基本情報

所属

• 北海道大学病院

職名

• 教授

学位

• 博士（医学）（北海道大学大学院医学研究科）

ホームページURL

http://www.hucc.hokudai.ac.jp/~e20677/

J-Global ID

• 200901031450258564

研究キーワード

• 臨床免疫学   臨床免疫学   血栓止血学   リウマチ膠原病学   内科学   

研究分野

• ライフサイエンス / 膠原病、アレルギー内科学 / 膠原病学

担当教育組織

•  修士課程　医学院
•  博士課程　医学院

職歴

• 2013年04月 - 現在 北海道大学病院 病院長補佐
• 2015年04月 - 2017年03月 北海道大学大学院医学研究科 副研究科長
• 2012年 - 医学研究科 教授
• 2012年 - Professor
• 2010年 - 2011年 医学研究科准教授 職員（教務系）
• 2010年 - 2011年 School Affairs Staff

学歴

• 1988年04月 - 1992年03月   北海道大学大学院   医学研究科
• 1982年04月 - 1988年03月   北海道大学   医学部   医学科

所属学協会

• 日本肺高血圧・肺循環学会   日本骨粗鬆症学会   日本国際医療学会   日本脊椎関節炎学会   日本炎症・再生医学会   日本骨代謝学会   日本透析医学会   日本腎臓学会   日本肥満学会   日本糖尿病学会   日本内分泌学会   国際血栓止血学会   日本臨床リウマチ学会   日本内科学会   日本リウマチ学会   日本臨床免疫学会   日本臨床分子医学会   アメリカリウマチ学会   日本血栓止血学会   

研究活動情報

論文

• Inhibition of Toll-like receptor 4 and Interleukin-1 receptor prevent SARS-CoV-2 mediated kidney injury.

  Daigo Nakazawa, Yohei Takeda, Masatoshi Kanda, Utano Tomaru, Haruko Ogawa, Takashi Kudo, Satoka Shiratori-Aso, Kanako Watanabe-Kusunoki, Yusho Ueda, Atsuko Miyoshi, Fumihiko Hattanda, Saori Nishio, Ryo Uozumi, Akihiro Ishizu, Tatsuya Atsumi

  Cell death discovery 9 1 293 - 293 2023年08月10日 

  Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury.
• Angioedema: hereditary or C1-inhibitor deficiency associated with systemic lupus erythematosus?

  Michihiro Kono, Michihito Kono, T Atsumi

  Scandinavian journal of rheumatology 1 - 2 2023年07月13日
• Inverse association between glucose variability and body fat in type 2 diabetes with impaired endogenous insulin secretion assessed using continuous glucose monitoring: A prospective observational study.

  Aika Miya, Akinobu Nakamura, Yuka Suzuki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yoichi M Ito, So Nagai, Hideaki Miyoshi, Tatsuya Atsumi

  Diabetes, obesity & metabolism 25 7 1883 - 1889 2023年07月 

  AIM: To evaluate the contribution of body fat mass and serum adiponectin concentration to glucose variability (GV) stability in people with type 2 diabetes with impaired versus preserved endogenous insulin secretion. MATERIALS AND METHODS: This multicentre prospective observational study included 193 people with type 2 diabetes who underwent ambulatory continuous glucose monitoring, abdominal computed tomography and fasting blood sampling. A fasting C-peptide (FCP) concentration >2 ng/mL was defined as preserved endogenous insulin secretion. The participants were divided into high (FCP > 2 ng/mL) and low FCP subgroups (FCP ≤ 2 ng/mL). Multivariate regression analysis was performed in each subgroup. RESULTS: In the high FCP subgroup, the coefficient of variation (CV) in GV was unrelated to abdominal fat area. In the low FCP subgroup, a high CV was significantly related to small abdominal visceral fat area (β = -0.11, standard error 0.03; P < 0.05) and to small subcutaneous fat area (β = -0.09, standard error 0.04; P < 0.05). No significant relationship between serum adiponectin concentration and continuous glucose monitoring-related variables was found. CONCLUSIONS: The contribution of body fat mass to GV depends on the endogenous insulin secretion residue. A small body fat area has independent adverse effects on GV in people with type 2 diabetes and impaired endogenous insulin secretion.
• Favorable Effect of Pemafibrate on Insulin Resistance and β-Cell Function in Subjects with Type 2 Diabetes and Hypertriglyceridemia: A Subanalysis of the PARM-T2D Study.

  Hiroshi Nomoto, Kenichi Kito, Hiroshi Iesaka, Yuki Oe, Shinichiro Kawata, Kazuhisa Tsuchida, Shingo Yanagiya, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Ichiro Sakuma, Naoki Manda, Akinobu Nakamura, Tatsuya Atsumi

  Pharmaceutics 15 7 2023年06月27日 

  Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has beneficial effects on lipid metabolism. However, its effects on glucose metabolism in individuals with type 2 diabetes (T2DM) remain to be fully clarified. This was a subanalysis of the PARM-T2D study, a multicenter prospective observational study on the use of pemafibrate versus conventional therapy for 52 weeks in subjects with T2DM complicated with hypertriglyceridemia. The subanalysis included participants who did not change their treatment for diabetes and did not receive insulin or insulin secretagogues during the study period. Changes in glucose metabolism markers, including homeostatic model assessment (HOMA2) scores and disposition index, were assessed. A total of 279 participants (141 in the pemafibrate group; 138 in the control group) met the criteria for the subanalysis. There were no significant changes in HbA1c during the 52-week study period in both groups. However, the pemafibrate group showed significant improvements versus the control group for insulin resistance assessed by HOMA2-R (-0.15 versus 0.08; estimated treatment difference -0.23 (95% confidence interval -0.44, -0.02); p = 0.03) and maintenance of β-cell function assessed by disposition index (0.015 versus -0.023; estimated treatment difference 0.037 (95% confidence interval 0.005, 0.069); p = 0.02). Correlation analyses showed that improvements in HOMA2-R and disposition index were significantly associated with improvements in lipid abnormalities and γ-glutamyl transpeptidase. In conclusion, pemafibrate reduced insulin resistance and maintained β-cell function in subjects with T2DM and hypertriglyceridemia, presumably by improving lipid profiles and lipid-related hepatocyte stress.
• CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.

  Satoka Shiratori-Aso, Daigo Nakazawa, Takashi Kudo, Masatoshi Kanda, Yusho Ueda, Kanako Watanabe-Kusunoki, Saori Nishio, Sari Iwasaki, Takahiro Tsuji, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu, Tatsuya Atsumi

  JCI insight 2023年06月27日 

  Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed pro-inflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase (MPO)-ANCA titers with a reduction in NETs formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.
• Intravenous immunoglobulin treatment for obstetric antiphospholipid syndrome refractory to conventional therapy: a single-arm and open-labelled multicentre clinical trial.

  Kayoko Kaneko, Seiji Tsutsumi, Daisuke Fujita, Mayumi Sugiura-Ogasawara, Nobuaki Mitsuda, Keiichi Matsubara, Tatsuya Atsumi, Eisuke Inoue, Tetsuya Takimoto, Atsuko Murashima

  Modern rheumatology 2023年06月21日 

  OBJECTIVES: To compare the efficacy of intravenous immunoglobulin (IVIG) therapy for obstetric antiphospholipid syndrome (APS) refractory to conventional treatment. METHODS: We conducted a single-arm and open-label multicentre clinical intervention trial. The enrolled criteria were patients with refractory APS who had a history of still or premature birth before 30 weeks of gestational age, even though they had been treated with conventional treatment, i.e., heparin and low-dose aspirin. After confirming the foetal heartbeats, a single course of IVIG (0.4 g/kg body weight daily for five days) was added to conventional treatment. The primary outcome was a live birth ratio of more than 30 weeks gestational period, and the secondary included improving pregnancy outcomes comparing to previous pregnancy. RESULTS: Twenty-five percent of the patients (2 of 8 cases) achieved a live birth after the 30th week of pregnancy by IVIG-only add-on treatment, which is the same prevalence as the historical control. However, by adding other second-line therapy to IVIG and conventional treatment, further three patients (37.5%) achieved improvements in pregnancy outcome compared to previous treatments. In total, five patients (62.5%) were able to achieve preferable pregnancy outcomes through combination treatment including IVIG. CONCLUSIONS: Our clinical trial could not demonstrate the efficacy of IVIG-only add-on therapy at improving the pregnancy outcomes of patients with obstetric APS refractory to conventional treatment. However, the combination of IVIG with rituximab or statins adding to conventional treatment improved pregnancy outcomes and resulted in more live births. Further studies are needed to investigate the efficacy of multi-targeted therapy to treat obstetric refractory APS.
• Damage measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in antiphospholipid antibody-positive patients included in the APS ACTION registry

