グランユアーズフクイ（福井県福井市）
  • Year and Date: 2016-09-02 – 2016-09-03
  • Invited
• [Presentation] THE PREDICTORS FOR 12 MONTHS EFFICACY OF DENOSUMAB, AN ANTI-RANKL ANTIBODY, ON OSTEOPOROSIS IN PATIENTS WITH RHEUMATOID ARTHRITIS FROM MULTICENTER STUDY (TBCR-BONE) (2016)
  • Author(s): Y. Hirano, Y. Kanayama, M. Isono, N. Ishiguro, T. Kojima, on behalf of TBCR-BONE
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] DRUG SURVIVAL OF GOLIMUMAB IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS IS INDEPENDENT OF METHOTREXATE AND PREDNISOLONE CONCOMITANCE: RESULTS FROM THE MULTICENTER BIOLOGICS REGISTRY (2016)
  • Author(s): M. Hayashi, T. Kanamono, H. Matsubara, K. Kishimoto, N. Takahashi, T. Kojima, N. Ishiguro
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] EFFICACY OF INFLIXIMAB FOR SUPPRESSING RADIOGRAPHIC PROGRESSION OF CERVICAL LESIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS COMPARISON WITH METHOTREXATE; TWO YEARS OF FOLLOW-UP A MULTICENTER REGISTRY STUDY (2016)
  • Author(s): Y. Kanayama, T. Kojima, Y. Hirano, N. Takahashi, Y. Yabe, N. Ishiguro, on behalf of TBCR Study Group
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] RETENTION RATE OF BIOLOGIC AGENTS AFTER REMISSION INDUCED WITH AND WITHOUT CONCOMITANT GLUCOCORTICOID TREATMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS: A PROPENSITY SCORE MATCHED ANALYSIS (2016)
  • Author(s): S. Asai, T. Kojima, N. Takahashi, K. Funahashi, N. Ishiguro, on behalf of TBCR Study Group
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] INFLUENCE OF ORAL PREDNISOLONE ON EFFECT OF DENOSUMAB ON OSTEOPOROSIS IN PATIENTS WITH JAPANESE RHEUMATOID ARTHRITIS; 12 MONTHS OF FOLLOW-UP A MULTICENTER REGISTRY STUDY (2016)
  • Author(s): Y. Kanayama, Y. Hirano, N. Takahashi, S. Asai, N. Ishiguro, T. Kojima, on behalf of TBCR-BONE Study Group
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] DAILY TERIPARATIDE TREATMENT AFTER BISPHOSPHONATE THERAPY IN OSTEOPOROSIS OF PATIENTS WITH RHEUMATOID ARTHRITIS (2016)
  • Author(s): Y. Hirano, M. Isono, J. Fukui, J. Hasegawa, N. Ishiguro, T. Kojima
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] RELATIONSHIP BETWEEN BIOLOGICAL DMARDS TREATMENT AND COMPLICATIONS AFTER SURGICAL TREATMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS (2016)
  • Author(s): Y. Hirano, S. Hirabara, M. Isono, N. Ishiguro, T. Kojima.
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] SERO-POSITIVITY FOR RHEUMATOID FACTOR IS AN INDEPENDENT PREDICTOR FOR ACHIEVEMENT OF GOOD EULAR RESPONSE AT 24 WEEKS IN ACPA POSITIVE RHEUMATOID ARTHRITIS PATIENTS TREATED WITH ABATACEPT: RESULTS FROM JAPANESE MULTICENTER REGISTRY (2016)
  • Author(s): N. Takahashi, T. Kojima, K. Funahashi, N. Ishiguro, on behalf of TBCR Study Group
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] PROGNOSTIC FACTORS FOR ABATACEPT RETENTION IN PATIENTS WITH RHEUMATOID ARTHRITIS IN A JAPANESE MULTICENTER REGISTRY (2016)
  • Author(s): M. Hanabayashi, N. Takahashi, Y. Yokota, H. Miyake, T. Kojima, N. Ishiguro, on behalf of TBCR
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: London（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] THE ASSOCIATION BETWEEN METHOTREXATE USE AND EFFECTS OF TREATMENT WITH A SECOND BIOLOGIC AGENT IN RHEUMATOID ARTHRITIS (2016)
  • Author(s): Y. Ogawa, T. Kojima, N. Takahashi, K. Funahashi, N. Ishiguro
  • Organizer: ＥＵＬＡＲ
  • Place of Presentation: LonDon（ＵＫ）
  • Year and Date: 2016-06-08 – 2016-06-11
  • Int'l Joint Research
• [Presentation] 周術期における生物学的製剤の使い方 (2016)
  • Author(s): 小嶋俊久
  • Organizer: 日本整形外科学会
  • Place of Presentation: パシフィコ横浜及びヨコハマグランドインターコンチネンタルホテル（神奈川県横浜市）
  • Year and Date: 2016-05-12 – 2016-05-15
  • Invited
• [Presentation] 現在そして今後のリウマチ治療を考える (2016)
  • Author(s): 小嶋俊久
  • Organizer: 日本整形外科学会
  • Place of Presentation: パシフィコ横浜及びヨコハマグランドインターコンチネンタルホテル（神奈川県横浜市）
  • Year and Date: 2016-05-12 – 2016-05-15
  • Invited