Investigation of novel multi-biomarker indices to predict for joint destruction in rheumatoid arthritis

• Project/Area Number: 25460713
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: HIRATA Shintaro 産業医科大学, 大学病院, 講師 (90525461)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 関節リウマチ / バイオマーカー / 国際情報交換

Outline of Final Research Achievements

To establish objective methods to evaluate disease activity and to predict clinical outcomes in RA, the multi-biomarker disease activity (MBDA) score and novel biomarkers were investigated. (1) Serum IL-6 levels oppositely moved by different therapeutic target, while the MBDA score predictive value for clinical outcomes was superior to conventional methods. (2) The MBDA score predicted joint destruction more precisely than conventional methods. (3)The MBDA score was predictive for flare after drug withdrawal. (4) For novel biomarkers, 14-3-3η guided to diagnosis and to choosing therapeutic. C1M, C2M, C3M were associated with disease activity. Pro-C3 that indicated fibrogenesis revealed anti-fibrogenic effect of a JAK inhibitor.

Research Products

• [Int'l Joint Research] Crescendo Bioscience Inc.(米国)
• [Int'l Joint Research] Augurex Life Science Corp.(Canada)
• [Int'l Joint Research] Nordic Bioscience(Denmark)
• [Journal Article] Association of the multi-biomarker disease activity score with joint destruction in patients with rheumatoid arthritis receiving tumor necrosis factor-alpha inhibitor treatment in clinical practice. (2016)
  • Author(s): Hirata S, Li W, Kubo S, Fukuyo S, Mizuno Y, Hanami K, Sawamukai N, Yamaoka K, Saito K, Defranoux NA, Tanaka Y.
  • Journal Title: Mod Rheumatol. Volume: Epub Mar 30
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study. (2015)
  • Author(s): Hirata S, Li W, Defranoux N, Cavet G, Bolce R, Yamaoka K, Saito K, Tanaka Y.
  • Journal Title: Mod Rheumatol. Volume: 25 Issue: 3 Pages: 344-9
  • DOI: 10.3109/14397595.2014.958893
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Serum 14-3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab. (2015)
  • Author(s): Hirata S, Marotta A, Gui Y, Hanami K, Tanaka Y.
  • Journal Title: Arthritis Res Ther. Volume: 17 Issue: 1 Pages: 280-280
  • DOI: 10.1186/s13075-015-0799-7
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Combination therapy for early rheumatoid arthritis: a treatment holiday perspective. (2015)
  • Author(s): Hirata S, Tanaka Y.
  • Journal Title: Expert Rev Clin Pharmacol. Volume: 8 Issue: 1 Pages: 115-22
  • DOI: 10.1586/17512433.2015.984689
  • Peer Reviewed
• [Journal Article] A multi-biomarker disease activity score tracks clinical response consistently in patients with rheumatoid arthritis treated with different anti-tumor necrosis factor therapies: A retrospective observational study. (2014)
  • Author(s): Hirata S, Li W, Defranoux N, Cavet G, Bolce R, Yamaoka K, Saito K, Tanaka Y.
  • Journal Title: Mod Rheumatol. Volume: Oct 8: 1-6. Epub
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. (2014)
  • Author(s): Tanaka Y, Hirata S, Kubo S, Fukuyo S, Hanami K, Sawamukai N, Nakano K, Nakayamada S, Yamaoka K, Sawamura F, Saito K.
  • Journal Title: Ann Rheum Dis Volume: in press Issue: 2 Pages: 389-95
  • DOI: 10.1136/annrheumdis-2013-204016
  • Peer Reviewed / Open Access
• [Journal Article] Is It Possible to Withdraw Biologics From Therapy in Rheumatoid Arthritis? (2014)
  • Author(s): TanakaY, Hirata S.
  • Journal Title: Clin Ther Volume: in press Issue: 12 Pages: 2028-2035
  • DOI: 10.1016/j.clinthera.2013.10.008
  • Peer Reviewed
• [Journal Article] Abatacept inhibits radiographic progression in patients with rheumatoid arthritis: a retrospective analysis of 6 months of abatacept treatment in routine clinical practice. The ALTAIR study. (2014)
  • Author(s): Kubo S, Saito K, Hirata S, Fukuyo S, Yamaoka K, Sawamukai N, Nawata M, Iwata S, Mizuno Y, Tanaka Y.
  • Journal Title: Mod Rheumatol Volume: 24 Issue: 1 Pages: 42-51