  Gustavo G M Balbi, Yasaman Ahmadzadeh, Maria G Tektonidou, Vittorio Pengo, Savino Sciascia, Amaia Ugarte, H Michael Belmont, Chary Lopez-Pedrera, Paul R Fortin, Denis Wahl, Maria Gerosa, Guilherme R de Jesús, Lanlan Ji, Tatsuya Atsumi, Maria Efthymiou, D Ware Branch, Cecilia Nalli, Esther Rodriguez Almaraz, Michelle Petri, Ricard Cervera, Jason S Knight, Bahar Artim-Esen, Rohan Willis, Maria Laura Bertolaccini, Hannah Cohen, Robert Roubey, Doruk Erkan, Danieli Castro Oliveira de Andrade, JoAnn Vega, Guillermo Pons-Estel, Bill Giannakopoulos, Steve Krilis, Guilherme de Jesus, Roger Levy, Flavio Signorelli, Danieli Andrade, Gustavo Balbi, Ann E Clarke, Leslie Skeith, Paul R Fortin, Lanlan Ji, Zhouli Zhang, Chengde Yang, Hui Shi, Stephane Zuily, Denis Wahl, Maria G Tektonidou, Cecilia Nalli, Laura Andreoli, Angela Tincani, Cecilia B Chighizola, Maria Gerosa, Pierluigi Meroni, Vittorio Pengo, Chunyan Cheng, Giulia Pazzola, Savino Sciascia, Silvia Foddai, Massimo Radin, Stacy Davis, Olga Amengual, Tatsuya Atsumi, Imad Uthman, Maarten Limper, Philip de Groot, Guillermo Ruiz - Irastorza, Amaia Ugarte, Ignasi Rodriguez-Pinto, Ricard Cervera, Jose Pardos-Gea, Esther Rodriguez Almaraz, Maria Angeles Aguirre Zamorano, Chary Lopez-Pedrera, Bahar Artim-Esen, Maria Laura Bertolaccini, Hannah Cohen, Maria Efthymiou, Ian Mackie, Giovanni Sanna, Jason Knight, Yu Zuo, Michelle Petri, Rebecca K Leaf, Robert Roubey, Thomas Ortel, Rohan Willis, Nina Kello, Michael Belmont, Steven Levine, Jacob Rand, Medha Barbhaiya, Doruk Erkan, Jane Salmon, Michael Lockshin, Ali A Duarte Garcia, D Ware Branch

  Rheumatology 2023年06月12日 

  Abstract Objectives Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. Methods In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. Results Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aβ2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P &lt; 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). Conclusions DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.
• The management of women of childbearing age with rheumatoid arthritis: an expert report.

  Yoshiya Tanaka, Atsuko Murashima, Tatsuya Atsumi, Hiroaki Dobashi, Yohko Murakawa, Shigeki Momohara, Haruna Kawaguchi, Shinji Tanigaki, Shintaro Makino, Shigeru Saito

  Expert review of clinical immunology 19 6 655 - 669 2023年06月 

  INTRODUCTION: The introduction of biologic therapies and a treat-to-target approach has transformed the management of rheumatoid arthritis (RA), which has led to improved outcomes for women with RA who wish to become pregnant. However, guidelines for the management of reproductive health in female patients with RA are still lacking. AREAS COVERED: A task force (Women of Childbearing Age [WoCBA]-Rheumatoid Arthritis in Japan) comprising 10 experts in the fields of rheumatology, obstetrics and orthopedic surgery developed 10 clinical questions (CQ) related to the management of WoCBA with RA. For each CQ, a systematic literature review was conducted to identify relevant evidence. Based on this evidence, a set of recommendations for each CQ were drafted and evaluated using the modified Delphi method. This article describes the agreed recommendations along with the supporting evidence. EXPERT OPINION: There are many ongoing challenges associated with the provision of reproductive healthcare in WoCBA with RA. It is hoped that the consensus-based recommendations provided here can be implemented in clinical practice in order to increase collaboration between rheumatologists and obstetricians/gynecologists and to improve reproductive health outcomes for WoCBA with RA.
• Associations Among Antiphospholipid Antibody Types, Isotypes, and Titers: An AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Study

  Elena Gkrouzman, Rohan Willis, Danieli Andrade, Maria G. Tektonidou, Vittorio Pengo, Guillermo Ruiz-Irastorza, H. Michael Belmont, Paul R. Fortin, Maria Gerosa, Flavio Signorelli, Tatsuya Atsumi, D. Ware Branch, Cecilia Nalli, Esther Rodriguez-Almaraz, Michelle A. Petri, Ricard Cervera, Jason S. Knight, Maria Efthymiou, Hannah Cohen, Maria Laura Bertolaccini, Doruk Erkan, Robert Roubey, Guillermo Pons-Estel, Bill Giannakopoulos, Steve Krilis, Guilherme de Jesus, Roger Levy, Flavio Signorelli, Danieli Andrade, Gustavo Balbi, Ann E. Clarke, Leslie Skeith, Paul R. Fortin, Lanlan Ji, Zhouli Zhang, Chengde Yang, Hui Shi, Stephane Zuily, Denis Wahl, Maria G. Tektonidou, Cecilia Nalli, Laura Andreoli, Angela Tincani, Cecilia B. Chighizola, Maria Gerosa, Pierluigi Meroni, Vittorio Pengo, Chunyan Cheng, Giulia Pazzola, Savino Sciascia, Silvia Foddai, Massimo Radin, Stacy Davis, Olga Amengual, Tatsuya Atsumi, Imad Uthman, Maarten Limper, Philip de Groot, Guillermo Ruiz—Irastorza, Amaia Ugarte, Ignasi Rodriguez-Pinto, Ricard Cervera, Jose Pardos-Gea, Esther Rodriguez Almaraz, Maria Jose Cuadrado, Maria Angeles Aguirre Zamorano, Chary Lopez-Pedrera, Bahar Artim-Esen, Murat Inanc, Maria Laura Bertolaccini, Hannah Cohen, Maria Efthymiou, Munther Khamashta, Ian Mackie, Giovanni Sanna, Jason Knight, Yu Zuo, Michelle Petri, Rebecca K. Leaf, Robert Roubey, Thomas Ortel, Emilio Gonzalez, Rohan Willis, Nina Kello, Michael Belmont, Steven Levine, Jacob Rand, Medha Barbhaiya, Doruk Erkan, Jane Salmon, Michael Lockshin, Ali A. Duarte Garcia, D. Ware Branch

  Laboratory Investigation 103 6 100147 - 100147 2023年06月
• Alcoholic Ketoacidosis Manifesting With Hypoglycemia Exacerbated by an SGLT2 Inhibitor in a Nondiabetic Patient.

  Hiroshi Iesaka, Hiroshi Nomoto, Tatsuya Atsumi

  Mayo Clinic proceedings 98 6 947 - 948 2023年06月
• 第1子妊娠中に一過性の尿崩症を呈し,第2子妊娠中に再び尿崩症が出現した1例

  小野 翼, 亀田 啓, 横関 恵, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也

  日本内分泌学会雑誌 99 1 294 - 294 (一社)日本内分泌学会 2023年05月
• COVID-19感染症を契機に多彩な電解質異常を呈し尿細管機能障害が疑われた一例

  高橋 明広, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也

  日本内分泌学会雑誌 99 1 295 - 295 (一社)日本内分泌学会 2023年05月
• 腹腔鏡下スリーブ状胃切除術は脂肪肝と膵β細胞機能を改善する 前向きコホート研究

  大江 悠希, 中村 昭伸, 曹 圭龍, 宮 愛香, 野本 博司, 亀田 啓, 渥美 達也, 三好 秀明

  日本内分泌学会雑誌 99 1 296 - 296 (一社)日本内分泌学会 2023年05月
• GH産生下垂体腺腫でのβ-カテニンの細胞内局在と75g経口ブドウ糖負荷試験におけるGHの奇異性上昇

  桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 伊師 雪友, 茂木 洋晃, 藤村 幹, 渥美 達也

  日本内分泌学会雑誌 99 1 332 - 332 (一社)日本内分泌学会 2023年05月
• db/dbマウス副腎におけるステロイドホルモン合成亢進機序DHCR24阻害薬の効果

  上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 99 1 392 - 392 (一社)日本内分泌学会 2023年05月
• 抗rabphilin-3A抗体陽性であったリンパ球性汎下垂体炎の一例

