Elucidation of the mechanisms of rheumatoid arthritis flare and the importance of symptoms in it

• Project/Area Number: 15K09535
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Toho University
• Principal Investigator: KAMEDA Hideto 東邦大学, 医学部, 教授 (00265795)
• Project Period (FY): 2015-04-01 – 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: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 関節リウマチ / 生物学的製剤 / 寛解 / 休薬 / 自覚症状 / 関節超音波 / サイトカイン / 再燃

Outline of Final Research Achievements

A total of 36 patients with rheumatoid arthritis (RA) who had been in sustained remission for at least 6 months with biologic disease-modifying anti rheumatic drug (bDMARD) and preferred to discontinue bDMARD were enrolled in this study. Twenty patients developed RA flare and almost all of them returned to remission state with the re-introduction of the same bDMARD. It was difficult to predict the RA flare after bDMARD discontinuation. However, this study demonstrates that patient symptom is a sensitive measure of disease flare, blood concentration of cytokines and their receptors varies among patients receiving different bDMARDs, and interleukin-6 is the best biomarker of RA activity.

Academic Significance and Societal Importance of the Research Achievements

生物学的製剤の寛解休薬は医療経済学的観点からも大きなメリットがあり、関節の違和感を感じた際には早期に受診することで再燃の早期診断・早期治療が可能になり、休薬のリスクを最小化できると考えられた。さらにサイトカインおよびサイトカイン受容体の血中濃度の継時的測定結果から、患者間におけるサイトカインプロファイルの多様性と同一患者における再現性が示されたことから、テーラーメイド医療への道筋にも大きく貢献する結果となった。

