関節リウマチの精密医療の実現を目指す多角的な病態解析研究

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19K08886
• Research Institution: Nagasaki University
• Principal Investigator: 川上 純 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90325639)
• Co-Investigator(Kenkyū-buntansha): 古賀 智裕 長崎大学, 医歯薬学総合研究科(医学系), 助教 (90537284) ; 玉井 慎美 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (60380862) ; 川尻 真也 長崎大学, 医歯薬学総合研究科(医学系), 講師 (20457576) ; 千葉 恒 長崎大学, 医歯薬学総合研究科(医学系), 助教 (00457574) ; 佐藤 俊太朗 長崎大学, 病院(医学系), 助教 (20738926) ; 大山 要 長崎大学, 医歯薬学総合研究科(薬学系), 准教授 (50437860)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 関節リウマチ / 関節画像評価 / 滑膜炎 / 骨破壊 / バイオマーカー / ACPA / コラーゲン誘発関節炎 / イムノフェノタイピング

Outline of Annual Research Achievements

関節リウマチ（RA）の関節傷害は滑膜増殖、関節裂隙狭小化、骨びらんに特徴づけられる。これら3つの病変はお互いに関連し、多くのエフェクター細胞・分子が作用するが不明な点も多く、今回の多角的な研究を計画した。プロトコールに準じてRA症例を登録しサンプリングを行い、解析した。2021年度は超音波（US）、MRI、HR-pQCT、血清バイオマーカーを中心とした解析において：1.T細胞活性化抑制が主たる効果発現機序と考えられるアバタセプトの有効性を超音波指標と血清骨代謝マーカーで解析し、パワードプラにおける反応性に最も寄与する因子としてアバタセプト導入前のDkk-1が抽出され、それ以外にも治療経過中のSOSTやOPGの変動が有意に関連した。 2.治療抵抗性のRA（D2T RA）の特徴を超音波指標で評価すると、non-D2T RAと比較して、分子標的薬導入前の自己抗体RF陽性率が高く、炎症反応および超音波指標が強く、併存症間質性肺疾患（ILD）が多かった。分子標的治療経過における超音波指標の改善も、D2T RAはnon-D2T RAと比較して乏しかったが、その中でも、改善が得られやすい患者群の臨床的特徴を特定しつつあり、今後はこの特性のバイオマーカーでの裏付けを目指す。3.MRI、US、HR-pQCTの複合的解析はデノスマブ治療群（vs 通常治療群）で実施し、デノスマブ治療でHR-pQCT骨びらん改善傾向、骨密度・骨微細構造改善、MRI骨髄浮腫・超音波滑膜炎は変化なしのデータが得られており、今後はこの特性のバイオマーカーでの裏付けを目指す。4.コラーゲン誘発関節炎を用いて関節炎と骨変化をデュアルに修飾する因子を評価中であり、その系における上記1.-3.で明らかとなった分子の発現を、炎症と骨破壊の両面から解析中である（これらが協調的に、もしくは、独立的に進展する可能性がある）。