  高橋 明広, 亀田 啓, 古澤 翔, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 岩田 尚子, 藤沢 治樹, 鈴木 敦詞, 椙村 益久, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 99 Suppl.Update 11 - 13 (一社)日本内分泌学会 2023年05月
• Hypothalamic lesion in a neuropsychiatric lupus patient with narcolepsy

  H Moriya, Y Fujieda, O Amengual, T Kanbayashi, T Atsumi

  Scandinavian Journal of Rheumatology 52 4 444 - 446 2023年04月12日
• 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝と膵β細胞機能に及ぼす効果

  大江 悠希, 中村 昭伸, 曹 圭龍, 高瀬 崇宏, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 渥美 達也, 三好 秀明

  日本臨床分子医学会学術総会プログラム・抄録集 58回 50 - 50 日本臨床分子医学会 2023年04月
• 肥満糖尿病病態における膵β細胞の細胞内代謝変化

  千葉 幸輝, 野本 博司, 泉原 里美, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 58回 52 - 52 日本臨床分子医学会 2023年04月
• 日本人2型糖尿病患者の剖検膵を用いた膵β細胞内のエネルギー代謝変化と膵の組織学的所見との関連

  泉原 里美, 野本 博司, 千葉 幸輝, 亀田 啓, 中村 昭伸, 三好 秀明, 水上 浩哉, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 58回 52 - 52 日本臨床分子医学会 2023年04月
• 成長ホルモン産生下垂体腺腫におけるβ-カテニンの細胞内局在と腫瘍径および術後寛解率との関連

  桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 伊師 雪友, 茂木 洋晃, 藤村 幹, 三好 秀明, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 58回 58 - 58 日本臨床分子医学会 2023年04月
• ニューロメジンB受容体拮抗薬のクッシング病に対する効果の検討

  関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 58回 58 - 58 日本臨床分子医学会 2023年04月
• db/dbマウスにおける副腎ステロイドホルモン合成亢進に対するDHCR24阻害薬の効果と副腎内代謝変化の検討

  上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 58回 59 - 59 日本臨床分子医学会 2023年04月
• 日本人2型糖尿病患者における膵β細胞の細胞内代謝変化の解明 剖検膵組織を用いた検討

  野本 博司, 泉原 里美, 中村 昭伸, 千葉 幸輝, 亀田 啓, 三好 秀明, 水上 浩哉, 渥美 達也

  糖尿病 66 Suppl.1 S - 137 (一社)日本糖尿病学会 2023年04月
• 高中性脂肪血症合併2型糖尿病患者におけるペマフィブラート投与による耐糖能への影響 PARM-T2D studyサブ解析

  野本 博司, 鬼頭 健一, 佐久間 一郎, 大江 悠希, 山内 裕貴, 土田 和久, 大森 一乃, 柴山 惟, 曹 圭龍, 竹内 淳, 種田 紳二, 栗原 義夫, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 66 Suppl.1 S - 155 (一社)日本糖尿病学会 2023年04月
• 高齢者における既存のGLP-1受容体作動薬からセマグルチド皮下注への切り替えによる代謝因子の改善効果 SWITCH-SEMA1サブ解析

  高橋 由華, 野本 博司, 横山 宏樹, 高野 善成, 永井 聡, 続木 惇, 曹 圭龍, 土田 和久, 宮 愛香, 宮崎 あすか, 亀田 啓, 大場 知穂, 濱谷 柚香, 中田 健人, 泉原 里美, 上垣 里紗, 山下 久美子, 竹内 淳, 木島 弘道, 種田 紳二, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 66 Suppl.1 S - 162 (一社)日本糖尿病学会 2023年04月
• 2型糖尿病におけるDPP-4阻害薬から経口セマグルチド切り替えによる血糖マネジメントへの影響 SWITCH SEMA-2 study

  古澤 翔, 野本 博司, 濱谷 柚香, 横関 恵, 宮本 麻唯子, 中田 健人, 大江 悠希, 泉原 里美, 家坂 光, 続木 惇, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 高橋 清彦, 竹内 淳, 安井 彩乃, 関崎 知紀, 高瀬 崇宏, 永井 聡, 種田 紳二, 横山 宏樹, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 66 Suppl.1 S - 197 (一社)日本糖尿病学会 2023年04月
• 2型糖尿病における膵β細胞機能指標と血糖変動との関連

  宮 愛香, 中村 昭伸, 野本 博司, 亀田 啓, 渥美 達也

  糖尿病 66 Suppl.1 S - 216 (一社)日本糖尿病学会 2023年04月
• 肥満糖尿病病態への介入は膵島の細胞内代謝変化を是正する

  千葉 幸輝, 野本 博司, 泉原 里美, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 66 Suppl.1 S - 222 (一社)日本糖尿病学会 2023年04月
• 2型糖尿病患者の高血糖・低血糖に対する認識と実測値とのずれに関する因子の検討

  濱谷 柚香, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 66 Suppl.1 S - 264 (一社)日本糖尿病学会 2023年04月
• 食餌誘導性肥満・糖尿病モデルマウスにおけるグルコキナーゼ抑制が膵β細胞機能・量に与える影響

  重沢 郁美, 中村 昭伸, 山内 裕貴, 川田 晋一朗, 宮崎 あすか, 野本 博司, 亀田 啓, 三好 秀明, 寺内 康夫, 渥美 達也

  糖尿病 66 Suppl.1 S - 282 (一社)日本糖尿病学会 2023年04月
• 日本人2型糖尿病患者の膵β細胞内代謝変化の機序の解明

  泉原 里美, 野本 博司, 千葉 幸輝, 亀田 啓, 中村 昭伸, 三好 秀明, 水上 浩哉, 渥美 達也

  糖尿病 66 Suppl.1 S - 283 (一社)日本糖尿病学会 2023年04月
• 耐糖能異常症例における腎移植後の耐糖能,インスリン分泌,インスリン抵抗性の変化

  宮本 麻唯子, 中村 昭伸, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也

  糖尿病 66 Suppl.1 S - 309 (一社)日本糖尿病学会 2023年04月
• DPP-4阻害薬とメトホルミン併用療法へのイメグリミン追加によるHbA1c低下効果 研究プロトコル(MEGMI study)

  高橋 明広, 野本 博司, 中村 昭伸, 宮 愛香, 亀田 啓, 曹 圭龍, 川田 晋一郎, 栗原 弘義, 竹内 淳, 永井 聡, 和田 典男, 横山 宏樹, 種田 紳二, 三好 秀明, 渥美 達也

  糖尿病 66 Suppl.1 S - 318 (一社)日本糖尿病学会 2023年04月
• Progressive cognitive dysfunction with subdural polycystic hygroma and systemic inflammation under immunosuppressive therapy.

  Masato Tarumi, Nobuya Abe, Tatsuya Atsumi

  International journal of rheumatic diseases 26 4 808 - 809 2023年04月
• Dynamics of corticocortical brain functional connectivity relevant to therapeutic response to biologics in inflammatory arthritis.

  Kodai Sakiyama, Nobuya Abe, Yuichiro Fujieda, Khin K Tha, Hisashi Narita, Kohei Karino, Masatoshi Kanda, Michihito Kono, Masaru Kato, Tatsuya Atsumi

  Cerebral cortex (New York, N.Y. : 1991) 33 13 8342 - 8351 2023年04月01日 

  Aberrant functional connectivity (FC) of the brain regions, evaluated by functional magnetic resonance imaging (fMRI), affects clinical courses in inflammatory arthritis (IA). The static analysis methods would be simplistic to estimate the whole picture of resting-state brain function because blood oxygen level-dependent (BOLD) signals fluctuate over time. The effects of FC dynamics on clinical course are unknown in IA. Therefore, we aimed to evaluate dynamic FC for therapeutic responsiveness to biologics in IA patients. We analyzed resting-state fMRI data of 64 IA patients in 2 cohorts. Dynamic FC was derived as a correlation coefficient of the windowed BOLD signal time series. We determined representative whole-brain dynamic FC patterns by k-means++ cluster analysis, leading to 4 distinct clusters. In the first cohort, occurrence probability of the distinct cluster was associated with favorable therapeutic response in disease activity and patients' global assessment, which was validated by the second cohort. The whole-brain FC of the distinct cluster indicated significantly increased corticocortical connectivity, and probabilistically decreased after therapy in treatment-effective patients compared with -ineffective patients. Taken together, frequent emergence of corticocortical connections was associated with clinical outcomes in IA. The coherence of corticocortical interactions might affect pain modulation, possibly relevant to therapeutic satisfaction.
• Predictors of damage accrual in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A nationwide prospective study.

