Establishment of diagnostic imaging, novel biomarkers and prognostic factor in IgG4-related diseases

• Project/Area Number: 20K08594
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Kochi University
• Principal Investigator: 谷口 義典 高知大学, 教育研究部医療学系臨床医学部門, 講師 (70584431)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Granted (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: IgG4関連疾患 / コリンエステラーゼ / 線維化 / 臓器病変数 / 腫瘍化 / 血管炎 / シェーグレン症候群 / サイトカイン / 炎症 / 画像診断 / バイオマーカー / 予後因子

Outline of Research at the Start

我々の教室では生検サンプルを用いたRT-PCRやconfocal microscopy imagingの技術が充実し、さらに、優れたFDG-PET/CT検査によりIgG4関連疾患をフォローできる体制も整えており、基礎的知見と臨床的知見を両立して臨床/基礎研究を行いうる独創性を有している。
本研究で、1)IgG4関連疾患の新規の画像による診断および治療評価法の確立、2）IgG4関連疾患の病態機序の解明および悪性腫瘍や肉芽腫病変との関連の解析、3）培養細胞系を用いた病因解明や新規治療ターゲットの開発などを目指す。

Outline of Annual Research Achievements

血清コリンエステラーゼ(ChE)活性低下を来すIgG4関連疾患（IgG4RD）の症例をしばしば経験する。IgG4RDにおける血清ChE活性の意義についての研究結果を以前にRheumatology Advances and Practive誌に投稿し、掲載され、現在も症例数を増やし検討継続中である。研究方法としては、IgG4RD 70例を対照群（健常対照、血管炎（AAV群）、シェーグレン症候群（SjS群））と比較し、臨床症候・所見、臓器病変数、各種血清学的検査、各種サイトカインなどを後方視的に解析した。研究の結果として、まずは、IgG4RD 60例のうち、低ChE活性を呈した34例の血清ChE活性(130.5±40.2U/L)は、36例のChE正常群(316.2±60.5 U/L)や健常対照群、AAV群、SjS群と比較して有意に低かった。またIgG4RD患者において、低ChE活性群における臓器病変数(5.3±1.1)は、正常ChE活性群(1.7±1.2)よりも有意に多かった。低ChE活性群では治療開始後ChE活性の改善を認め、疾患活動性と合致した。多臓器病変を有するIgG4RDにおけるChE値は、各種サイトカイン値や血清学的炎症反応の値などの影響を受けず低値であったのに対し、AAV群のChE値は、各種サイトカイン値や血清学的炎症反応の値などの影響を有意に受けた。さらにIgG4RDのChEは、線維化マーカーDKK-1やTGF-βとの有意な相関を認めた。本年度の結論として、IgG4RDにおいて、血清ChE活性は病変広がりおよび活動性の指標として、さらにN数を増やすことで有用性が高まった可能性がある。
IgG4関連疾患の腫瘍化の検討において、悪性腫瘍の既往または疾患発症後の悪性腫瘍の発症の頻度が有意に高く、悪性腫瘍発生に関与する因子を同定中であり、さらに集積し、解析予定である。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

昨年度までのCOVID-19蔓延の影響もあり、診療への従事時間も増え、また、患者さんの受診頻度も減少したことで、検体採取の機会が減ったことも影響し、少々の遅れが生じている。

Strategy for Future Research Activity

COVID-19が収束に向かっており、またCOVID-19への対策もできており、患者さんの受診も戻ってきているため、検体採取を小まめに行い、研究のスピードを上げていく予定である。