Research Products

• [Journal Article] Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis in a real-world clinical setting (2018)
  • Author(s): Atsumi Tatsuya、Fujio Keishi、Yamaoka Kunihiro、Tomobe Minako、Kuroyanagi Kazuyuki、Kameda Hideto
  • Journal Title: Modern Rheumatology Volume: in press Issue: 5 Pages: 1-9
  • DOI: 10.1080/14397595.2017.1416760
  • NAID: 120006539252
  • Peer Reviewed
• [Journal Article] Reply (2018)
  • Author(s): Hirata Ayako、Ogura Takehisa、Hayashi Norihide、Takenaka Sayaka、Ito Hideki、Mizushina Kennosuke、Fujisawa Yuki、Yamashita Naoko、Nakahashi Sumie、Imamura Munetsugu、Kujime Rie、Kameda Hideto
  • Journal Title: Arthritis Care & Research Volume: in press Issue: 7 Pages: 1-1
  • DOI: 10.1002/acr.23344
  • Peer Reviewed
• [Journal Article] Safety and effectiveness of certolizumab pegol in patients with rheumatoid arthritis: Interim analysis of post-marketing surveillance (2017)
  • Author(s): 亀田 秀人、西田 圭一郎、南木 敏宏、渡辺 彰、大島 行哉、桃原 茂樹
  • Journal Title: Japanese Journal of Clinical Immunology Volume: 40 Issue: 3 Pages: 196-205
  • DOI: 10.2177/jsci.40.196
  • NAID: 130005865141
  • ISSN: 0911-4300, 1349-7413
  • Peer Reviewed
• [Journal Article] Global assessments of disease activity are age-dependent determinant factors of clinical remission in rheumatoid arthritis (2017)
  • Author(s): Ito Hideki、Ogura Takehisa、Hirata Ayako、Takenaka Sayaka、Mizushina Kennosuke、Fujisawa Yuki、Katagiri Takaharu、Hayashi Norihide、Kameda Hideto
  • Journal Title: Seminars in Arthritis and Rheumatism Volume: 47 Issue: 3 Pages: 310-314
  • DOI: 10.1016/j.semarthrit.2017.04.008
• [Journal Article] Consensus statements for medical practice: Biological agents and lung disease [Abridged English translation by the Japanese Respiratory Society] (2017)
  • Author(s): Tokuda Hitoshi、Harigai Masayoshi、Kameda Hideto、Tomono Kazunori、Takayanagi Noboru、Watanabe Akira、Tasaka Sadatomo、Suda Takafumi、Tateda Kazuhiro、Kadota Junichi
  • Journal Title: Respiratory Investigation Volume: 55 Issue: 3 Pages: 229-251
  • DOI: 10.1016/j.resinv.2017.01.002
• [Journal Article] Possible preventive effect of salazosulfapyridine against development of Pneumocystis pneumonia in methotrexate-receiving patients with rheumatoid arthritis (2016)
  • Author(s): Mizushina K, Hirata A, Hayashi N, Takenaka S, Ito H, Ogura T, Fujisawa Y, Imamura M, Yamashita N, Kujime R, Nakahashi S, Kameda H
  • Journal Title: Mod Rheumatol Volume: 26 Issue: 6 Pages: 976-978
  • DOI: 10.3109/14397595.2015.1118196
  • Peer Reviewed
• [Journal Article] Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study (2016)
  • Author(s): Nakamura S, Suzuki K, Iijima H, Hata Y, Lim CR, Ishizawa Y, Kameda H, Amano K, Matsubara K, Matoba R, Takeuchi T
  • Journal Title: Arthritis Res Ther Volume: 18 Issue: 1 Pages: 159-159
  • DOI: 10.1186/s13075-016-1052-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation (2016)
  • Author(s): Le L, Yoshimoto K, Morita A, Kameda H, Takeuchi T
  • Journal Title: Int Immunopharmacol Volume: 39 Pages: 273-279
  • DOI: 10.1016/j.intimp.2016.07.033
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Concordance between patient-reported joint symptoms, physician-examined arthritic signs and ultrasound-detected synovitis in rheumatoid arthritis (2016)
  • Author(s): Hirata A, Ogura T, Hayashi N, Takenaka S, Ito H, Mizushina K, Fujisawa Y, Yamashita N, Nakahashi S, Imamura M, Kujime R, Kameda H
  • Journal Title: Arthritis Care Res Volume: 印刷中 Issue: 6 Pages: 801-806
  • DOI: 10.1002/acr.23006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comparison of ultrasonographic joint and tendon findings in hands between early, treatment-naive patients with systemic lupus erythematosus and rheumatoid arthritis (2016)