Research Products

• [Journal Article] Analysis of bone erosions in rheumatoid arthritis using HR-pQCT: Development of a measurement algorithm and assessment of longitudinal changes (2022)
  • Author(s): Shiraishi K, Watanabe K, Oki N, Iwamoto N, Amano S, Yonekura A, Tomita M, Uetani M, Kawakami A, Osaki M.
  • Journal Title: PLOS ONE Volume: 17 Pages: -
  • DOI: 10.1371/journal.pone.0265833
  • Peer Reviewed / Open Access
• [Journal Article] ACPA‐IgG variable domain glycosylation increases before the onset of rheumatoid arthritis and stabilizes thereafter; a cross‐sectional study encompassing 1500 samples (2022)
  • Author(s): Kissel T, Hafkenscheid L, Wesemael TJ, Tamai M, Kawashiri SY, Kawakami A, El-Gabalawy HS, van Schaardenburg D, Rantapaa-Dahlqvist S, Wuhrer M, van der Helm-van Mi AHM, Allaart CF, van der Woude D, Scherer HU, Toes REM, Huizinga TWJ.
  • Journal Title: Arthritis & Rheumatology Volume: - Pages: -
  • DOI: 10.1002/art.42098
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evolution of anti-modified protein antibody responses can be driven by consecutive exposure to different post-translational modifications (2021)
  • Author(s): Volkov M, Kampstra ASB. Van Schie KA, Kawakami A. Tamai M, Kawashiri SY, T Maeda T, Huizinga TWJ, Toes REM , Van der Woude D.
  • Journal Title: Arthritis Research & Therapy Volume: 23 Pages: -
  • DOI: 10.1186/s13075-021-02687-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methotrexate Alters the Expression of microRNA in Fibroblast-like Synovial Cells in Rheumatoid Arthritis (2021)
  • Author(s): Iwamoto N, Furukawa K, Endo Y, Shimizu T, Sumiyoshi R, Umeda M, Koga T, Kawashiri SY, Igawa T, Ichinose K, Tamai M, Origuchi T, Kawakami A.
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Pages: 11561～11561
  • DOI: 10.3390/ijms222111561
  • Peer Reviewed / Open Access
• [Journal Article] Ultrasound efficacy of targeted-synthetic disease-modifying anti-rheumatic drug treatment in rheumatoid arthritis: a multicenter prospective cohort study in Japan (2021)
  • Author(s): Endo Y, Kawashiri SY, Nishino A, Michitsuji T, Tomokawa T, Nishihata S, Okamoto M, Tsuji Y, Tsiji S, Shimizu T, Sumiyoshi R, Igawa T, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Kawakami A, et al.
  • Journal Title: Scandinavian Journal of Rheumatology Volume: - Pages: 1～9
  • DOI: 10.1080/03009742.2021.1927389
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness and safety of non-tumor necrosis factor inhibitor therapy for anti-human T-cell leukemia virus type 1 antibody-positive rheumatoid arthritis (2021)
  • Author(s): Endo Y, Fukui S, Umekita K, Suzuki T, Miyamoto J, Morimoto S, Shimizu T, Koga T, Kawashiri SY, Iwamoto N, Ichinose K, Tamai M, Origuchi T, Okada A, Fujikawa K, Mizokami A, Matsuoka N, Aramaki T, Ueki Y, Eguchi K, Kariya Y, Hashida Y, Hidaka T, Okayama A, Kawakami A, Nakamura H.
  • Journal Title: Modern Rheumatology Volume: 31 Pages: 972～978
  • DOI: 10.1080/14397595.2020.1847802
  • Peer Reviewed / Open Access
• [Journal Article] Genetic predisposition (HLA-SE) is associated with ACPA-IgG variable domain glycosylation in the predisease phase of RA (2021)
  • Author(s): Kissel T, Wesemael TJV, Lundquist A, Kokkonen H, Kawakami A, Tamai M, Schaardenburg DV, Wuhrer M, Huizinga TWJ, Scherer HU, Woude DVD, Dahlqvist SR, Toes REM.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 81 Pages: 141～143
  • DOI: 10.1136/annrheumdis-2021-220841
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cold-inducible RNA-binding protein (CIRP) potentiates uric acid-induced IL-1β production (2021)
  • Author(s): Fujita Y, Yago T, Matsumoto H, Asano T, Matsuoka N, Temmoku J, Sato S, Yashiro-Furuya M, Suzuki E, Watanabe H, Kawakami A, Migita K.
  • Journal Title: Arthritis Research & Therapy Volume: 23 Pages: -
  • DOI: 10.1186/s13075-021-02508-9
  • Peer Reviewed / Open Access
• [Journal Article] Effect of abatacept treatment on serum osteoclast-related biomarkers in patients with rheumatoid arthritis (RA) (2021)
  • Author(s): Kawashiri SY, Endo Y, Nishino A, Okamoto M, Tsuji S, Takatani A, Shimizu T, Sumiyoshi R, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Aramaki T, Ueki Y, Yoshitama T, Eiraku N, Matsuoka N, Okada A, Fujikawa K, Hamada H, Nagano S, Tada Y, Kawakami A.