Research Products

• [Journal Article] Comparison of clinicopathological features between patients with and without hypocomplementemia in IgG4-related kidney disease (2023)
  • Author(s): Saeki T, Nagasawa T, Ubara Y, Taniguchi Y, Yanagita M, Nishi S, Nagata M, Yamaguchi Y, Saito T, Nakashima H, Kawano M
  • Journal Title: Nephrology Dialysis Transplantation Volume: 38 Issue: 4 Pages: 1053-1056
  • DOI: 10.1093/ndt/gfac317
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Images: Nivolumab-induced tracheobronchial chondritis in a patient with hypopharyngeal cancer (2023)
  • Author(s): Hamada-Ode K, Taniguchi Y, Osaki M, Yoshimatsu R, Nitta N
  • Journal Title: Arthritis and Rheumatology Volume: 75 Issue: 1 Pages: 121-121
  • DOI: 10.1002/art.42317
  • Peer Reviewed / Open Access
• [Journal Article] A multicentre study of clinical features and HLA typing in Japanese patients with ankylosing spondylitis (2023)
  • Author(s): Tada K, Dobashi H, Taniguchi Y, Shuto T, Hagimori K, Hayashi E, Inoue H, Kobayashi S, Ymaji K, Tamura N
  • Journal Title: Modern Rheumatology Volume: 33 Issue: 2 Pages: 392-397
  • DOI: 10.1093/mr/roac008
  • Peer Reviewed
• [Journal Article] Clinical characteristics of patients with spondyloarthritis and inflammatory bowel disease versus inflammatory bowel disease-related arthritis (2022)
  • Author(s): Ono K, Kishimoto M, Deshpande GA, Fukui S, Kawaai S, Sawada H, Matsuura M, Rodriguez VR, Proft F, Tada K, Tamura N, Taniguchi Y, Hirata A, Kameda H, Tsuji S, Kaneko Y, Dobashi H, Okano T, Haji Y, Morita A, Okada M, Komagata Y, Medina CL, Molto A, Dougados M, Hisamatsu T, Tomita T, Kaname S
  • Journal Title: Rheumatology International Volume: 42 Issue: 10 Pages: 1751-1766
  • DOI: 10.1007/s00296-022-05117-0
  • Peer Reviewed
• [Journal Article] Reactive Arthritis After Intravesical Bacillus Calmette-Guerin Therapy (2022)
  • Author(s): Taniguchi Y, Nishikawa H, Kimata T, Yoshinaga Y, Kobayashi S, Terada Y
  • Journal Title: Journal of Clinical Rheumatology Volume: 28 Issue: 2 Pages: e583-e588
  • DOI: 10.1097/rhu.0000000000001768
  • Peer Reviewed / Open Access
• [Journal Article] Ultrasonography of auricular cartilage is a potential tool for diagnosing relapsing polychondritis and monitoring disease activity (2022)
  • Author(s): Yoshida M, Taniguchi Y, Yoshida T, Nishikawa H, Terada Y
  • Journal Title: International Journal of Rheumatic Diseases Volume: 25 Issue: 2 Pages: 201-209
  • DOI: 10.1111/1756-185x.14256
  • Peer Reviewed / Open Access
• [Journal Article] Validation of the 2019 ACR/EULAR criteria for IgG4-related disease in a Japanese kidney disease cohort: a multicentre retrospective study by the IgG4-related kidney disease working group of the Japanese Society of Nephrology (2021)
  • Author(s): Saeki T, Nagasawa T, Ubara Y, Taniguchi Y, Yanagita M, Nishi S, Nagata M, Yamaguchi Y, Saito T, Nakashima H, Kawano M
  • Journal Title: Annals of the Rheumatic Diseases Volume: 80 Issue: 7 Pages: 956-957
  • DOI: 10.1136/annrheumdis-2020-219510
  • Peer Reviewed / Open Access
• [Journal Article] Expanding the spectrum of reactive arthritis (ReA): classic ReA and infection-related arthritis including poststreptococcal ReA, Poncet's disease, and iBCG-induced ReA (2021)
  • Author(s): Taniguchi Y, Nishikawa H, Yoshida T, Terada Y, Tada K, Tamura N, Kobayashi S
  • Journal Title: Rheumatology International Volume: 41 Issue: 8 Pages: 1387-1398
  • DOI: 10.1007/s00296-021-04879-3
  • Peer Reviewed / Open Access
• [Journal Article] SARS-CoV2-triggered acute arthritis: Viral arthritis rather than reactive arthritis (2021)
  • Author(s): Kobayashi S, Taniguchi Y, Kida I, Tamura N
  • Journal Title: Journal of Medical Virology Volume: 93 Issue: 12 Pages: 6458-6459
  • DOI: 10.1002/jmv.27229
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of non-radiographic versus radiographic axial spondyloarthritis in Asia and non-radiographic axial spondyloarthritis in other regions: results of the cross-sectional ASAS-COMOSPA study. (2021)