  • Author(s): Ogura T, Hirata A, Hayashi N, Takenaka S, Ito H, Mizushina K, Fujisawa Y, Imamura M, Yamashita N, Nakahashi S, Kujime R, Kameda H
  • Journal Title: Lupus Volume: 印刷中 Issue: 7 Pages: 707-714
  • DOI: 10.1177/0961203316676375
  • Peer Reviewed
• [Journal Article] Fcγ receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis (2016)
  • Author(s): Tsukamoto M, Kameda H, Ohshige T, Kaneko Y, Yoshimoto K, Suzuki K, Takeuchi T
  • Journal Title: Mod Rheumatol Volume: 印刷中 Issue: 5 Pages: 778-781
  • DOI: 10.1080/14397595.2016.1254709
  • Peer Reviewed
• [Journal Article] The effect of tocilizumab on preventing relapses in adult-onset Still's disease; a retrospective, single center study (2015)
  • Author(s): Nishina N, Kaneko Y, Kameda H, Takeuchi T.
  • Journal Title: Mod Rheumatol Volume: 25 Issue: 3 Pages: 401-404
  • DOI: 10.3109/14397595.2014.973659
  • Peer Reviewed
• [Presentation] 関節リウマチ（RA）患者の手の関節における診察所見と超音波（US）所見の関連についての検討 (2018)
  • Author(s): 林則秀, 小倉剛久, 平田絢子, 久次米吏江, 伊東秀樹, 武中さや佳, 今村宗嗣, 井上有希, 今泉ちひろ, 高倉悠人, 亀田秀人.
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] Concordance between ultrasound joint synovitis and clinical joint assessments by patients or physicians in rheumatoid arthritis sorted by disease activity (2018)
  • Author(s): Hirata A, Ogura T, Ito H, Takenaka S, Inoue Y, Imaizumi C, Takakura Y, Kujime R, Hayashi N, Imamura M, Mizushina K, Katagiri T, Kameda H
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] 関節リウマチの寛解導入に関連する因子の検討 (2017)
  • Author(s): 伊東秀樹, 小倉剛久, 藤澤有希, 水品研之介, 武中さや佳, 平田絢子, 林則秀, 亀田秀人
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] 関節リウマチ患者に対するTNF阻害薬の治療効果と関連する遺伝子発現シグネチャの同定 (2017)
  • Author(s): 中村誠二, 鈴木勝也, 亀田秀人, 天野宏一, 竹内勤
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] Concordance between ultrasound joint synovitis and clinical joint assessments by patients or physicians in rheumatoid arthritis (2017)
  • Author(s): Hirata A, Ogura T, Ito H, Takenaka S, Fujisawa Y, Mizushina K, Imamura M, Hayashi N, Kameda H
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] Persistence with biological disease-modifying anti rheumatic drugs - A retrospective database study in Japanese patients with rheumatoid arthritis (2017)
  • Author(s): Mahlich J, Kameda H, Sruamsiri R
  • Organizer: Annual European Congress of Rheumatology (EULAR 2017)
  • Int'l Joint Research
• [Presentation] Finger joint cartilage thickness evaluated by ultrasound in patients with rheumatoid arthritis (RA) (2017)
  • Author(s): Ogura T, Hirata A, Hayashi N, Ito H, Takenaka S, Fujisawa Y, Mizushina K, Katagiri T, Kujime R, Imamura M, Yamashita N, Kameda H
  • Organizer: Annual European Congress of Rheumatology (EULAR 2017)
  • Int'l Joint Research
• [Presentation] 関節リウマチ（RA）における超音波による手指軟骨の検討 (2017)
  • Author(s): 小倉剛久, 平田絢子, 伊東秀樹, 武中さや佳, 藤澤有希, 水品研之介, 片桐翔治, 林則秀, 久次米吏江, 今村宗嗣, 亀田秀人
  • Organizer: 第38回日本炎症・再生医学会
• [Presentation] 生物学的製剤による全身性炎症性疾患に対する治療戦略の現況と未来 (2017)
  • Author(s): 亀田秀人
  • Organizer: 第38回日本炎症・再生医学会
  • Invited
• [Presentation] Evidence of IL-6 targeted therapy in Japan (2017)
  • Author(s): Hideto Kameda
  • Organizer: Taiwan Rheumatology Association Annual Meeting
  • Int'l Joint Research / Invited
• [Presentation] 関節リウマチ（RA）における超音波によるMCP, PIP関節軟骨の検討 (2017)
  • Author(s): 小倉剛久, 平田絢子, 伊東秀樹, 武中さや佳, 水品研之介, 井上有希, 片桐翔治, 今泉ちひろ, 高倉悠人, 亀田秀人
  • Organizer: 第45回日本臨床免疫学会総会
• [Presentation] Finger joint cartilage thickness evaluated by semiquantitative ultrasound score in patients with rheumatoid arthritis (2017)
  • Author(s): Ogura T, Hirata A, Takenaka S, Ito H, Inoue Y, Imaizumi C, Takakura Y, Mizushina K, Katagiri T, Hayashi N, Kujime R, Imamura M, Kameda H
