Development of a new rheumatoid arthritis monitoring method by analysis of anti-CCP antibody-producing B cell repertoire

• Project/Area Number: 17K08973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Tohoku University
• Principal Investigator: ISHII Tomonori 東北大学, 大学病院, 特任教授 (10282138)
• Co-Investigator(Kenkyū-buntansha): 小笠原 康悦 東北大学, 加齢医学研究所, 教授 (30323603) ; 白井 剛志 東北大学, 大学病院, 助教 (20646997) ; 藤井 博司 東北大学, 医学系研究科, 准教授 (30531321) ; 城田 祐子 東北医科薬科大学, 医学部, 准教授 (20455819)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 関節リウマチ / レパトア解析 / アバタセプト / TCRレパトア / ＢＣＲレパトア / BCRレパトア / 生物学的製剤 / 抗CCP抗体 / B細胞レパトア解析

Outline of Final Research Achievements

Abatacept was administered to 15 patients with rheumatoid arthritis who did not lose their activity despite existing treatment. Before treatment, peripheral blood was collected from patients and lymphocytes were separated from peripheral blood. Repertoire analysis of B cell receptor and T cell receptor was performed on the obtained lymphocytes. Abatacept was treated for more than three months in these patients. After treatment, a second repertoire analysis of B cells and T cells was performed and compared with the repertoire before treatment. Abatacept treatment was effective in 70% of patients. Specific T cell repertoire decreased before and after treatment in lymphocytes obtained from patients who responded to these treatments

Academic Significance and Societal Importance of the Research Achievements

本研究により、関節リウマチ患者における活動性と関連したTCRのレパトアが存在する事が解明された。またこうしたレパトアがアバタセプトの治療により正常化することが確認できた。これにより、治療前に、こうした特定のレパトアの存在の有無をみることで、治療前からアバタセプトの有効性が期待できる患者群を特定できることが可能性が示された。また、治療後にこうしたレパトアが改善したことをマーカーに治療方針を決定することができる可能性が示唆された。これにより、薬剤の効率的な使用が可能になり、無駄な治療をする確率を減らすことで、患者の安全性のみでなく社会経済的観点からも有用性が考えられる。