  Akinori Hara, Ken-Ei Sada, Takashi Wada, Koichi Amano, Hiroaki Dobashi, Tatsuya Atsumi, Takahiko Sugihara, Kouichi Hirayama, Shogo Banno, Yohko Murakawa, Midori Hasegawa, Kunihiro Yamagata, Yoshihiro Arimura, Hirofumi Makino, Masayoshi Harigai

  Modern rheumatology 2023年03月17日 

  OBJECTIVES: This study elucidated the prognosis and risk factors associated with damage accrual during long-term remission maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We obtained data from 120 patients registered in a nationwide prospective cohort study on remission induction therapy in Japanese patients with AAV and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN), who achieved remission at 24 months after treatment initiation and were followed up for additional 24 months. The primary outcome was the vasculitis damage index (VDI) score at Month 48, and the secondary outcome included risk factors associated with increased total VDI at Month 48. RESULTS: The understudied patients comprised 52 men and 68 women aged 68 ± 13 years. Between Months 25 and 48, the patients' survival rate was 95% (114/120). End-stage renal disease developed in seven patients by Month 48, and 64 cases had increased VDI. The multivariable analysis results revealed that oral prednisolone (PSL) doses at Month 24 were associated with damage accrual between Months 24 and 48. CONCLUSIONS: VDI accrual was observed in more than half of patients with AAV during maintenance therapy, and increased VDI scores were associated with oral PSL doses 24 months after initiating remission induction therapy in Japan.
• Subcutaneous Panniculitis-like T-cell Lymphoma Lacking Subcutaneous Tumor Mimicking Adult-onset Still's Disease.

  Maria Tada, Shion Kachi, Masahiro Onozawa, Yuichiro Fujieda, Shota Yoshida, Yotaro Oki, Kazuro Kamada, Jun Nagai, Satomi Okada, Ryo Kikuchi, Ryo Hisada, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Shinichi Nakazato, Yoshihiro Matsuno, Takanori Teshima, Tatsuya Atsumi

  Internal medicine (Tokyo, Japan) 2023年03月15日 

  We herein report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) resembling adult-onset Still's disease (AOSD). A 40-year-old woman presented with a fever, erythema, and painful subcutaneous nodules on the trunk. Laboratory data and a bone marrow analysis showed hemophagocytic syndrome. Although AOSD was suspected, based on a histopathological evaluation of the erythema, she was diagnosed with SPTCL. She was refractory to combination chemotherapy but achieved durable remission with cyclosporine monotherapy. Genetic testing revealed a homozygous HAVCR2 c.245A>G variant (rs184868814) that had caused NLRP3 inflammasome activation. SPTCL and AOSD share a pathogenesis in terms of NLRP3 inflammasome activation, so the clinical phenotype of SPTCL reasonably mimics AOSD.
• 2型糖尿病合併肥満患者における減量代謝改善手術後の甲状腺機能の変化 前向き観察研究

  大江 悠希, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明

  日本内分泌学会雑誌 98 5 1293 - 1293 (一社)日本内分泌学会 2023年03月
• GH産生下垂体腺腫におけるβ-カテニンの細胞内局在と臨床所見との関連

  桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 伊師 雪友, 茂木 洋晃, 藤村 幹, 渥美 達也

  日本内分泌学会雑誌 98 5 1394 - 1394 (一社)日本内分泌学会 2023年03月
• 肥満・2型糖尿病モデルマウスにおける副腎ステロイドホルモン合成亢進に対するDHCR24阻害薬の効果

  上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 5 1443 - 1443 (一社)日本内分泌学会 2023年03月
• SLEのコホート研究 若年全身性エリテマトーデス患者における睡眠健康状態と精神神経症状との関連性 PRESURE-Jコホートを用いた検討

  吉村 大, 藤枝 雄一郎, 多田 麻里亜, 阿部 靖矢, 加藤 将, 奥 健志, 金子 佳代子, 金子 祐子, 田中 良哉, 藤尾 圭志, 松下 雅和, 宮前 多佳子, 矢嶋 宣幸, 和田 隆志, 村島 温子, 中島 亜矢子, 渥美 達也

  日本リウマチ学会総会・学術集会プログラム・抄録集 67回 517 - 517 (一社)日本リウマチ学会 2023年03月
• Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming

  Kuniyuki Aso, Michihito Kono, Masatoshi Kanda, Yuki Kudo, Kodai Sakiyama, Ryo Hisada, Kohei Karino, Yusho Ueda, Daigo Nakazawa, Yuichiro Fujieda, Masaru Kato, Olga Amengual, Tatsuya Atsumi

  Nature Communications 14 1 2023年02月27日 

  Abstract Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.
• 副腎不全疑いに対する比較的低用量のステロイド投与により急性ステロイド誘発性精神障害を呈した低ナトリウム血症の1例

  小野 翼, 亀田 啓, 横関 恵, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 4 716 - 716 (一社)日本内分泌学会 2023年02月
• 副腎皮質ホルモン合成阻害薬の変更によりテストステロンの低下を認めた術後非寛解のクッシング病の1例

  古澤 翔, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 4 717 - 717 (一社)日本内分泌学会 2023年02月
• ステロイド減量中に再燃したリンパ球性下垂体炎の1例

  澁佐 知歩, 亀田 啓, 濱谷 柚香, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 茂木 洋晃, 松野 吉宏, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 4 717 - 717 (一社)日本内分泌学会 2023年02月
• 鞍上部に生じた毛様細胞性星細胞腫により続発性副腎皮質機能低下症を呈した1例

  関 萌花, 亀田 啓, 宮本 麻唯子, 小野 翼, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 山口 秀, 田中 伸哉, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 4 718 - 718 (一社)日本内分泌学会 2023年02月
• 99mTc-MIBIシンチグラフィで集積を認めず術中intact PTH測定が有効だった高齢発症の原発性副甲状腺機能亢進症の1例

  横関 恵, 亀田 啓, 濱谷 柚香, 泉原 里美, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 鈴木 崇祥, 稲村 直哉, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 4 719 - 719 (一社)日本内分泌学会 2023年02月
• DPP-4阻害薬からSGLT2阻害薬への切替による脈拍日内変動の改善

  亀田 玲奈, 曹 圭龍, 野本 博司, 宮 愛香, 亀田 啓, 中村 昭伸, 竹内 淳, 永井 聡, 栗原 義夫, 渥美 達也, 三好 秀明

  糖尿病 66 2 171 - 171 (一社)日本糖尿病学会 2023年02月
• SGLT2阻害薬投与による尿中L-FABPの変化

  曹 圭龍, 家坂 光, 大場 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 竹内 淳, 渥美 達也

  糖尿病 66 2 171 - 171 (一社)日本糖尿病学会 2023年02月
• イメグリミン追加またはメトホルミン増量による糖代謝の比較研究

  高橋 明広, 野本 博司, 中村 昭伸, 栗原 弘義, 竹内 淳, 永井 聡, 種田 紳二, 三好 秀明, 渥美 達也

  糖尿病 66 2 171 - 171 (一社)日本糖尿病学会 2023年02月
• DPP-4阻害薬から経口セマグルチド切替えによる糖代謝の比較 多施設共同研究プロトコル

  古澤 翔, 野本 博司, 高橋 清彦, 竹内 淳, 永井 聡, 種田 紳二, 横山 宏樹, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 66 2 172 - 172 (一社)日本糖尿病学会 2023年02月
• 認知機能低下を伴う高齢2型糖尿病患者における経口セマグルチドの有効性

  大江 悠希, 野本 博司, 曹 圭龍, 小野 翼, 横関 恵, 宮 愛香, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 66 2 172 - 172 (一社)日本糖尿病学会 2023年02月
• 既存のGLP-1受容体作動薬からセマグルチド切替えは血糖コントロールとQOLを改善する

  高橋 由華, 野本 博司, 横山 宏樹, 竹内 淳, 永井 聡, 種田 紳二, 木島 弘道, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 66 2 173 - 173 (一社)日本糖尿病学会 2023年02月
• 2型糖尿病患者の高血糖に対する認識と実際の高血糖時間との不一致に関連する背景因子

  濱谷 柚香, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 66 2 173 - 173 (一社)日本糖尿病学会 2023年02月
• 腎移植後の耐糖能改善は移植前の維持透析療法の有無に影響されない

  宮本 麻唯子, 中村 昭伸, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也

  糖尿病 66 2 173 - 173 (一社)日本糖尿病学会 2023年02月
• 腹腔鏡下スリーブ状胃切除術が肥満2型糖尿病の脂肪肝と膵β細胞機能に及ぼす効果

  大江 悠希, 曹 圭龍, 中村 昭伸, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 渥美 達也, 三好 秀明

  糖尿病 66 2 174 - 174 (一社)日本糖尿病学会 2023年02月
• 高度肥満症患者における減量・代謝改善手術後の栄養アセスメント蛋白と微量元素の変化

  横関 恵, 曹 圭龍, 大江 悠希, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 66 2 174 - 174 (一社)日本糖尿病学会 2023年02月
• 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの脂質改善効果

  鬼頭 健一, 野本 博司, 佐久間 一郎, 曹 圭龍, 山下 久美子, 半田 喬久, 永井 聡, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 66 2 174 - 174 (一社)日本糖尿病学会 2023年02月
• ペマフィブラートは高中性脂肪血症合併2型糖尿病のインスリン抵抗性を改善させる

  家坂 光, 野本 博司, 鬼頭 健一, 佐久間 一郎, 萬田 直紀, 川田 晋一朗, 亀田 啓, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 66 2 175 - 175 (一社)日本糖尿病学会 2023年02月
• Lipid Droplet Protein PLIN1 Regulates Inflammatory Polarity in Human Macrophages and is Involved in Atherosclerotic Plaque Development by Promoting Stable Lipid Storage.

