A multitiered study for clinical subtypes, treatments, and biomarkers using inception cohorts of patients with ANCA-associated vasculitis

• Project/Area Number: 17K09986
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Tsutsumino Michi 東京女子医科大学, 医学部, 非常勤講師 (50277141)
• Co-Investigator(Kenkyū-buntansha): 針谷 正祥 東京女子医科大学, 医学部, 教授 (20238207) ; 要 伸也 杏林大学, 医学部, 教授 (60224581) ; 勝又 康弘 東京女子医科大学, 医学部, 講師 (60349719) ; 佐田 憲映 岡山大学, 大学病院, 准教授 (70423308)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ANCA関連血管炎 / クラスター解析 / 治療戦略 / シクロホスファミド / ANCA測定法 / ANCA測定方法 / 新規臨床サブセット / 治療戦略評価 / バイオマーカー

Outline of Final Research Achievements

We obtained following results by using clinical information and samples from patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis registered in two Japanese cohort studies. We identified novel clusters of patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). We demonstrated effectiveness of treatments with cyclophosphamide (CY) in MPO-ANCA positive patients with MPA and GPA. Proportions of patients who achieved disease activity score of BVAS=0 and daily prednisolone doses of 10 mg or less were 49% and 31% in patients treated with and without CY, respectively (p=0.02). We compared several assay kits for ANCA. All methods except for a latex immune-agglutination method showed satisfactory sensitivity and specificity.

Academic Significance and Societal Importance of the Research Achievements

抗好中球細胞質抗体(ANCA)関連血管炎(AAV)は、わが国の指定難病の一つに含まれている。その希少性から診断・治療に関する研究を進めることは難しい疾患の一つである。本研究では、厚生労働省難治性血管炎研究班ですでに実施されたAAV患者コホート研究で蓄積された臨床情報と患者検体を用いて、新規臨床サブセット同定、治療戦略の検討、ANCA測定法の有用性比較を行い、新たな知見が得られた点に学術的な意義がある。ANCA測定法の有用性比較は、臨床に直結する結果を提示しており、社会的な意義が高い研究である。

