Clinical and immunogenetic study for the association between autoimmune pancreatitis or IgG4-related disease and malignancy formation

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K09045
• Research Institution: Matsumoto Dental University
• Principal Investigator: 川 茂幸 松本歯科大学, 歯学部, 特任教授 (10177628)
• Co-Investigator(Kenkyū-buntansha): 太田 正穂 信州大学, 医学部, 特任教授 (50115333) ; 伊藤 哲也 信州大学, 医学部, 助教(特定雇用) (50748605) ; 亀子 文子 純真学園大学, 検査科学科, 教授 (60126670)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 自己免疫性膵炎 / IgG4関連疾患 / 悪性腫瘍 / IgG4関連動脈周囲病変

Outline of Annual Research Achievements

IgG4関連疾患（IgG4-RD）診断1年以内、1年以後における悪性腫瘍発生の標準化罹患比はそれぞれ3.53(95%信頼区間：1.23-5.83)、1.48(95%信頼区間：0.99-1.98)で悪性腫瘍は診断1年以内に診断されることが多かった。IgG4-RD27例に悪性腫瘍を認め、治療に良好に反応した11例中8例で再燃を認めなかった。以上より、悪性腫瘍の存在がIgG4-RDに影響を及ぼし、IgG4-RDがparaneoplastic syndrome である可能性が考えられた。IgG4-RD 179例中、動脈周囲病変を65例(36.3%)に認め、腎動脈分枝部以下の大動脈の領域に80％以上認めた。動脈周囲病変群で活動性マーカーが有意に高値で、腎病変合併が有意に多かった。ステロイド治療後全例に画像所見の改善を認めたが、血管内腔拡張の増悪を20.9%に認め、増悪因子として治療前の内腔拡張が同定された(p=0.0092、オッズ比135)。
自己免疫性膵炎（AIP）発症に関わる遺伝子について、GWASスクリーニング解析を行ったデータを用いて、画像所見で血管周囲病変を生じた群(41名)と病変を伴わない群（83名）における関連解析を行ったところ、血管炎発症に有意な相関を示す候補遺伝子（CAMK2A, VPS13B, IL1R1）内のSNPsを検出した。特に、炎症発症に関わるIL1R1遺伝子に注目し、8種類のTaqManプローブを用いたfine mappingを行なった。その結果、rs951192, rs3917318, rs7582198のminor alleleにおいてadditive modelで、OR値が>4、p<0.0009を示し血管発症群に相関を示した。これらの結果からIgG-RDで血管炎発症を誘発する遺伝的要因としてIL1R1遺伝子多型が関与していることが示唆された。