  • DOI: 10.3109/14397595.2013.854051
  • Peer Reviewed
• [Journal Article] Primary and secondary surveys on epidemiology of Sjören's syndrome in Japan. (2014)
  • Author(s): Tsuboi H, Asashima H, Takai C, Hagiwara S, Hagiya C, Yokosawa M, Hirota T, Umehara H, Kawakami A, Nakamura H, Sano H, Tsubota K, Ogawa Y, Takamura E, Saito I, Inoue H, Nakamura S, Moriyama M, Takeuchi T, Tanaka Y, Hirata S, Mimori T, Yoshifuji H, Ohta A, Matsumoto I, Sumida T.
  • Journal Title: Mod Rheumatol Volume: in press
  • Peer Reviewed
• [Journal Article] Effects of tofacitinib on lymphocytes in rheumatoid arthritis: Relation to efficacy and infectious adverse events. (2014)
  • Author(s): Sonomoto K, Yamaoka K, Kubo S, Hirata S, Fukuyo S, Maeshima K, Suzuki K, Saito K, Tanaka Y.
  • Journal Title: Rheumatology (Oxford). Volume: in press
  • Peer Reviewed
• [Journal Article] Efficacy and safety of reducing duration of infliximab infusion. (2014)
  • Author(s): Fukuyo S, Saito K, Yamaoka K, Sawamukai N, Hirata S, Nawata M, Iwata S, Tanaka Y.
  • Journal Title: Mod Rheumatol Volume: in press
  • Peer Reviewed
• [Journal Article] A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. (2013)
  • Author(s): Hirata S, Dirven L, Shen Y, Centola M, Cavet G, Lems WF, Tanaka Y, Huizinga TW, Allaart CF.
  • Journal Title: Rheumatology (Oxford) Volume: 52 Issue: 7 Pages: 1202-7
  • DOI: 10.1093/rheumatology/kes362
  • Peer Reviewed
• [Journal Article] Discontinuation of adalimumab after attaining disease activity score 28-erythrocyte sedimentation rate remission in patients with rheumatoid arthritis (HONOR study): an observational study. (2013)
  • Author(s): Hirata S, Saito K, Kubo S, Fukuyo S, Mizuno Y, Iwata S, Nawata M, Sawamukai N, Nakano K, Yamaoka K, Tanaka Y.
  • Journal Title: Arthritis Res Ther Volume: 15 Issue: 5
  • DOI: 10.1186/ar4315
  • Peer Reviewed
• [Journal Article] Discontinuation of biologics in patients with rheumatoid arthritis. (2013)
  • Author(s): Tanaka Y, Hirata S, Saleem B, Emery P.
  • Journal Title: Clin Exp Rheumatol Volume: 31
  • Peer Reviewed
• [Presentation] 14-3-3η Positive Status and Higher Titres Are Associated with More Severe RA (2015)
  • Author(s): Shintaro Hirata, Kentaro Hanami, Anthony Marotta, Yoshiya Tanaka
  • Organizer: ACR2015
  • Place of Presentation: San Francisco, United States
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] JAK Inhibition Significantly Reduced Fibrogenesis in Rheumatoid Arthritis Patients (2015)
  • Author(s): Shintaro Hirata, Natasja Stæhr Gudman, Kentaro Hanami, Satoshi Kubo, Anne C. Bay-Jensen, Morten Asser Karsdal, Yoshiya Tanaka
  • Organizer: ACR2015
  • Place of Presentation: San Francisco, United States
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] 関節リウマチにおいてベースライン14-3-3η低値はtocilizumabによる1年後のDAS28-ESR寛解達成を予測する. (2015)
  • Author(s): 平田信太郎, 花見健太郎, 山形 薫, 宮川一平, 久保智史, 岩田慈, 澤向範文, 中野和久, 中山田真吾, 齋藤和義, Anthony Marotta, 田中良哉
  • Organizer: 第43回日本臨床免疫学会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-10-22
• [Presentation] Neo-epitopes of connective tissue turnover are biomarkers of disease activity and modulated in response to tofacitinib or tocilizumab in rheumatoid arthritis (2015)
  • Author(s): Shintarto Hirata, Natasja S. Gudmann, Morten Karsdal, Anne C. Bay-Jensen, Yoshiya Tanaka
  • Organizer: The Annual European Congress of Rheumatology EULAR 2015
  • Place of Presentation: Fiera Roma, Rome, Italy
  • Year and Date: 2015-06-10 – 2015-06-13
• [Presentation] Neo-epitopes of connective tissue turnover are biomarkers of disease activity and modulated in response to tofacitinib or tocilizumab in rheumatoid arthritis (2015)
  • Author(s): Shintarto Hirata, Natasja S. Gudmann, Morten Karsdal, Anne C. Bay-Jensen, Yoshiya Tanaka
  • Organizer: EULAR2015
  • Place of Presentation: Rome, Italy
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] Predictive value of the MBDA score and composite measures for sustained remission at 1 year after withdrawal of adalimumab in the HONOR study (2015)
