Investigation of revolutionary predictive biomarkers for structural damage and risk of flare after withdrawal of drugs due to remission in rheumatoid arthritis

• Project/Area Number: 16K08956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Hiroshima University
• Principal Investigator: Hirata Shintaro 広島大学, 病院(医), 講師 (90525461)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 関節リウマチ / バイオマーカー / 関節破壊 / 予後予測 / 臨床検査医学 / 寛解休薬後再燃リスク

Outline of Final Research Achievements

MBDA, 14-3-3η and collagen degeneration products were identified as useful biomarkers to predict or detect the risk of structural damage in patients with rheumatoid arthritis (RA). As well, type III collagen degenerated products by MMPs (C3M) and type III pro-collagen (ProC3) were identified as new biomarkers for fibrogenesis in RA, through investigating various possible biomarkers including cytokines, cytokine receptors, adhesion molecules, proteinases, and metabolic markers. These results were presented at international or domestic scientific meetings and published on international journals.

Academic Significance and Societal Importance of the Research Achievements

本研究は、本邦では未だ臨床適用されていない新たなバイオマーカーとして、MBDAスコア、14-3-3η、コラーゲン代謝産物の日本人RA患者における可能性を初めて明らかにした。これらの新規バイオマーカーはRA病態の詳細な理解に繋がり、かつ将来わずかな血液で簡便かつ客観的に病態把握が可能となる端緒となりうる。またRAの適切な治療選択および寛解休薬の導入に貢献しprecision medicineの実現に役立つ可能性が示された。

