Omics-based analysis of molecular pathogenesis of systemic juvenile idiopathic arthritis and development of novel therapeutic intervention

• Project/Area Number: 15H04873
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kanazawa University
• Principal Investigator: Yachie Akihiro 金沢大学, 医学系, 教授 (40210281)
• Co-Investigator(Kenkyū-buntansha): 東馬 智子 金沢大学, 附属病院, 助教 (00377392) ; 清水 正樹 金沢大学, 附属病院, 講師 (10401902) ; 和田 泰三 金沢大学, 附属病院, 講師 (30313646)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: sJIA / MAS / biomarker / IL-18 / NK 細胞 / バイオマーカー / オミクス / iPS 細胞 / サイトカイン / sTNF-Rs / iPS / cytokine profile / オミクス情報 / 小児免疫 / アレルギー / 膠原病 / 若年性特発性関節炎 / angiopoietin / 先制医療

Outline of Final Research Achievements

sJIA is a chronic inflammatory illness characterized by fever and join pain. Although its etiology remains unknown, extremely elevated serum level of IL-18 is a cardinal feature of the disease. When the inflammatory condition is not properly controlled, there often exists s risk of inducing macrophage activation syndrome, or MAS, which occasionally leads to fatal outcome. It is therefore very important to establish efficient system to diagnose sJIA early and predict the onset of MAS timely to start immediate therapeutic intervention. In this study, several biomarkers were found to be useful for this purpose and risk factors of MAS induction was also revealed. The whole study contributed a lot to the diagnosis and treatment of sJIA/MAS.

Academic Significance and Societal Importance of the Research Achievements

小児における難治性炎症性疾患である、全身型若年性特発性関節炎の病態について、様々な有用な血清バイオマーカーを見出すことにより明らかにした。また、重篤な合併症であるマクロファージ活性化症候群発症のリスク因子を明らかにし、その予測や早期発見のためのバイオマーカーも提示した。これらの成果は、本疾患を病態から理解し、適切な診断・治療のための指標と提示することとなった。