  Kyu Yong Cho, Hideaki Miyoshi, Akinobu Nakamura, Andrew S Greenberg, Tatsuya Atsumi

  Journal of atherosclerosis and thrombosis 30 2 170 - 181 2023年02月01日 

  AIM: Perilipins (PLINs), peripheral lipid droplet (LD) proteins, play important roles in lipid accumulation and maturation in adipocytes. The relationship between PLIN family proteins and macrophage polarization in atherosclerosis has not been elucidated. METHODS: The experiments used tissues from human arteries of 65 patients who had undergone a carotid endarterectomy, and cultured macrophages generated from healthy human peripheral blood mononuclear cells. RESULTS: Plaque immunohistochemistry demonstrated co-expression of PLIN1 and PLIN2 in both symptomatic (n=31) and asymptomatic patients (n=34). PLIN2 mRNA expression increased 3.38-fold in the symptomatic group compared with those from asymptomatic. PLIN1 was not expressed on small LDs at a shorter incubation but was on large LDs at longer incubation with oxidized LDL and VLDL, while PLIN2 was observed after 24 h and increased with a longer incubation in cultured M1 macrophage. In M2 macrophages, PLIN1 was seen as early as 24 h following incubation with VLDL, and LD size increased with longer incubation. PLIN1 overexpression increased the size of LDs in M1 macrophages, even after a short incubation, and reduced the RNA expression of TNFA, MMP2, ABCA1, and ABCG1 versus the M1 control. Conversely, silencing of PLIN1 in M2 macrophages had the opposite effects on LD size and RNA expression. CONCLUSION: There was a relationship between macrophage polarity, cytosolic LD size, and PLIN1/PLIN2 expression levels. PLIN2 was mainly expressed in arterial plaques in symptomatic stroke patients, and associated with the inflammatory phenotype of human macrophages, while PLIN1 expression is closely associated with plaque stability and the anti-inflammatory phenotype.
• Improvement of glycemic control and treatment satisfaction by switching from liraglutide or dulaglutide to subcutaneous semaglutide in patients with type 2 diabetes: A multicenter, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 1 study).

  Yuka Takahashi, Hiroshi Nomoto, Hiroki Yokoyama, Yoshinari Takano, So Nagai, Atsushi Tsuzuki, Kyu Yong Cho, Aika Miya, Hiraku Kameda, Jun Takeuchi, Shinji Taneda, Yoshio Kurihara, Tatsuya Atsumi, Akinobu Nakamura, Hideaki Miyoshi

  Diabetes, obesity & metabolism 25 6 1503 - 1511 2023年02月01日 

  OBJECTIVE: To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycemic control and treatment satisfaction in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicenter, open-labeled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8 mg/day (plan A) or dulaglutide 0.75 mg/week (plan B) were either switched to semaglutide or continued on current therapy. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) over 24 weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire (DTSQ) scores, body weight, and metabolic indices. RESULTS: In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. HbA1c levels were significantly reduced in the semaglutide group in both plans (plan A, 7.8 ± 1.0% to 7.8 ± 0.7% [liraglutide] vs. 7.9 ± 0.7% to 7.3 ± 0.7% [semaglutide], P < 0.01; plan B, 7.8 ± 1.0% to 7.9 ± 1.2% [dulaglutide] vs. 7.8 ± 0.8% to 7.1 ± 0.6% [semaglutide], P < 0.01). Semaglutide also improved DTSQ scores in both groups (plan A, + 0.1 vs. +8.3, P < 0.01; plan B, -1.2 vs. + 3.5, P < 0.01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters. CONCLUSIONS: Once-weekly semaglutide administration improved glycemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite GLP-1 receptor agonist treatment. This article is protected by copyright. All rights reserved.
• Letter to the Editor Regarding Efficacy of IDegLira Versus IDegAsp Therapy in Patients with Type 2 Diabetes: A Randomized Crossover Study by isCGM.

  Yuki Oe, Hiroshi Nomoto, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Tatsuya Atsumi

  Advances in therapy 40 1 383 - 386 2023年01月
• Low disease activity of microscopic polyangiitis in patients with anti-myosin light chain 6 antibody that disrupts actin rearrangement necessary for neutrophil extracellular trap formation.

  Miku Yoshinari, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Yoshihiro Arimura, Koichi Amano, Yukio Yuzawa, Ken-Ei Sada, Tatsuya Atsumi, Hiroaki Dobashi, Hitoshi Hasegawa, Masayoshi Harigai, Seiichi Matsuo, Hirofumi Makino, Akihiro Ishizu

  Arthritis research & therapy 24 1 274 - 274 2022年12月16日 

  BACKGROUND: Neutrophil extracellular traps (NETs) are critically involved in microscopic polyangiitis (MPA) pathogenesis, and some patients with MPA possess anti-NET antibody (ANETA). Anti-myosin light chain 6 (MYL6) antibody is an ANETA that affects NETs. This study aimed to determine the significance of anti-MYL6 antibody in MPA. METHODS: The influence of anti-MYL6 antibody on NET formation and actin rearrangement necessary for NET formation was assessed by fluorescent staining. An enzyme-linked immunosorbent assay was established to detect serum anti-MYL6 antibody, and the prevalence of this antibody in MPA was determined. Furthermore, the disease activity and response to remission-induction therapy of MPA were compared between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients. RESULTS: Anti-MYL6 antibody disrupted G-actin polymerization into F-actin, suppressing phorbol 12-myristate 13-acetate-induced NET formation. Serum anti-MYL6 antibody was detected in 7 of 59 patients with MPA. The Birmingham vasculitis activity score (BVAS) of anti-MYL6 antibody-positive MPA patients was significantly lower than anti-MYL6 antibody-negative MPA patients. Among the nine BVAS evaluation items, the cutaneous, cardiovascular, and nervous system scores of anti-MYL6 antibody-positive MPA patients were significantly lower than anti-MYL6 antibody-negative MPA patients, although other items, including the renal and chest scores, were equivalent between the two groups. The proportion of patients with remission 6 months after initiation of remission-induction therapy in anti-MYL6 antibody-positive MPA patients was significantly higher than in anti-MYL6 antibody-negative MPA patients. CONCLUSIONS: Collective findings suggested that anti-MYL6 antibody disrupted actin rearrangement necessary for NET formation and could reduce the disease activity of MPA.
• Beneficial effects of nintedanib on cardiomyopathy in patients with systemic sclerosis: a pilot study.

  Keita Ninagawa, Masaru Kato, Satonori Tsuneta, Suguru Ishizaka, Hideyuki Ujiie, Ryo Hisada, Michihito Kono, Yuichiro Fujieda, Yoichi M Ito, Tatsuya Atsumi

  Rheumatology (Oxford, England) 62 7 2550 - 2555 2022年12月02日 

  OBJECTIVES: Nintedanib is an inhibitor of tyrosine kinases that has been shown to slow the progression of interstitial lung disease (ILD), including ILD associated with systemic sclerosis (SSc). The aim of this study was to explore the effect of nintedanib on cardiomyopathy associated with SSc. METHODS: Twenty consecutively hospitalized patients with SSc-ILD were enrolled and prospectively followed. The rate of change at six months in cardiac magnetic resonance (CMR) parametric mapping, including myocardial extracellular volume, was primarily evaluated. Other endpoints included changes in CMR functional parameters, echocardiographic parameters, modified Rodnan skin score, serum biomarkers, and pulmonary function test. RESULTS: Nintedanib was administered in 10 patients, whereas the other 10 were treated without nintedanib or watched, according to ILD severity and progression. Baseline values of CMR parametric mapping were not different between the two groups. The rate of change at six months in myocardial extracellular volume was largely different, almost divergent between the nintedanib group and the control group (-1.62% vs. +2.00%, p= 0.0001). Among other endpoints, the change in right ventricular ejection fraction was significantly different between the two groups (p= 0.02), with a preferential change in the nintedanib group. CONCLUSION: Our data indicate beneficial signals of nintedanib on cardiomyopathy associated with SSc. The anti-fibrotic effect of nintedanib might not be limited to the lung.
• Disease activity at conception predicts lupus flare up to two years after birth: A multicentre long term follow-up study.