Research Products

• [Journal Article] Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis (2021)
  • Author(s): Ishizaki J, Takemori A, Horie K, Hiraoka D, Suemori K, Matsumoto T, Sada KE, Amano K, Harigai M, Arimura Y, Makino H, Takenaka K, Takemori N, Hasegawa H, and Hirahashi J as a collaborator..
  • Journal Title: Arthritis Research & Therapy Volume: 23 Issue: 1 Pages: 91-91
  • DOI: 10.1186/s13075-021-02471-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exploratory classification of clinical phenotypes in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis using cluster analysis (2021)
  • Author(s): Watanabe H, Sada KE, Harigai M, Amano K, Dobashi H, Takasaki Y, Fujimoto S, Atsumi T, Yamagata K, Homma S, Arimura Y, Makino H
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-84627-6
  • NAID: 120007027577
  • Peer Reviewed / Open Access
• [Journal Article] JCS 2017 Guideline on Management of Vasculitis Syndrome ― Digest Version ― (2020)
  • Author(s): Isobe, M. Amano, K. Arimura, Y. Ishizu, A. Ito, S. Kaname, S. Takahashi, K. Tanemoto, K. Hasegawa, H. Harigai, M. Fujimoto, S. Miyazaki, T. et.al.
  • Journal Title: Circulation Journal Volume: 84 Issue: 2 Pages: 299-359
  • DOI: 10.1253/circj.CJ-19-0773
  • NAID: 130007789906
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-01-24
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (2020)
  • Author(s): Yokoe Y、Tsuboi N、Imaizumi T、Kitagawa A、Karasawa M、Ozeki T、Endo N、Sawa Y、Kato S、Katsuno T、Maruyama S、Yamagata K、Usui J、Nagata M、Sada K、Sugiyama H、Amano K、Arimura Y、Atsumi T、Yuzawa Y、Dobashi H、Takasaki Y、Harigai M、Hasegawa H、Makino H、Matsuo S
  • Journal Title: Nephrology Dialysis Transplantation Volume: in press Issue: 8 Pages: 1-12
  • DOI: 10.1093/ndt/gfaa097
  • Peer Reviewed / Open Access
• [Journal Article] Treatment-related damage in elderly-onset ANCA-associated vasculitis: safety outcome analysis of two nationwide prospective cohort studies (2020)
  • Author(s): Sada KE, Ohashi K, Asano Y, Hayashi K, Morishita M, Watanabe H, Matsumoto Y, Fujimoto S, Takasaki Y, Yamagata K, Banno S, Dobashi H, Amano K, Harigai M, Arimura Y, Makino H and Hirahashi J as a collaborator.
  • Journal Title: Arthritis Research & Therapy Volume: 22 Issue: 1
  • DOI: 10.1186/s13075-020-02341-6
  • Peer Reviewed / Open Access
• [Journal Article] Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study (2020)
  • Author(s): Fukui S、Ichinose K、Sada K-E、Miyamoto J、Harigai M、Amano K、Atsumi T、Takasaki Y、Dobashi H、Arimura Y、Hasegawa H、Yuzawa Y、Yamagata K、Tsuboi N、Maruyama S、Matsuo S、Makino H、Maeda T、Kawakami A
  • Journal Title: Scandinavian Journal of Rheumatology Volume: 49 Issue: 4 Pages: 301-311
  • DOI: 10.1080/03009742.2019.1695927
  • Peer Reviewed / Open Access
• [Journal Article] Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study (2020)
  • Author(s): Kawasaki Aya、Namba Natsumi、Sada Ken-ei、Hirano Fumio、Kobayashi Shigeto、Nagasaka Kenji、Sugihara Takahiko、Ono Nobuyuki、Fujimoto Takashi、Kusaoi Makio、Tamura Naoto、Yamagata Kunihiro、Sumida Takayuki、Hashimoto Hiroshi、Ozaki Shoichi、Makino Hirofumi、Arimura Yoshihiro、Harigai Masayoshi、Tsuchiya Naoyuki
  • Journal Title: Arthritis Research & Therapy Volume: 22 Issue: 1
  • DOI: 10.1186/s13075-020-02347-0
  • NAID: 120007188741
  • Peer Reviewed / Open Access
• [Journal Article] Rationale of concomitant cyclophosphamide for remission-induction in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A propensity score-matched analysis of two nationwide prospective cohort studies. (2020)
  • Author(s): Watanabe H
  • Journal Title: Mod Rheumatol. Volume: 6 Issue: 1 Pages: 1-9
  • DOI: 10.1080/14397595.2019.1707997
  • Peer Reviewed / Open Access
• [Presentation] Optimal initial dose of glucocorticoid for elderly-onset ANCA associated vasculitis: safety outcome analysis of two nationwide, prospective, inception cohort studies. (2019)
  • Author(s): Keiji Ohashi
  • Organizer: EULAR 2019. Jun,12-15; Madrid, Spain.
  • Int'l Joint Research
• [Presentation] Effectiveness of remission-induction therapy with concomitant cyclophosphamide and glucocorticoid for microscopic polyangiitis and granulomatosis with polyangiitis in Japan: a propensity score matched analysis of two nationwide prospective cohort studies (2018)
  • Author(s): Haruki Watanabe
  • Organizer: 第19回欧州リウマチ学会
  • Int'l Joint Research
• [Presentation] Effectiveness of remission-induction therapy with concomitant Cyclophosphamide and glucocorticoid for patients with microscopic polyangiitis and granulomatosis with polyangiitis in Japan (2018)
  • Author(s): Haruki Watanabe
  • Organizer: 第20回アジア太平洋リウマチ学会
  • Int'l Joint Research
• [Presentation] クラスター解析を用いたANCA関連血管炎の分類と重症度に関する検討 (2018)
  • Author(s): 佐田 憲映
  • Organizer: 第62回日本リウマチ学会
• [Remarks] 東京女子医科大学 膠原病リウマチ痛風センター
  • URL: http://www.twmu.ac.jp/IOR/
• [Remarks] 難治性血管炎の医療水準・患者QOL向上に資する研究班
  • URL: https://www.vas-mhlw.org/