Research Products

• [Int'l Joint Research] Crescendo Bioscience Inc.(米国)
• [Int'l Joint Research] Augurex(カナダ)
• [Int'l Joint Research] Nordic Bioscience(デンマーク)
• [Int'l Joint Research] Crescendo Bioscience Inc.(米国)
• [Int'l Joint Research] Augurex(カナダ)
• [Int'l Joint Research] Nordic Bioscience(デンマーク)
• [Int'l Joint Research] Crescendo Bioscience Inc.(米国)
• [Int'l Joint Research] Augurex(カナダ)
• [Int'l Joint Research] Nordic Bioscinece(デンマーク)
• [Journal Article] Increased remodelling of interstitial collagens and basement membrane is suppressed by treatment in patients with rheumatoid arthritis: serological evaluation of a one-year prospective study of 149 Japanese patients. (2018)
  • Author(s): Gudmann NS, Hirata S, Karsdal MA, Kubo S, Bay-Jensen AC, Tanaka Y.
  • Journal Title: Clin Exp Rheumatol. Volume: 36 Pages: 462-470
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SLEバイオマーカーとしての可溶性VCAM-1 (2017)
  • Author(s): 平田 信太郎
  • Journal Title: リウマチ科 Volume: 57 Pages: 317-320
• [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: 26 Issue: 6 Pages: 850-856
  • DOI: 10.3109/14397595.2016.1153449
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] OPTIMISATION OF METHOTREXATE DOSE INDUCED SUCCESSFUL REDUCTION OF GLUCOCORTICOIDS WITHOUT IMPAIRED DISEASE CONTROL IN PATIENTS WITH RHEUMATOID ARTHRITIS. (2018)
  • Author(s): 251.S. Hirata, T. Kondo, K. Yukawa, T. Tokunaga, T. Kuranobu, K. Oi, Y. Yoshida, M. Funaki, K. Oda, T. Nojima, E. Sugiyama
  • Organizer: EULAR2018
  • Int'l Joint Research
• [Presentation] 疾患活動性評価の正確化 （Multi-biomarker disease activity（MBDA）score による活動性評価） (2018)
  • Author(s): 平田信太郎
  • Organizer: 第33回日本臨床リウマチ学会
  • Invited
• [Presentation] Practical Optimization of Methotrexate Dose Improves Disease Control of Rheumatoid Arthritis Despite Reduction or Discontinuation of Oral Glucocorticoids. (2018)
  • Author(s): Shintaro Hirata, Kei Araki, Hiroki Kohno, Kazutoshi Yukawa, Tadahiro Tokunaga, Tatsuomi Kuranobu, Katsuhiro Oi, Yusuke Yoshida, Tomohiro Sugimoto, Keisuke Oda, Takaki Nojima, Eiji Sugiyama
  • Organizer: ACR/ARHP2018
  • Int'l Joint Research
• [Presentation] 14-3-3ETA PREDICTS JOINT DAMAGE PROGRESSION AND FLARING AFTER ADALIMUMAB DISCONTINUATION． (2017)
  • Author(s): S. Hirata, A. Marotta, K. Hanami, Y. Tanaka.
  • Organizer: EULAR 2017
  • Int'l Joint Research
• [Presentation] MULTICENTER 14-3-3ETA BIOMARKER REPRODUCIBILITY; THE JAPANESE EXPERIENCE. (2017)
  • Author(s): S. Hirata, M. Kaneda, T. Isayama, Y. Gui, A. Marotta, W. P. Maksymowych, Y. Tanaka.
  • Organizer: EULAR 2017
  • Int'l Joint Research
• [Presentation] 関節リウマチに伴う間質性肺疾患(RA-ILD)に対するタクロリムス(TAC)の有効性 (2017)
  • Author(s): 平田信太郎、中野和久、久保智史、杉山英二、田中良哉
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] 血清１４－３－３ηは関節リウマチ患者のトシリツマブ治療反応性を予測できる (2017)
  • Author(s): 田中良哉、平田信太郎、花見健太郎、Anthony Marotta
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] 血清１４－３－３ηによる関節リウマチ患者に於けるアダリムマブ(ADA)治療中止後の関節破壊進行と再燃の予測 (2017)
  • Author(s): 田中良哉、平田信太郎、花見健太郎、Anthony Marotta
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] 当科開設以来の関節リウマチ（RA）に対する生物学的抗リウマチ薬（ｂDMARDｓ）選択と継続に関する検討． (2017)
  • Author(s): 平田信太郎、近藤拓馬、湯川和俊、德永忠浩、倉信達臣、大井勝博、吉田雄介、舟木将雅、小田啓介、野島崇樹、杉山英二
  • Organizer: 第28回日本リウマチ学会中国・四国支部学術集会
• [Presentation] Lower Baseline 14-3-3η Levels Are Associated with Better Patient Reported Outcomes in Tocilizumab Treated Patients (2016)
  • Author(s): Shintaro Hirata, Anthony Marotta, Kentaro Hanami, Yoshiya Tanaka
  • Organizer: ACR/ARHP 2016
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2016-11-06
  • Int'l Joint Research
• [Presentation] Predicting Flare and Sustained Clinical Remission after Adalimumab Withdrawal Using the Multi-Biomarker Disease Activity (MBDA) Score (2016)
  • Author(s): Shintaro Hirata, Xingbin Wang, CC Hwang, Ippei Miyagawa, Satoshi Kubo, Kazuhisa Nakano, Shingo Nakayamada, Kazuyoshi Saito, Nadine A. Defranoux, Yoshiya Tanaka
  • Organizer: ACR/ARHP 2016
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2016-11-06
  • Int'l Joint Research
• [Presentation] PREDICTIVE VALUE OF THE MULTI-BIOMARKER DISEASE ACTIVITY (MBDA) SCORE FOR FLARE AND SUSTAINED REMISSION IN THE HONOR STUDY (2016)
  • Author(s): S. Hirata, S. Tang, C.C. Hwang, I. Miyagawa, S. Kubo, K. Nakano, S. Nakayamada, K. Saito, N.A. Defranoux, Y. Tanaka
  • Organizer: EULAR2016
  • Place of Presentation: London, UK
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] BASELINE SERUM 14-3-3 ETA INDEPENDENTLY PREDICTS CLINICALLY IMPORTANT IMPROVEMENTS IN HAQ-DI IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOCILIZUMAB (2016)
  • Author(s): S. Hirata, K. Hanami, A. Marotta, Y. Tanaka
  • Organizer: EULAR2016
  • Place of Presentation: London, UK
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] ANTI-JAK IS ANTI-FIBROTIC IN PATIENTS WITH RHEUMATOID ARTHRITIS (2016)
  • Author(s): S. Hirata, N.S. Gudmann, S. Kubo, M. Karsdal, A.C. Bay-Jensen, Y. Tanaka
  • Organizer: EULAR2016
  • Place of Presentation: London, UK
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Remarks] 広島大学病院リウマチ・膠原病科＞研究紹介
  • URL: https://home.hiroshima-u.ac.jp/hrheuma/reseach/index.html
• [Funded Workshop] EULAR (European League Against Rheumatism Annual scientific meeting) (2017)