  Massimo Radin, Karen Schreiber, Irene Cecchi, Flavio Signorelli, Guilherme de Jesús, Kuniyuki Aso, Michihito Kono, Maria Letizia Urban, Beatrice Bacco, Silvia Gallo Cassarino, Luca Lo Sardo, Silvia Grazietta Foddai, Alice Barinotti, Ignacio Gómez-García, María Isabel Quaglia, Yohana Tissera, Fiammetta Gervasoni, María Ángeles Aguirre-Zamorano, Paula Alba, Chiara Benedetto, Tatsuya Atsumi, Olga Amengual, Giacomo Emmi, Danieli Andrade, Luca Marozio, Dario Roccatello, Savino Sciascia

  Seminars in arthritis and rheumatism 57 152113 - 152113 2022年12月 

  OBJECTIVE: To assess predicting factors that might influence systemic lupus erythematosus (SLE) disease activity in women in an extended follow-up period of two years after giving birth with clinical assessments every three months. METHODS: The study was design as an international retrospective study, enrolling 119 women with a first birth and with a two years follow-up. RESULTS: Joint involvement was present in 80% of patients, acute cutaneous in 64%, haematological in 54%, renal in 41% and 75% of patients were positive for anti-dsDNA. The mean SLE disease activity index 2000 (SLEDAI-2K) at diagnosis was 13.5±6.8 and at first birth was 2.8±4.4. At follow-up, 51.3% of patients had at least one flare after a mean time after birth of 9±6.3 months (mean flare per patient 0.94±1.1). The most frequent flare manifestations were joint involvement (48%), renal (33%), cutaneous (28%) and haematologic (20%). Patients with remission of disease (SLEDAI-2K=0; no clinical or laboratory manifestations of SLE) at conception had significantly lower rates of flares (18/49-37% vs. 43/70-61%; p=0.008). Patients who experienced a flare during pregnancy (17 patients) had higher rates of flares during follow-up (76% vs. 47%; p=0.019), lower time for first flare (4.4±2.3 months vs. 10.3±6.5; p<0.001), lower rate of remission of disease at conception (12% vs. 46%; p<0.001), lower rates of SLEDAI-2K at conception (5.9±5.6 vs. 2.3±4; p<0.001) and lower rates of exclusive breastfeeding (24% vs. 57%: p=0.009). Results were confirmed after performing multivariate analysis. CONCLUSION: Remission at conception can influence SLE disease positively, even at long-term. Planned pregnancy counseling is fundamental when managing SLE patients.
• Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function

  Yuki Yamauchi, Akinobu Nakamura, Takashi Yokota, Kiyohiko Takahashi, Shinichiro Kawata, Kazuhisa Tsuchida, Kazuno Omori, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Toshihisa Anzai, Shinya Tanaka, Yasuo Terauchi, Hideaki Miyoshi, Tatsuya Atsumi

  Scientific Reports 12 1 2022年12月 

  Abstract We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.
• Add-on imeglimin versus metformin dose escalation regarding glycemic control in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin: study protocol for a multicenter, prospective, randomized, open-label, parallel-group comparison study (MEGMI study).

  Hiroshi Nomoto, Akihiro Takahashi, Akinobu Nakamura, Hiroyoshi Kurihara, Jun Takeuchi, So Nagai, Shinji Taneda, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Hideaki Miyoshi, Tatsuya Atsumi

  BMJ open diabetes research & care 10 6 2022年11月 

  INTRODUCTION: Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin. RESEARCH DESIGN AND METHODS: This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500-1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52-85 mmol/mol (7.0%-9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects. RESULTS: This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy. CONCLUSIONS: This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D. TRIAL REGISTRATION NUMBER: jRCT1011220005.
• Transcriptional dynamics of granulocytes in direct response to incubation with SARS-CoV-2.

  Daigo Nakazawa, Yohei Takeda, Masatoshi Kanda, Utano Tomaru, Haruko Ogawa, Takashi Kudo, Satoka Shiratori-Aso, Kanako Watanabe-Kusunoki, Yusho Ueda, Atsuko Miyoshi, Fumihiko Hattanda, Saori Nishio, Ryo Uozumi, Akihiro Ishizu, Tatsuya Atsumi

  FEBS open bio 2022年10月22日 

  Severe coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome and multiple organ dysfunction, in which the host immune response plays a pivotal role. Excessive neutrophil activation and subsequent superfluity of neutrophil extracellular traps (NETs) can lead to tissue damage, and several studies have shown the involvement of neutrophils in severe COVID-19. However, the detailed responses of each neutrophil subset to SARS-CoV-2 infection has not been fully described. To explore this issue, we incubated normal-density granulocytes (NDGs) and low-density granulocytes (LDGs) with different viral titers of SARS-CoV-2. NDGs form NETs with chromatin fibers in response to SARS-CoV-2, whereas LDGs incubated with SARS-CoV-2 display a distinct morphology with condensed nuclei and moderate transcriptional changes. Based on these transcriptional changes, we suggest that AGO2 possibly plays a role in LDG regulation in response to SARS-CoV-2.
• Chemoprophylaxis against Pneumocystis jirovecii pneumonia in Japanese patients with ANCA-associated vasculitis: an observational study.

  Izaya Nakaya, Ken-Ei Sada, Masayoshi Harigai, Jun Soma, Koichi Amano, Hiroaki Dobashi, Tatsuya Atsumi, Yukio Yuzawa, Shouichi Fujimoto, Takahiko Sugihara, Yoshinari Takasaki, Yoshihiro Arimura, Hirofumi Makino

  Modern rheumatology 2022年10月05日 

  OBJECTIVES: This study investigated the current practice of prophylactic treatment against PCP (Pneumocystis jirovecii) and its effectiveness in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: This study included 319 patients registered from 53 institutions in Japan and newly diagnosed with AAV. During the 2-year observation period, we examined the frequency of usage, effectiveness and safety of prophylactic drugs against PCP. RESULTS: Most patients received prophylactic drugs against PCP with the initiation of immunosuppressive agents, and >50% of these remained on chemoprophylaxis against PCP at 2 years after. The initial daily dose of oral prednisolone and proportion of cyclophosphamide administration were higher in patients who received chemoprophylaxis against PCP than in those who did not. PCP occurred in nine patients (3%) and resulted in the death of four. The incidence rate of PCP in patients who received chemoprophylaxis was 1.13/100 patient-years (95% confidence interval, 0.38-2.68) and that in those who did not was 2.74 (1.04-6.02). The incidence rate ratio was 0.41 (0.11-1.53). CONCLUSION: The markedly low incidence of PCP may be attributed to the continuous chemoprophylaxis against PCP received by >50% of Japanese patients with AAV, though the effectiveness of chemoprophylaxis against PCP was not statistically confirmed.
• ラブフィリン3A抗体陽性であったリンパ球性汎下垂体炎の一例

  高橋 明広, 古澤 翔, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也, 岩田 尚子, 藤沢 治樹, 鈴木 敦詞, 椙村 益久

  日本内分泌学会雑誌 98 2 564 - 564 (一社)日本内分泌学会 2022年10月
• CDC73遺伝子変異を認めた家族性副甲状腺機能亢進症の一例

  濱谷 柚香, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 鈴木 崇祥, 清水 亜衣, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 2 589 - 589 (一社)日本内分泌学会 2022年10月
• FGF23関連低リン血症性骨軟化症を呈したクローン病の一例

  澁佐 知歩, 亀田 啓, 横関 恵, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 2 590 - 590 (一社)日本内分泌学会 2022年10月
• COVID-19肺炎治療中に冠攣縮性狭心症を発症した褐色細胞腫の一例