Research Products

• [Journal Article] Serum Leucine-Rich α2-Glycoprotein as a Biomarker for Monitoring Disease Activity in Patients with Systemic Juvenile Idiopathic Arthritis. (2019)
  • Author(s): Shimizu M, Inoue N, Mizuta M, Nakagishi Y, Yachie A.
  • Journal Title: J Immunol Res. Volume: 2019 Pages: 3140204-3140204
  • DOI: 10.1155/2019/3140204
  • Peer Reviewed
• [Journal Article] Cytokine profile of macrophage activation syndrome associated with Kawasaki disease. (2019)
  • Author(s): Jinkawa A, Shimizu M, Nishida K, Kaneko S, Usami M, Sakumura N, Irabu H, Takakuwa M, Inoue N, Mizuta M, Ikawa Y, Fujita S, Yachie A.
  • Journal Title: Cytokine. Volume: 119 Pages: 52-56
  • DOI: 10.1016/j.cyto.2019.03.001
  • Peer Reviewed
• [Journal Article] Clinical significance of serum CXCL9 levels as a biomarker for systemic juvenile idiopathic arthritis associated macrophage activation syndrome. (2019)
  • Author(s): Mizuta M, Shimizu M, Inoue N, Nakagishi Y, Yachie A.
  • Journal Title: Cytokine Volume: 119 Pages: 182-187
  • DOI: 10.1016/j.cyto.2019.03.018
  • Peer Reviewed
• [Journal Article] Changes in serum interleukin-6 levels as possible predictor of efficacy of tocilizumab treatment in rheumatoid arthritis (2018)
  • Author(s): Aizu Motohiko、Mizushima Ichiro、Nakazaki Satoshi、Nakashima Akikatsu、Kato Takashi、Murayama Takashi、Kato Shinichi、Katsuki Yasuo、Ogane Kunihiro、Fujii Hiroshi、Yamada Kazunori、Nomura Hideki、Yachie Akihiro、Yamagishi Masakazu、Kawano Mitsuhiro
  • Journal Title: Modern Rheumatology Volume: 28 Issue: 4 Pages: 592-598
  • DOI: 10.1080/14397595.2017.1370766
  • Peer Reviewed
• [Journal Article] Longitudinal analysis of serum interleukin-18 in patients with familial Mediterranean fever carrying MEFV mutations in exon 10. (2018)
  • Author(s): Wada T, Toma T, Miyazawa H, Koizumi E, Shirahashi T, Matsuda Y, Yachie A.
  • Journal Title: Cytokine. Volume: 104 Pages: 143-146
  • DOI: 10.1016/j.cyto.2017.10.007
  • NAID: 120006464071
  • Peer Reviewed
• [Journal Article] Clinical significance of serum soluble TNF receptor II level and soluble TNF receptor II/I ratio as indicators of coronary artery lesion development in Kawasaki disease. (2018)
  • Author(s): Shimizu M, Mizuta M, Usami M, Inoue N, Sakakibara Y, Yamada K, Konishi M, Ohta K, Yachie A.
  • Journal Title: Cytokine Volume: 108 Pages: 168-172
  • DOI: 10.1016/j.cyto.2018.03.037
  • Peer Reviewed
• [Journal Article] Soluble CD163, a unique biomarker to evaluate the disease activity, exhibits macrophage activation in systemic juvenile idiopathic arthritis. (2018)
  • Author(s): Sakumura N, Shimizu M, Mizuta M, Inoue N, Nakagishi Y, Yachie A.
  • Journal Title: Cytokine Volume: 110 Pages: 459-465
  • DOI: 10.1016/j.cyto.2018.05.017
  • Peer Reviewed
• [Journal Article] Transient natural killer cell dysfunction associated with interleukin-18 overproduction in systemic juvenile idiopathic arthritis. (2018)
  • Author(s): Takakura M, Shimizu M, Yakoyama T, Mizuta M, Yachie A.
  • Journal Title: Pediatr Int. Volume: 60 Issue: 10 Pages: 984-985
  • DOI: 10.1111/ped.13679
  • Peer Reviewed
• [Journal Article] Musculoskeletal manifestations occur predominantly in patients with later-onset familial Mediterranean fever: Data from a multicenter, prospective national cohort study in Japan. (2018)
  • Author(s): Endo Y, Koga T, Ishida M, Fujita Y, Tsuji S, Takatani A, Shimizu T, Sumiyoshi R, Igawa T, Umeda M, Fukui S, Nishino A, Kawashiri SY, Iwamoto N, Ichinose K, Tamai M, Nakamura H, Origuchi T, Agematsu K, Yachie A, Masumoto J, Migita K, Kawakami A.