  • Author(s): Kishimoto M, Ono K, Fukui S, Kawaai S, Deshpande GA, Yoshida K, Ichikawa N, Kaneko Y, Kawasaki T, Matsui K, Morita M, Tada K, Takizawa N, Tamura N, Taniguchi A, Taniguchi Y, Tsuji S, Okada M, Kobayashi S, Komagata Y, Lopez-Medina C, Molto A, van der Heijde D, Dougados M, Tomita T, Kaname S
  • Journal Title: RMD Open Volume: 7 Issue: 3 Pages: e001752-e001752
  • DOI: 10.1136/rmdopen-2021-001752
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ocular Involvement in Relapsing Polychondritis (2021)
  • Author(s): Fukuda K, Mizobuchi T, Nakajima I, Kishimoto T, Miura Y, Taniguchi Y
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 21 Pages: 4970-4970
  • DOI: 10.3390/jcm10214970
  • Peer Reviewed / Open Access
• [Journal Article] Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2011, and proposal of a new 2020 version (2021)
  • Author(s): Saeki T, Kawano M, Nagasawa T, Ubara Y, Taniguchi Y, Yanagita M, Nishi S, Nagata M, Hisano S, Yamaguchi Y, Nomura H, Saito T, Nakashima H
  • Journal Title: Clinical and Experimental Nephrology Volume: 25 Issue: 2 Pages: 99-109
  • DOI: 10.1007/s10157-020-01993-7
  • Peer Reviewed / Open Access
• [Journal Article] Is serum cholinesterase level a predictor of the extent of organ involvement in immunoglobulin G4-related disease? (2020)
  • Author(s): Hamada-Ode K, Yoshida M, Terada Y, Taniguchi Y
  • Journal Title: Rheumatology Advances in Practice Volume: 4 Issue: 2
  • DOI: 10.1093/rap/rkaa031
  • Peer Reviewed / Open Access
• [Journal Article] Dyskeratotic cells in persistent pruritic skin lesions as a prognostic factor in adult-onset Still disease (2020)
  • Author(s): Maeda-Aoyama N, Hamada-Ode K, Taniguchi Y, Nishikawa H, Arii K, Nakajima K, Fujimoto S, Terada Y
  • Journal Title: Medicine (Baltimore) Volume: 99 Issue: 6 Pages: e19051-e19051
  • DOI: 10.1097/md.0000000000019051
  • Peer Reviewed / Open Access
• [Journal Article] Breathlessness, pleural effusions, fibromas, and Meigs syndrome: look beyond the chest and don't delay! (2020)
  • Author(s): Taniguchi Y, Nishikawa H, Maeda N, Terada Y
  • Journal Title: Lancet Volume: 395 Issue: 10223 Pages: e32-e32
  • DOI: 10.1016/s0140-6736(20)30111-2
  • Peer Reviewed
• [Journal Article] Clinical characteristics of cancer-associated myositis complicated by interstitial lung disease: a large-scale multicentre cohort study (2020)
  • Author(s): Kaneko Y, Nunokawa T, Taniguchi Y, Yamaguchi Y, Gono T, Masui K, Kawakami A, Kawaguchi Y, Sato S, Kuwana M; JAMI investigators
  • Journal Title: Rheumatology (Oxford) Volume: 59 Issue: 1 Pages: 112-119
  • DOI: 10.1093/rheumatology/kez238
  • Peer Reviewed
• [Journal Article] The Diagnosis and Treatment of Adult Patients with SAPHO Syndrome: Controversies Revealed in a Multidisciplinary International Survey of Physicians (2020)
  • Author(s): Furer V, Kishimoto M, Tsuji S, Taniguchi Y, Ishihara Y, Tomita T, Helliwell PS, Elkayam O
  • Journal Title: Rheumatology and Therapy Volume: 7 Issue: 4 Pages: 883-891
  • DOI: 10.1007/s40744-020-00235-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 日本腎臓学会IgG4関連腎臓病ワーキンググループ(WG)：低補体血症の有無によるIgG4関連腎臓病の臨床、病理学的差異 (2022)
  • Author(s): 佐伯敬子、長澤将、乳原善文、谷口義典、柳田素子、西慎一、長田道夫、山口裕、斉藤喬雄、中島衡、川野充弘
  • Organizer: 日本腎臓学会総会・学術集会
• [Presentation] The potential treatment with dupilumab for IgG4-related disease (2021)
  • Author(s): Taniguchi Y, Inotani S, Nishikawa H, Ode K, Nakajima I, Tsuji H, Mizobuchi T, Fukuda K, Uchida K, Terada Y
  • Organizer: The 4th International Symposium on IgG4-Related Diseases 2020+1
  • Int'l Joint Research
• [Presentation] Ultrasonography of auricular cartilage is a useful tool for diagnosing and monitoring disease activity in relapsing polychondritis (2021)
  • Author(s): Taniguchi Y, Nishikawa H, Yoshida T, Inotani S, Terada Y
  • Organizer: American College of Rheumatology 2021
  • Int'l Joint Research
• [Presentation] IgG4関連腎臓病（IgG4-RKD）診断基準2020（2011改訂版）：日本腎臓学会IgG4-RKDワーキンググループ（WG）報告 (2021)
  • Author(s): 佐伯敬子、乳原善文、谷口義典、斎藤孝雄、中島衞、川野充弘
  • Organizer: 第65回日本リウマチ学会総会・学術集会
• [Presentation] BCG膀胱内注入療法を施行された日本人膀胱癌患者における反応性関節炎の発症率およびHLA表現型の検討 (2020)
  • Author(s): 谷口義典、西川浩文、小笠原真沙実、猪谷哲司、松本竜季、大出佳寿、島村芳子、堀野太郎、小林茂人、寺田典生
  • Organizer: 第64回日本リウマチ学会総会・学術集会