  • Organizer: 81th Annual Scientific Meeting of American College of Rheumatology
  • Int'l Joint Research
• [Presentation] Improvement in overall work productivity among biologic-naive patients with rheumatoid arthritis treated with tocilizumab subcutaneous injection: A prospective, real world, observational study in Japan (2017)
  • Author(s): Tanaka Y, Kameda H, Saito K, Kaneko Y, Tanaka E, Yasuda S, Tamura N, Fujio K, Kojima T, Anzai T, Hamada C, Fujino Y, Matsuda S, Kohsaka H
  • Organizer: 81th Annual Scientific Meeting of American College of Rheumatology
  • Int'l Joint Research
• [Presentation] Concordance between ultrasound joint synovitis and clinical joint assessments by patients or physicians in rheumatoid arthritis (2016)
  • Author(s): Hirata A, Ogura T, Takenaka S, Ito H, Fujisawa Y, Mizushina K, Imamura M, Hayashi N, Kameda H
  • Organizer: 80th Annual Scientific meeting of American College of Rheumatology
  • Place of Presentation: Washington DC.(U.S.A)
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] 関節リウマチ患者に対する3つの生物学的製剤の治療効果と関連する遺伝子発現シグネチャの同定 (2016)
  • Author(s): 中村誠二, 鈴木勝也, 飯島寛, 羽田裕子, 石澤洋平, 亀田秀人, 天野宏一, 松原謙一, 的場亮, 竹内勤.
  • Organizer: 第31回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
• [Presentation] RAにおける炎症性サイトカインの制御 (2016)
  • Author(s): 亀田秀人
  • Organizer: 第37回日本炎症・再生医学会
  • Place of Presentation: 京都市勧業館みやこめっせ（京都府・京都市）
  • Year and Date: 2016-06-17
  • Invited
• [Presentation] The factors associated with remission induction for patients with rheumatoid arthritis (2016)
  • Author(s): Ito H, Ogura T, Fujisawa Y, Yamashita N, Nakahashi S, Mizushina K, Takenaka S, Imamura M, Kujime R, Hayashi N, Hirata A, Kameda H
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-04-22
• [Presentation] Are the patient-reported pain and stiffness at each joint level clinically relevant in the evaluation of patients with rheumatoid arthritis? (2016)
  • Author(s): Hirata A, Ogura T, Hayashi N, Takenaka S, Ito H, Mizushina K, Fujisawa Y, Imamura M, Yamashita N, Nakahashi S, Kujime R, Kameda H
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-04-22
• [Presentation] Clinical significance of patient-reported pain and stiffness at each joint level in the evaluation of patients with rheumatoid arthritis. (2015)
  • Author(s): Hirata A, Ogura T, Norihide H, Takenaka S, Ito H, Mizushina K, Fujisawa Y, Imamura M, Yamashita N, Kameda H.
  • Organizer: 9th Annual Scientific meeting of American College of Rheumatology
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-11-10
  • Int'l Joint Research
• [Presentation] 関節リウマチにおけるサイトカインの役割 (2015)
  • Author(s): 亀田秀人
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（ 東京都港区）
  • Year and Date: 2015-07-21
  • Invited
• [Presentation] Concordance between joint symptom/swelling/tenderness and ultrasonography (US) synovitis in rheumatoid arthritis: Which clinical finding is more relevant to US synovitis than others? (2015)
  • Author(s): Hirata A, Ogura T, Hayashi N, Fujisawa Y, Nakahashi S, Mizushina K, Imamura M, Takenaka S, Ito H, Kameda H.
  • Organizer: Annual European Congress of Rheumatology (EULAR 2015)
  • Place of Presentation: Rome, Italy
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] Concordance between joint symptom/swelling/tenderness and US synovitis: Which clinical finding is more relevant to US? (2015)
  • Author(s): Hirata A, Ogura T, Hayashi N, Takenaka S, Ito H, Mizushina K, Nakahashi S, Fujisawa Y, Kameda H.
  • Organizer: 第59回日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋国際会議場（ 愛知県名古屋市）
  • Year and Date: 2015-04-23
• [Remarks] 東邦大学医療センター大橋病院膠原病リウマチ科 学術活動
  • URL: http://www.lab.toho-u.ac.jp/med/ohashi/kogen/research/index.html