Research Products

• [Journal Article] Insufficient Use of Corticosteroids without Immunosuppressants Results in Higher Relapse Rates in Takayasu Arteritis (2019)
  • Author(s): Mutoh Tomoyuki、Shirai Tsuyoshi、Fujii Hiroshi、Ishii Tomonori、Harigae Hideo
  • Journal Title: The Journal of Rheumatology Volume: 47 Issue: 2 Pages: 255-263
  • DOI: 10.3899/jrheum.181219
  • Peer Reviewed
• [Journal Article] Four distinct clinical phenotypes of vasculitis affecting medium-sized arteries. (2019)
  • Author(s): Shirai T, Shirota Y, Fujii H, Ishii T, Harigae H.
  • Journal Title: Scand J Rheumatol Volume: 48 Issue: 4 Pages: 1-7
  • DOI: 10.1080/03009742.2018.1551965
  • Peer Reviewed
• [Journal Article] Takayasu Arteritis Coexisting with Sclerosing Osteomyelitis (2018)
  • Author(s): Shirai T, Hanaoka R, Goto Y, Kojima I, Ishii Y, Hoshi Y, Fujita Y, Shirota Y, Fujii H, Ishii T, Harigae H.
  • Journal Title: Internal Medicine Volume: 57 Issue: 13 Pages: 1929-1934
  • DOI: 10.2169/internalmedicine.0329-17
  • NAID: 130007387190
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis (AAV) Restricted to the Limbs (2018)
  • Author(s): Ojima Y, Sawada K, Fujii H, Shirai T, Saito A, Kagaya S, Aoki S, Takeuchi Y, Ishii T, Nagasawa T.
  • Journal Title: Internal Medicine Volume: 57 Issue: 9 Pages: 1301-1308
  • DOI: 10.2169/internalmedicine.9848-17
  • NAID: 130006730798
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-05-01
  • Peer Reviewed / Open Access
• [Journal Article] A randomized, double-blind, parallel-group, phase III study of shortening the dosing interval of subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis and an inadequate response to subcutaneous tocilizumab every other week: Results of the 12-week double-blind period (2018)
  • Author(s): Ogata A1,2, Tanaka Y, Ishii T, Kaneko M, Miwa H, Ohsawa S; SHINOBI study group.
  • Journal Title: Mod Rheumatol Volume: 28 Issue: 1 Pages: 76-84
  • DOI: 10.1080/14397595.2017.1332507
  • Peer Reviewed
• [Journal Article] Long-term safety and efficacy of weekly subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis who had an inadequate response to subcutaneous tocilizumab every other week: Results from the open-label extension of the SHINOBI study (2018)
  • Author(s): Ogata A, Tanaka Y, Ishii T, Kaneko M, Miwa H, Ohsawa S, Yamakawa R
  • Journal Title: Mod Rheumatol Volume: Epub ahead of print Issue: 5 Pages: 767-774
  • DOI: 10.1080/14397595.2018.1533514
  • Peer Reviewed
• [Journal Article] Multicenter double-blind randomized controlled trial to evaluate the effectiveness and safety of bortezomib as a treatment for refractory systemic lupus erythematosus. (2018)
  • Author(s): Ishii T, Tanaka Y, Kawakami A, Saito K, Ichinose K, Fujii H, Shirota Y, Shirai T, Fujita Y, Watanabe R, Chiu SW, Yamaguchi T, Harigae H.
  • Journal Title: Modern Rheumatology Volume: - Issue: 6 Pages: 1-7
  • DOI: 10.1080/14397595.2018.1432331
  • Peer Reviewed / Open Access
• [Journal Article] Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity. (2017)
  • Author(s): Ikeda T, Fujii H, Nose M, Kamogawa Y, Shirai T, Shirota Y, Ishii T, Harigae H.
  • Journal Title: Arthritis Research & Therapy Volume: 19（1） Issue: 1 Pages: 187-187
  • DOI: 10.1186/s13075-017-1397-7
  • Peer Reviewed / Open Access
• [Journal Article] Relapsing Polychondritis Complicated by Myelodysplastic Syndrome Is Resistant to Immunosuppression: Comment on the Article by Dion et al. (2017)
  • Author(s): Shirai T, Fujii H, Saito R, Nasu K, Kamogawa Y, Fukuhara N, Fujita Y, Shirota Y, Ishii T, Harigae H.
  • Journal Title: Arthritis & Rheumatology Volume: 69 Issue: 3 Pages: 682-683
  • DOI: 10.1002/art.39969
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] SARILUMAB AND TOCILIZUMAB RECEPTOR OCCUPANCY (RO), AND EFFECTS ON C-REACTIVE PROTEIN (CRP) LEVELS, IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), (2019)
  • Author(s): Christine Xu, Patrick Nolain, Qiang Lu, Anne Paccaly, Melitza Iglesias-Rodriguez, Gregory St John, Chad Nivens, Rafael Maldonado, Tomonori Ishii, Ernest Choy, Vanaja Kanamaluru
  • Organizer: ＥＵＬＡＲ
  • Int'l Joint Research
• [Presentation] Sarilumab and Tocilizumab Receptor Occupancy (RO), and Effects on C-Reactive Protein (CRP) Levels, in Patients with Rheumatoid Arthritis (RA) (2019)
  • Author(s): Christine Xu, Patrick Nolain , Qiang Lu , Anne Paccaly , Melitza Iglesias-Rodriguez , Gregory St John , Chad Nivens , Rafael Maldonado , Tomonori Ishii , Ernest Choy and Vanaja Kanamaluru
  • Organizer: ＡＣＲ
  • Int'l Joint Research
• [Presentation] 強皮症・MCTD・重複症候群1 全身性強皮症に伴う難治性皮膚潰瘍に対する低出力衝撃波療法の有効性・安全性検証試験 (2018)
  • Author(s): 石井 智徳(東北大学病院 臨床研究推進センター), 川口 鎮司, 石川 治, 竹森 弘光, 高澤 徳彦, 小林 仁, 安岡 秀剛, 高橋 裕一, 小寺 隆雄, 高井 修, 中屋 来哉, 泉山 朋政, 齋藤 真一郎, 鴨川 由起子, 藤田 洋子, 白井 剛志, 城田 祐子, 藤井 博司, 張替 秀郎
  • Organizer: 日本リウマチ学会総会
• [Presentation] 全国多施設前向きコホート研究(Apple study)を用いた関節リウマチ患者における機能的改善の予測因子に関する検討 (2018)
  • Author(s): 古賀 智裕, 日高 利彦, 岡田 覚丈, 荒牧 俊幸, 福田 孝昭, 高橋 裕一, 石井 智徳
  • Organizer: 九州リウマチ
• [Presentation] リウマチ性疾患の合併症(感染症以外・アミロイドーシス・その他)3:その他2 膠原病性肺動脈性肺高血圧症(CTD-PAH)における予後予測因子と死因について (2018)
  • Author(s): 城田 祐子, 星 陽介, 佐藤 紘子, 藤田 洋子, 白井 剛志, 藤井 博司, 石井 智徳, 張替 秀郎
  • Organizer: 日本リウマチ学会総会
• [Presentation] 全身性エリマトーデスにおける新規治療薬の開発戦略 (2017)
  • Author(s): 石井智徳
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] Four-Distinct Phenotypes of Patients with Necrotizing Arteritis of Medium and Small Artery (2017)
  • Author(s): Ishii T, Kawaguchi Y, Ishikawa O, Takasawa N, Kodera T, Yasuoka H, Takahashi Y, Takai O, Nakaya I, Fujii H, Kamogawa Y, Shirota Y, Shirai T, Fujita Y, Saito S, Shimokawa H and Harigae H.
  • Organizer: 2017 ACR/ARHP Annual Meeting
  • Int'l Joint Research
• [Presentation] 全身性強皮症における皮膚潰瘍 (2017)
  • Author(s): 石井 智徳
  • Organizer: 第32回日本臨床リウマチ学会
• [Remarks] 東北大学 血液・免疫病学分野
  • URL: http://www.rh.med.tohoku.ac.jp/index.html