  • Journal Title: Arthritis Res Ther. Volume: 20 Issue: 1 Pages: 257-257
  • DOI: 10.1186/s13075-018-1738-1
  • NAID: 120006987889
  • Peer Reviewed / Open Access
• [Journal Article] A case of incomplete Kawasaki disease with extremely high serum ferritin and interleukin-18 levels. (2018)
  • Author(s): Noto T, Seto H, Fukuhara J, Murabayashi M, Yachie A, Ayusawa M, Morioka I.
  • Journal Title: BMC Pediatr Volume: 18 Issue: 1 Pages: 386-386
  • DOI: 10.1186/s12887-018-1365-7
  • Peer Reviewed
• [Journal Article] Characteristic elevation of soluble TNF receptor II : I ratio in macrophage activation syndrome with systemic juvenile idiopathic arthritis (2017)
  • Author(s): Shimizu M.、Inoue N.、Mizuta M.、Nakagishi Y.、Yachie A.
  • Journal Title: Clinical Experimental Immunology Volume: 191 Issue: 3 Pages: 349-355
  • DOI: 10.1111/cei.13026
  • Peer Reviewed
• [Journal Article] Comparison of serum inflammatory cytokine concentrations in familial Mediterranean fever and rheumatoid arthritis patients (2017)
  • Author(s): Koga T、Kawashiri S-y、Migita K、Sato S、Umeda M、Fukui S、Nishino A、Nonaka F、Iwamoto N、Ichinose K、Tamai M、Nakamura H、Origuchi T、Ueki Y、Masumoto J、Agematsu K、Yachie A、Eguchi K、Kawakami A
  • Journal Title: Scandinavian Journal of Rheumatology Volume: - Issue: 4 Pages: 1-3
  • DOI: 10.1080/03009742.2017.1363281
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MicroRNA-204-3p inhibits lipopolysaccharide-induced cytokines in familial Mediterranean fever via the phosphoinositide 3-kinase γ pathway (2017)
  • Author(s): Koga Tomohiro,Migita Kiyoshi,Sato Tomohito,Sato Shuntaro,Umeda Masataka,Nonaka Fumiaki,Fukui Shoichi,Kawashiri Shin-ya,Iwamoto Naoki,Ichinose Kunihiro,Tamai Mami,Nakamura Hideki,Origuchi Tomoki,Ueki Yukitaka,Masumoto Junya,Agematsu Kazunaga,Yachie Akihiro,Yoshiura Koh-ichiro,Eguchi Katsumi,Kawakami Atsushi
  • Journal Title: Rheumatology Volume: 57 Issue: 4 Pages: 718-726
  • DOI: 10.1093/rheumatology/kex451
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FDG-PET in macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. (2017)
  • Author(s): Shimizu M, Ikawa Y, Mizuta M, Takakura M, Inoue N, Nishimura R, Yachie A.
  • Journal Title: Pediatr Int. Volume: 59 Issue: 4 Pages: 509-511
  • DOI: 10.1111/ped.13238
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Leucine-rich α2-glycoprotein as the acute-phase reactant to detect systemic juvenile idiopathic arthritis disease activity during anti-interleukin-6 blockade therapy: A case series. (2017)
  • Author(s): Shimizu M, Nakagishi Y, Inoue N, Mizuta M, Yachie A.
  • Journal Title: Mod Rheumatol. Volume: Jan 17 Issue: 5 Pages: 1-5
  • DOI: 10.1080/14397595.2016.1270795
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interleukin-33 as a marker of disease activity in rheumatoid factor positive polyarticular juvenile idiopathic arthritis. (2017)
  • Author(s): Ishikawa S, Shimizu M, Inoue N, Mizuta M, Nakagishi Y, Yachie A.
  • Journal Title: Mod Rheumatol Volume: 27 Issue: 4 Pages: 609-613
  • DOI: 10.1080/14397595.2016.1246118
  • Peer Reviewed
• [Journal Article] Microarray analysis of circulating microRNAs in familial Mediterranean fever. (2017)
  • Author(s): Wada T, Toma T, Matsuda Y, Yachie A, Itami S, Taguchi Y, Murakami Y.
  • Journal Title: Mod Rheumatol. Volume: Feb 6 Issue: 6 Pages: 1-18
  • DOI: 10.1080/14397595.2017.1285845
  • NAID: 120006226806