  • Journal Title: Medicine Volume: 100 Pages: e26592～e26592
  • DOI: 10.1097/MD.0000000000026592
  • Peer Reviewed / Open Access
• [Journal Article] Tocilizumab has no direct effect on cell lines infected with human T-cell leukemia virus type 1 (2021)
  • Author(s): Endo Y, Fukui S, Koga T, Sasaki D, Hasegawa H, Yanagihara K, Okayama A, Nakamura T, Kawakami A, Nakamura H.
  • Journal Title: Journal of International Medical Research Volume: 49 Pages: -
  • DOI: 10.1177/03000605211002083
  • Peer Reviewed / Open Access
• [Journal Article] Discrepancy between clinical and ultrasound remissions in rheumatoid arthritis: a multicentre ultrasound cohort study in Japan (2021)
  • Author(s): Endo Y, Kawashiri SY, Nishino A, Okamoto M, Tsuji S, Shimizu T, Sumiyoshi Remi, Igawa T, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Ueki Y, Yoshitama T, Eiraku N, Matsuoka N, Okada A, Fujikawa K, Otsubo H, Takaoka K, Hamada H, Tsuru T, Nagano S, Arinobu Y, Hidaka T, Tada Y, Kawakami A.
  • Journal Title: Scandinavian Journal of Rheumatology Volume: 50 Pages: 436～441
  • DOI: 10.1080/03009742.2021.1876914
  • Peer Reviewed / Open Access
• [Journal Article] Contributing factors of clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis patients with tightly controlled disease activity in clinical practice: a retrospective study (2021)
  • Author(s): Kawashiri SY, Endo Y, Okamoto M, Tsuji S, Shimizu T, Sumiyoshi R, Koga T, Iwamoto N, Ichinose K. Tamai M, Nakamura H, Origuchi T, Kawakami A.
  • Journal Title: Modern Rheumatology Volume: 31 Pages: 343～349
  • DOI: 10.1080/14397595.2020.1795392
  • Peer Reviewed / Open Access
• [Journal Article] Current insights and future prospects for the pathogenesis and treatment for rheumatoid arthritis (2021)
  • Author(s): Koga T, Kawakami A, Tsokos GC.
  • Journal Title: Clinical Immunology Volume: 225 Pages: 108680～108680
  • DOI: 10.1016/j.clim.2021.108680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis (2021)
  • Author(s): Endo Y, Kawashiri SY, Morimoto S, Nishino A, Okamoto M, Tsuji S, Takatani A, Shimizu T, Sumiyoshi R, Igawa T, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Kawakami A, et al.
  • Journal Title: Medicine Volume: 100 Pages: e23254～e23254
  • DOI: 10.1097/MD.0000000000023254
  • Peer Reviewed / Open Access
• [Journal Article] Significance of anti-Ro/SSA antibodies in the response and retention of abatacept in patients with rheumatoid arthritis: a multicentre cohort study (2021)
  • Author(s): Endo Y, Koga T, Kawashiri SY, Morimoto S, Nishino A, Okamoto M, Tsuji S, Takatani A, Shimizu T, Sumiyoshi R, Igawa T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Ueki Y, Yoshitama T, Eiraku N, Matsuoka N, Okada A, Fujikawa K, Hamada H, Tsuru T, Nagano S, Arinobu Y, Hidaka T, Tada Y, Kawakami A.
  • Journal Title: Scandinavian Journal of Rheumatology Volume: 50 Pages: 15～19
  • DOI: 10.1080/03009742.2020.1772361
  • Peer Reviewed / Open Access
• [Journal Article] Fluorescence optical imaging in patients with active rheumatoid arthritis: a comparison with ultrasound and an association with biomarkers (2021)
  • Author(s): Kawashiri SY, Nishino A, Shimizu T, Takatani A, Umeda M, Koga T, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Maeda T, Kawakami A.
  • Journal Title: Scandinavian Journal of Rheumatology Volume: 50 Pages: 95～103
  • DOI: 10.1080/03009742.2020.1794028
  • Peer Reviewed / Open Access
• [Presentation] 関節リウマチのHR-pQCTによる評価. (2021)
  • Author(s): 千葉 恒，白石和輝，渡邉航之助，大木 望，上谷雅孝，岩本直樹，川上 純，尾崎 誠.
  • Organizer: 第36回日本臨床リウマチ学会
  • Invited
• [Presentation] D2TRAの臨床的特徴の検討(九州地区多施設共同前向き関節リウマチ超音波コホート研究） (2021)
  • Author(s): 道辻 徹，遠藤友志郎，川尻真也，植木幸孝，榮樂信隆，岡田覚丈，吉玉珠美，松岡直樹，藤川敬太，高岡宏和，日髙利彦，有信洋二郎，濱田浩朗，都留智巳，川上 純.
  • Organizer: 第62回九州リウマチ学会
  • Invited
• [Presentation] Evolution of anti‐modified protein antibody responses can be driven by consecutive exposure to different post-translational modifications. (2021)
  • Author(s): Volkov M, Kampstra ASB, van Schie K, Kawakami A，Tamai M，Kawashiri SY，Maeda T，Huizinga T，Toes R，van der Woude D.
  • Organizer: EULAR 2021 European E‐Congress of Rheumatology.
  • Int'l Joint Research
• [Presentation] リウマチ性疾患の関節画像評価：利点とピットフォール. (2021)
  • Author(s): 川上 純.
  • Organizer: 第65回日本リウマチ学会総会・学術集会
  • Invited