  宮本 麻唯子, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 中久保 祥, 佐藤 琢真, 松本 隆児, 大塚 拓也, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 2 597 - 597 (一社)日本内分泌学会 2022年10月
• 同効薬からセマグルチド皮下注への切り替えによる有効性と安全性

  高橋 由華, 野本 博司, 横山 宏樹, 宮 愛香, 亀田 啓, 曹 圭龍, 竹内 淳, 永井 聡, 種田 紳二, 木島 弘道, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明

  日本内分泌学会雑誌 98 2 617 - 617 (一社)日本内分泌学会 2022年10月
• 肝線維化例は減量・代謝改善手術後のテストステロン上昇が乏しい

  大江 悠希, 亀田 啓, 高瀬 崇宏, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明

  日本内分泌学会雑誌 98 2 629 - 629 (一社)日本内分泌学会 2022年10月
• 糖尿病性ケトアシドーシスに高度脂肪肝を合併した2例

  横関 恵, 野本 博司, 濱谷 柚香, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 10 552 - 552 (一社)日本糖尿病学会 2022年10月
• 神経性やせ症の治療経過中に1型糖尿病を発症し治療に難渋した1例

  宮崎 あすか, 野本 博司, 桑原 咲, 山内 裕貴, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 10 554 - 554 (一社)日本糖尿病学会 2022年10月
• 週3回デグルデク投与の効果を持続血糖モニターにて評価した高齢者2型糖尿病の1例

  中田 健人, 野本 博司, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 10 555 - 555 (一社)日本糖尿病学会 2022年10月
• デグルデク/リラグルチド配合注は血糖変動を改善しQOLを向上させ得る

  大江 悠希, 野本 博司, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 宮 愛香, 亀田 啓, 曹 圭龍, 渥美 達也, 三好 秀明

  糖尿病 65 10 557 - 557 (一社)日本糖尿病学会 2022年10月
• 2型糖尿病における減量・代謝改善手術はインスリン抵抗性と分泌能を改善させる

  久住 麻唯子, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 65 10 558 - 558 (一社)日本糖尿病学会 2022年10月
• 減量・代謝改善手術1年後総体重減少率が18.2%を超えると糖尿病治療薬を中止し得る

  大藤 悠理, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 65 10 558 - 558 (一社)日本糖尿病学会 2022年10月
• 糖尿病合併肥満患者に対する腹腔鏡下スリーブ状胃切除術後の骨密度への影響

  濱谷 柚香, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 65 10 558 - 558 (一社)日本糖尿病学会 2022年10月
• 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの効果 前向きコホート研究

  鬼頭 健一, 野本 博司, 佐久間 一郎, 山下 久美子, 曹 圭龍, 中村 昭伸, 柳谷 真悟, 半田 喬久, 渥美 達也, 三好 秀明

  糖尿病 65 10 559 - 559 (一社)日本糖尿病学会 2022年10月
• ペマフィブラートは高中性脂肪血症合併2型糖尿病患者の肝機能・肝脂肪化を改善する

  古澤 翔, 鬼頭 健一, 野本 博司, 佐久間 一郎, 山下 久美子, 柳谷 真悟, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 65 10 559 - 559 (一社)日本糖尿病学会 2022年10月
• COVID-19肺炎治療中に冠攣縮性狭心症を発症した褐色細胞腫の一例

  宮本 麻唯子, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 中久保 祥, 佐藤 琢真, 松本 隆児, 大塚 拓也, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 2 597 - 597 (一社)日本内分泌学会 2022年10月
• Urethral injury related to peri‐urethral abscess as a complication of self‐catheterization in an older patient with type 2 diabetes

  Yuri Ofuji, Hiroshi Nomoto, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Tatsuya Atsumi

  Geriatrics & Gerontology International 22 10 894 - 895 2022年10月
• Effects of pemafibrate on lipid metabolism in patients with type 2 diabetes and hypertriglyceridemia: A multi-center prospective observational study, the PARM-T2D study

  Kenichi Kito, Hiroshi Nomoto, Ichiro Sakuma, Akinobu Nakamura, Kyu Yong Cho, Hiraku Kameda, Aika Miya, Kazuno Omori, Shingo Yanagiya, Takahisa Handa, Shinji Taneda, Jun Takeuchi, So Nagai, Kumiko Yamashita, Yoshio Kurihara, Tatsuya Atsumi, Hideaki Miyoshi

  Diabetes Research and Clinical Practice 192 110091 - 110091 2022年10月
• Inhibitor of nuclear factor kappa-B kinase epsilon contributes to neuropsychiatric manifestations in lupus-prone mice through microglial activation.

  Kohei Karino, Michihito Kono, Shuhei Takeyama, Yuki Kudo, Masatoshi Kanda, Nobuya Abe, Kuniyuki Aso, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Olga Amengual, Tatsuya Atsumi

  Arthritis & rheumatology (Hoboken, N.J.) 75 3 411 - 423 2022年09月13日 

  OBJECTIVES: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multi-organ dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30~40% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue-resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. Herein, we explored new therapeutic targets for NPSLE focusing on microglia. METHODS: RNA sequencing of microglia in MRL/lpr, lupus-prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified and its role on microglial activation and phagocytosis was investigated using specific inhibitors and siRNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL/lpr was also evaluated. RESULTS: Transcriptome analysis revealed the upregulation of Ikbke, which encodes the inhibitor of nuclear factor kappa-B kinase epsilon (IKBKE) in both microglia from MRL/lpr mice and cytokine-stimulated microglia in vitro. Intracerebroventricular administration of an IKBKE inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lpr mice. Mechanistically, IKBKE inhibition reduced glycolysis, which dampened microglial activation and phagocytosis. CONCLUSIONS: These findings suggest that IKBKE plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.
• Predicting the response to pulmonary vasodilator therapy in systemic sclerosis with pulmonary hypertension by using quantitative chest CT.

  Keita Ninagawa, Masaru Kato, Yasuka Kikuchi, Hiroyuki Sugimori, Michihito Kono, Yuichiro Fujieda, Ichizo Tsujino, Tatsuya Atsumi

  Modern rheumatology 33 4 758 - 767 2022年09月02日 

  OBJECTIVE: Systemic sclerosis (SSc) is associated with pulmonary vascular disease (PVD) and interstitial lung disease (ILD), making it difficult to differentiate pulmonary arterial hypertension and pulmonary hypertension (PH) due to lung diseases and/or hypoxia and to decide treatments. We aimed to predict the response to pulmonary vasodilators in patients with SSc and PH. METHODS: 84 SSc patients were included with 47 having PH. Chest CT was evaluated using a software to calculate abnormal lung volume (ALV). To define the response to vasodilators, Δ mean pulmonary artery pressure (mPAP)/basal mPAP was used (cut-off value: 10%). The predictive value was evaluated by using receiver operating characteristic curve. RESULTS: The mean (±SD) value of ALV was 26.8 (±32.2) %. A weak correlation was observed between ALV and forced vital capacity (FVC) (R = -0.46). The predictive value of ALV (area under curve; AUC = 0.74) was superior to that of FVC (AUC = 0.62) for the response to vasodilators. No hemodynamic parameters differed between patients with high and low ALV, whereas survival was worse in high ALV. CONCLUSION: Quantitative chest CT well predicted the response to vasodilators in patients with SSc and PH. Our results suggest its utility in differentiating the dominance of PVD or ILD.
• 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝と膵β細胞機能に及ぼす効果 前向きコホート研究

  大江 悠希, 中村 昭伸, 曹 圭龍, 高瀬 崇宏, 小川 浩司, 海老原 裕磨, 吉川 仁人, 西田 睦, 宮 愛香, 野本 博司, 亀田 啓, 荘 拓也, 須田 剛生, 倉島 庸, 阿保 大介, 工藤 與亮, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病合併症 36 Suppl.1 172 - 172 (一社)日本糖尿病合併症学会 2022年09月
• 内因性インスリン分泌が低下した2型糖尿病の血糖変動における内臓脂肪の関与

  宮 愛香, 中村 昭伸, 濱谷 柚香, 野本 博司, 亀田 啓, 曹 圭龍, 三好 秀明, 渥美 達也

  糖尿病合併症 36 Suppl.1 194 - 194 (一社)日本糖尿病合併症学会 2022年09月
• 耐糖能異常症例における腎移植後の耐糖能変化はインスリン分泌能の変化と関連する

  中村 昭伸, 宮本 麻唯子, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也

  糖尿病合併症 36 Suppl.1 195 - 195 (一社)日本糖尿病合併症学会 2022年09月
• 持効型インスリンからデグルデク/リラグルチド配合注への切替えによる血糖変動の改善効果には内因性インスリン分泌能が影響する

  野本 博司, 大江 悠希, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 宮 愛香, 亀田 啓, 曹 圭龍, 三好 秀明, 渥美 達也

  糖尿病合併症 36 Suppl.1 211 - 211 (一社)日本糖尿病合併症学会 2022年09月
• リラグルチドおよびデュラグルチドからセマグルチド切り替えによる血糖コントロール及びQOLへの影響 SWITCH-SEMA1 study

  高橋 由華, 野本 博司, 横山 宏樹, 続木 惇, 宮 愛香, 亀田 啓, 曹 圭龍, 大場 知穂, 竹内 淳, 永井 聡, 土田 和久, 種田 紳二, 高野 善成, 木島 弘道, 山下 久美子, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病合併症 36 Suppl.1 211 - 211 (一社)日本糖尿病合併症学会 2022年09月
• A randomised, double-blind, placebo-controlled phase III trial on the efficacy and safety of tocilizumab in patients with familial Mediterranean fever.