Research Products

• [Journal Article] Clinical course of type 1 autoimmune pancreatitis patients without steroid treatment: a Japanese multicenter study of 97 patients. (2018)
  • Author(s): Kubota K, Kamisawa T, Hirano K, Hirooka Y, Uchida K, Ikeura T, Shiomi H, Ohara H, Shimizu K, Arakura N, Kanno A, Sakagami J, Itoi T, Ito T, Ueki T, Nishino T, Inui K, Mizuno N, Yoshida H, Sugiyama M, Iwasaki E, Irisawa A, Okazaki K, Kawa S, Shimosegawa T, Takeyama Y, Chiba T.
  • Journal Title: J Hepatobiliary Pancreat Sci. Volume: 25 Pages: 223-230
  • DOI: 10.1002/jhbp.541.
  • Peer Reviewed
• [Journal Article] An International, Multi-Specialty Validation Study of the IgG4-Related Disease Responder Index. (2018)
  • Author(s): Wallace ZS, Khosroshahi A, Carruthers MD, Perugino CA, Choi H, Campochiaro C, Culver EL, Cortazar F, Della-Torre E, Ebbo M, Fernandes A, Frulloni L, Hart P, Karadag O, Kawa S, Kawano M, Kim MH, Lanzillotta M, Matsui S, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Tanasa P, Umehara H, Webster G, Zhang W, Stone JH.
  • Journal Title: Arthritis Care Res Volume: - Pages: -
  • DOI: 10.1002/acr.23543.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Promoter hypomethylation of SKI in autoimmune pancreatitis (2018)
  • Author(s): Kinugawa Y, Uehara T, Matsuda K, Kobayashi Y, Nakajima T, Hamano H, Kawa S, Higuchi K, Hosaka N, Shiozawa S, Ishigame H, Nakamura T, Maruyama Y, Nakazawa K, Nakaguro M, Sano K, Ota H.
  • Journal Title: Pathol Res Pract. Volume: 214 Pages: 492-497
  • DOI: 10.1016/j.prp.2018.03.005.
  • Peer Reviewed
• [Journal Article] Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis. (2017)
  • Author(s): Kinugawa Y, Uehara T, Sano K, Matsuda K, Maruyama Y, Kobayashi Y, Nakajima T, Hamano H, Kawa S, Higuchi K, Hosaka N, Shiozawa S, Ishigame H, Ota H.
  • Journal Title: Pancreas Volume: 46 Pages: 614-618
  • DOI: 10.1097/MPA.0000000000000804.
  • Peer Reviewed
• [Journal Article] Usefulness of three-dimensional magnetic resonance cholangiopancreatography with partial maximum intensity projection for diagnosing autoimmune pancreatitis. (2017)
  • Author(s): Yanagisawa S, Fujinaga Y, Watanabe T, Maruyama M, Muraki T, Takahashi M, Fujita A, Fujita S, Kurozumi M, Ueda K, Hamano H, Kawa S, Kadoya M.
  • Journal Title: Pancreatology Volume: 17 Pages: 567-571
  • DOI: 10.1016/j.pan.2017.05.001.
  • Peer Reviewed
• [Journal Article] Serum IgG4 Concentration in IgG4-Related Disease. (2017)
  • Author(s): Kawa S, Skold M, Ramsden DB, Parker A, Harding SJ.
  • Journal Title: Clin Lab. Volume: 63 Pages: 1323-1337
  • DOI: 10.7754/Clin.Lab.2017.170403.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical features of IgG4-related periaortitis/periarteritis based on the analysis of 179 patients with IgG4-related disease: a case-control study. (2017)
  • Author(s): Ozawa M, Fujinaga Y, Asano J, Nakamura A, Watanabe T, Ito T, Muraki T, Hamano H, Kawa S.
  • Journal Title: Arthritis Res Ther. Volume: - Pages: -
  • DOI: 10.1186/s13075-017-1432-8.
  • Peer Reviewed / Open Access
• [Journal Article] New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases. (2017)
  • Author(s): Yamada K, Yamamoto M, Saeki T, Mizushima I, Matsui S, Fujisawa Y, Hara S, Takahashi H, Nomura H, Kawa S, Kawano M.
  • Journal Title: Arthritis Res Ther. Volume: - Pages: -
  • DOI: 10.1186/s13075-017-1467-x.
  • Peer Reviewed / Open Access
• [Journal Article] Low-dose maintenance steroid treatment could reduce the relapse rate in patients with type 1 autoimmune pancreatitis: a long-term Japanese multicenter analysis of 510 patients. (2017)
  • Author(s): Kubota K, Kamisawa T, Okazaki K, Kawa S, Hirano K, Hirooka Y, Uchida K, Shiomi H, Ohara H, Shimizu K, Arakura N, Kanno A, Sakagami J, Itoi T, Ito T, Ueki T, Nishino T, Inui K, Mizuno N, Yoshida H, Sugiyama M, Iwasaki E, Irisawa A, Shimosegawa T, Takeyama Y, Chiba T.
  • Journal Title: J Gastroenterol. Volume: 52 Pages: 955-964
  • DOI: 10.1007/s00535-016-1302-1.
  • Peer Reviewed
• [Journal Article] International consensus for the treatment of autoimmune pancreatitis. (2017)
  • Author(s): Okazaki K, Chari ST, Frulloni L, Lerch MM, Kamisawa T, Kawa S, Kim MH, Levy P, Masamune A, Webster G, Shimosegawa T.
  • Journal Title: Pancreatology Volume: 17 Pages: 1-6
  • DOI: 10.1016/j.pan.2016.12.003.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IgG4-related Disease - A Systemic Disease that Deserves Attention Regardless of One's Subspecialty. (2017)
  • Author(s): Hamano H, Tanaka E, Ishizaka N, Kawa S.
  • Journal Title: Intern Med. Volume: - Pages: -
  • DOI: 10.2169/internalmedicine.9533-17.
  • Peer Reviewed / Open Access
• [Presentation] 自己免疫性膵炎に対する経口ステロイド維持療法3年後の再燃予測因子について (2017)
  • Author(s): 中村晃、北野真希子、浅野純平、渡邉貴之、伊藤哲也、村木崇、浜野英明、川茂幸
  • Organizer: 第48回 日本膵臓学会大会
• [Presentation] Recollections of IgG4 study at Shinshu University (2017)
  • Author(s): Shigeyuki Kawa
  • Organizer: The International Pancreas Research Forum 2017
  • Int'l Joint Research
• [Book] The Pancreas. 3rd ed (2018)
  • Author(s): Shigeyuki Kawa
  • Total Pages: 1173
  • Publisher: Willey Blackwell
  • ISBN: 978-1-119-18839-1