  • Author(s): Shintaro Hirata, Kentaro Hanami, Nadine Defranoux, Ippei Miyagawa, Satoshi Kubo, Shunsuke Fukuyo, Norifumi Sawamukai, Kazuhisa Nakano, Shingo Nakayamada, Kazuyoshi Saito, Yoshiya Tanaka
  • Organizer: 第59回日本リウマチ学会総会・学術集会 (JCR2015)
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-23
  • Int'l Joint Research
• [Presentation] The relevance of serum 14-3-3η levels to clinical and radiographic outcomes in patients with rheumatoid arthritis (2015)
  • Author(s): Shintaro Hirata, Kentaro Hanami, Kaoru Yamagata, Ippei Miyagawa, Satoshi Kubo, Shunsuke Fukuyo, Norifumi Sawamukai, Kazuhisa Nakano, Shingo Nakayamada, Kazuyoshi Saito, Anthony Marotta, Yoshiya Tanaka
  • Organizer: 第59回日本リウマチ学会総会・学術集会 (JCR2015)
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-23
  • Int'l Joint Research
• [Presentation] 14-3-3eta Informs Joint Pathological Mechanisms of Treatment Response to Assist with T2T Strategies (2014)
  • Author(s): Shintaro Hirata, Kentaro Hanami, Anthony Marotta, Yoshiya Tanaka
  • Organizer: 2014 ACR/ARHP Annual Meeting
  • Place of Presentation: Boston Convention & Exhibition Center, Boston, Massachusetts, USA
  • Year and Date: 2014-11-14 – 2014-11-19
• [Presentation] TNF阻害療法下のRA患者におけるmulti-biomarker disease activity (MBDA)スコアと関節破壊進行に関する検討 (2014)
  • Author(s): 平田信太郎, 齋藤和義, 久保智史, 福與俊介, 水野泰志, Wanying Li, Nadine A. Defranoux, Rebecca Bolce, Eric Sasso, 宮川一平,花見健太郎, 澤向範文, 中野和久, 中山田真吾, 山岡邦宏、田中良哉
  • Organizer: 第58回日本リウマチ学会総会・学術集会 (JCR2014)
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区）
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] A MULTI-BIOMARKER DISEASE ACTIVITY (VECTRA™ DA ALGORITHM) SCORE IS ASSOCIATED WITH RADIOGRAPHIC OUTCOMES IN RA PATIENTS TREATED WITH TNF INHIBITORS (2013)
  • Author(s): S.Hirata, W.Li, N.A.Defranoux, R.Bolce, D.J.Haney, E.H.Sasso, S.Kubo, S.Fukuyo, Y.Mizuno, K.Yamaoka, K.Saito, Y.Tanaka
  • Organizer: EULAR2013
  • Place of Presentation: Madrid, Spain
• [Presentation] BEHAVIOR OF THE MULTI-BIOMARKER DISEASE ACTIVITY (VECTRA® DA ALGORITHM) SCORE AND COMPONENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOCILIZUMAB (2013)
  • Author(s): K.Hanami, S.Hirata, H.Tasaka, W.Li, R.Bolce, E.H.Sasso, N.A.Defranoux, K.Yamaoka, K.Saito, Y.Tanaka
  • Organizer: EULAR2013
  • Place of Presentation: Madrid, Spain
• [Presentation] REPEATED HIGH OR LOW MULTI-BIOMARKER DISEASE ACTIVITY (VECTRA® DA ALGORITHM) SCORES ASSOCIATED WITH RADIOGRAPHIC OUTCOMES IN PATIENTS WITH RA TREATED WITH TNF INHIBITORS (2013)
  • Author(s): S.Hirata, W.Li, N.A.Defranoux, R.Bolce, E.H.Sasso, S.Kubo, S.Fukuyo, Y.Mizuno, K.Yamaoka, K.Saito, Y.Tanaka
  • Organizer: ACR2013
  • Place of Presentation: San Diego, USA
• [Presentation] A novel peripheral blood derived multi-biomarker disease activity (MBDA; Vectra™ DA Algorithm) score reflects clinical, functional, and radiographic outcomes in Japanese rheumatoid arthritis patients treated with TNF inhibitors (2013)
  • Author(s): Shintaro Hirata, Wanying Li, Nadine A. Defranoux, Rebecca Bolce, Kentaro Hanami, Satoshi Kubo, Shunsuke Fukuyo, Yasushi Mizuno, Kunihiro Yamaoka, Kazuyoshi Saito, Yoshiya Tanaka
  • Organizer: EAGOR2013
  • Place of Presentation: Seoul, South Korea
• [Presentation] Multi-biomarker disease activity (MBDA)スコアは関節リウマチにおける最も鋭敏に構造的寛解を予測、反映する疾患活動性マーカーである (2013)
  • Author(s): 平田 信太郎, 齋藤 和義, 久保 智史, 福與 俊介, 水野 泰志, Wanying Li, Douglas J. Haney, Nadine Defranoux, Rebecca Bolce, Guy Cavet, 園本 格士朗,花見 健太郎, 岩田 慈, 名和田 雅夫, 澤向 範文, 中野 和久, 中山田 真吾, 山岡 邦宏、田中 良哉
  • Organizer: 第57回日本リウマチ学会総会・学術集会（JCR2013)
  • Place of Presentation: 京都（国立京都国際会館）
• [Presentation] 血清MMP-3はTNF阻害療法下の関節リウマチにおける関節裂隙狭小化スコアと相関性が高い (2013)
  • Author(s): 平田 信太郎, 齋藤 和義, 久保 智史, 福與 俊介, 水野 泰志, 園本 格士朗, 花見 健太郎, 岩田 慈, 名和田 雅夫, 澤向 範文, 中野 和久, 中山田 真吾, 山岡 邦宏, 田中 良哉
  • Organizer: 第57回日本リウマチ学会総会・学術集会（JCR2013)
  • Place of Presentation: 京都（国立京都国際会館）