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interleukin-33 as a marker of disease activity in rheumatoid factor positive polyarticular juvenile idiopathic arthritis. (2016)
  • Author(s): Ishikawa S, Shimizu M, Inoue N, Mizuta M, Nakagishi Y, Yachie A.
  • Journal Title: Mod Rheumatol Volume: Oct.27 Pages: 1-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Familial Mediterranean fever is no longer a rare disease in Japan. (2016)
  • Author(s): Migita K, Izumi Y, Jiuchi Y, Iwanaga N, Kawahara C, Agematsu K, Yachie A, Masumoto J, Fujikawa K, Yamasaki S, Nakamura T, Ubara Y, Koga T, Nakashima Y, Shimizu T, Umeda M, Nonaka F, Yasunami M, Eguchi K, Yoshiura K, Kawakami A.
  • Journal Title: Arthritis Res Ther. Volume: 18 Issue: 1 Pages: 175-175
  • DOI: 10.1186/s13075-016-1071-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Serum ferritin levels as a useful diagnostic marker for the distinction of systemic juvenile idiopathic arthritis and Kawasaki disease. (2016)
  • Author(s): Mizuta M, Shimizu M, Inoue N, Kasai K, Nakagishi Y, Takahara T, Hamahira K, Yachie A.
  • Journal Title: Mod Rheumatol. Volume: 26 Issue: 6 Pages: 929-932
  • DOI: 10.3109/14397595.2016.1159120
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role of 18-fluoro-2-deoxyglucose positron emission tomography in detecting acute inflammatory lesions of non-bacterial osteitis in patients with a fever of unknown origin: A comparative study of 18-fluoro-2-deoxyglucose positron emission tomography, bone scan, and magnetic resonance imaging. (2016)
  • Author(s): Shimizu M, Saikawa Y, Yachie A.
  • Journal Title: Mod Rheumatol. Volume: Jun 20 Pages: 1-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiopoietin-1 and -2 as markers for disease severity in hemolytic uremic syndrome induced by enterohemorrhagic Escherichia coli. (2016)
  • Author(s): Shimizu M, Inoue N, Kuroda M, Mizuta M, Sugimoto N, Kaneda H, Ohta K, Yachie A.
  • Journal Title: Clin Exp Nephrol. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2. (2016)
  • Author(s): Tasaki Y, Shimizu M, Inoue N, Mizuta M, Nakagishi Y, Wada T, Yachie A.
  • Journal Title: Cytokine. Volume: 80 Pages: 1-6
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] An assessment of the effects of ectopic gp91phox expression in XCGD iPSC-derived neutrophils. (2015)
  • Author(s): Lin HT, Masaki H, Yamaguchi T, Wada T, Yachie A, Nishimura K, Ohtaka M, Nakanishi M, Nakauchi H, Otsu M.
  • Journal Title: Mol Ther Methods Clin Dev. Volume: 2 Pages: 15046-15046
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. (2015)
  • Author(s): Shimizu M, Nakagishi Y, Inoue N, Mizuta M, Ko G, Saikawa Y, Kubota T, Yamasaki Y, Takei S, Yachie A.
  • Journal Title: Clin Immunol. Volume: 160 Pages: 277-281
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency. (2015)
  • Author(s): Wada T, Akagi T, Muraoka M, Toma T, Kaji K, Agematsu K, Koeffler HP, Yokota T, Yachie A.
  • Journal Title: J Immunol. Volume: 195 Pages: 180-6
  • NAID: 120005647665
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 全身型若年性特発性関節炎における急性炎症反応評価のための血清 Leucine-rich a 2-glycoprotein 値の臨床的有用性 (2017)
  • Author(s): 清水正樹、作村直人、伊良部仁、高倉麻衣子、井上なつみ、水田麻雄、田崎優子、中岸保夫、金田尚、太田和秀、谷内江昭宏
  • Organizer: 第27回日本小児リウマチ学会
• [Presentation] 全身型若年性特発性関節炎における NK 細胞の IL-18 不応答性の経時的検討 (2017)
  • Author(s): 高倉麻衣子、清水正樹、井上なつみ、水田麻雄、清水陽、犀川太、川野充弘、谷内江昭宏
  • Organizer: 第27回日本小児リウマチ学会
• [Presentation] 全身型若年性特発性関節炎に合併するマクロファージ活性化症候群における soluble TNFR-II/I 比の臨床的有用性 (2017)
  • Author(s): 井上なつみ、清水正樹、水田麻雄、谷内江昭宏、中岸保夫
  • Organizer: 第27回日本小児リウマチ学会