  Tomohiro Koga, Shuntaro Sato, Naoko Hagimori, Hiroshi Yamamoto, Masataka Ishimura, Takahiro Yasumi, Yohei Kirino, Kei Ikeda, Akihiro Yachie, Kiyoshi Migita, Dai Kishida, Tatsuya Atsumi, Atsushi Kawakami

  Clinical and experimental rheumatology 40 8 1535 - 1542 2022年09月 

  OBJECTIVES: To evaluate the efficacy and safety of tocilizumab (TCZ), an interleukin 6 receptor monoclonal antibody, in a subset of Japanese patients with familial Mediterranean fever (FMF). METHODS: We performed a double-blind, randomised, parallel-group trial, followed by an open-label extension trial, in patients with colchicine-resistant or -intolerant FMF (crFMF) (UMIN000028010). Patients were randomly assigned (1:1) to receive TCZ (162 mg every week) or placebo, administered subcutaneously, for 24 weeks. Rescue treatment was allowed if the rescue criteria were met. The primary endpoint was the number of fever attacks over the 24 weeks of treatment. Secondary endpoints included the frequency of accompanying symptoms during attacks, serum CRP and SAA values, and adverse events (AEs). The open-label extension study evaluated the long-term safety and efficacy of TCZ in patients who had completed the preceding study (UMIN000032557). RESULTS: We randomly assigned 23 patients to either TCZ (n=1) or placebo (n=12). The TCZ-placebo rate ratios were 0.691 (95% confidence intervals (CI), 0.189-2.531; p=0.577) for the fever attacks, based on the group rates per week. The recurrence of attacks was significantly lower in the TCZ group (hazard ratio = 0.457; 95% CI, 0.240-0.869). Fever attacks, accompanying symptoms, serum CRP and SAA values were controlled in most of the patients who received long-term TCZ. In these trials, the numbers and severity of AEs did not differ between groups. CONCLUSIONS: Although a primary endpoint was not met in the preceding trial, long-term administration of TCZ showed stable efficacy and safety for patients with crFMF.
• リウマチ膠原病患者における非定型大腿骨骨折7例

  崎山 広大, 藤枝 雄一郎, 清水 智弘, 垂水 政人, 大江 悠希, 亀田 啓, 中沢 大悟, 加藤 将, 渥美 達也

  日本骨粗鬆症学会雑誌 8 Suppl.1 152 - 152 (一社)日本骨粗鬆症学会 2022年08月
• 免疫チェックポイント阻害薬投与中に早期に発見・治療し得た劇症1型糖尿病の1例

  桑原 咲, 野本 博司, 高橋 由華, 安井 彩乃, 泉原 里美, 大江 悠希, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 8 469 - 469 (一社)日本糖尿病学会 2022年08月
• 酸塩基平衡異常が遷延したSGLT2阻害薬服用下の糖尿病性ケトアシドーシスの2例

  上垣 里紗, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 8 470 - 470 (一社)日本糖尿病学会 2022年08月
• canagliflozinとteneligliptinの併用はTime Rangeと食後高血糖を改善する

  曹 圭龍, 野本 博司, 中村 昭伸, 川田 晋一朗, 亀田 啓, 渥美 達也, 三好 秀明

  糖尿病 65 8 472 - 472 (一社)日本糖尿病学会 2022年08月
• 持効型インスリン/GLP-1アナログ配合注の導入により血糖変動が改善した3例

  泉原 里美, 野本 博司, 桑原 咲, 高橋 由華, 安井 彩乃, 大江 悠希, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 8 473 - 473 (一社)日本糖尿病学会 2022年08月
• 腹腔鏡下スリーブ状胃切除術は肥満2型糖尿病患者の治療薬剤を減量し得る

  高橋 由華, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 8 473 - 473 (一社)日本糖尿病学会 2022年08月
• 肥満合併2型糖尿病患者において、術前骨格筋量が肥満手術の減量効果を予測する

  大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
• 腹腔鏡下スリーブ状胃切除術は脂質代謝および脂肪肝を改善させる

  安井 彩乃, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
• 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの肝機能改善効果

  鬼頭 健一, 野本 博司, 佐久間 一郎, 山下 久美子, 柳谷 真吾, 曹 圭龍, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
• 本邦における腹腔鏡下スリーブ状胃切除術後の骨密度変化と関連因子 前向きコホート研究

  大江 悠希, 曹 圭龍, 小川 浩司, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明

  日本骨粗鬆症学会雑誌 8 Suppl.1 158 - 158 (一社)日本骨粗鬆症学会 2022年08月
• 腹腔鏡下スリーブ状胃切除術は肥満2型糖尿病患者の治療薬剤を減量し得る

  高橋 由華, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 8 473 - 473 (一社)日本糖尿病学会 2022年08月
• 肥満合併2型糖尿病患者において、術前骨格筋量が肥満手術の減量効果を予測する

  大江 悠希, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
• 腹腔鏡下スリーブ状胃切除術は脂質代謝および脂肪肝を改善させる

  安井 彩乃, 高瀬 崇宏, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 8 474 - 474 (一社)日本糖尿病学会 2022年08月
• Cyclophilin D regulates NETosis and inflammation in myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis.

  Takashi Kudo, Daigo Nakazawa, Kanako Watanabe-Kusunoki, Masatoshi Kanda, Satoka Shiratori-Aso, Nobuya Abe, Saori Nishio, Jun-Ichiro Koga, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Miwako Yamasaki, Masahiko Watanabe, Sakiko Masuda, Utano Tomaru, Masaaki Murakami, Yasuaki Aratani, Akihiro Ishizu, Tatsuya Atsumi

  Arthritis & rheumatology (Hoboken, N.J.) 75 1 71 - 83 2022年07月29日 

  OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis where ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial necrosis occurs. Cyclophilin D (CypD) plays an important role in mediating cell necrosis and inflammation via opening of mitochondrial permeability transition pores (mPTP). Here, we examined the role of CypD in AAV pathogenesis. METHODS: In vitro, the role and mechanism of CypD in ANCA-stimulated neutrophils were assessed by immunostaining and electron microscopy. A comprehensive RNA sequencing analysis was performed on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, an-anti-MPO IgG-transfer AAV model or spontaneous AAV model mice were induced in CypD knockout or wild-type mice. RESULTS: In vitro, pharmacological and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species/cytochrome c release from the mitochondria. The analysis of RNA sequencing in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, and CypD deficiency reduced ANCA-induced alterations in gene expression. Furthermore, the upstream regulator analysis revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that CypD-dependent mPTP opening is associated with ANCA-induced neutrophil activation and NETosis. In both AAV models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSIONS: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.
• Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus.

  Nobuya Abe, Masato Tarumi, Yuichiro Fujieda, Nobuhiko Takahashi, Kohei Karino, Mona Uchida, Michihito Kono, Yuki Tanaka, Rie Hasebe, Masaru Kato, Olga Amengual, Yoshiyuki Arinuma, Kenji Oku, Wakiro Sato, Khin Khin Tha, Miwako Yamasaki, Masahiko Watanabe, Tatsuya Atsumi, Masaaki Murakami

  Annals of the rheumatic diseases 81 11 1564 - 1575 2022年07月11日 

  OBJECTIVES: The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients' data. METHODS: Sleep disturbance stress (SDS) for 2 weeks was placed on 6-8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. RESULTS: SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. CONCLUSIONS: The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.
• The agreement between measured HbA1c and optimized target HbA1c based on the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8): A cross-sectional study of elderly patients with diabetes.

  Aika Miya, Akinobu Nakamura, Isao Yokota, Kyu Yong Cho, Hiraku Kameda, Hiroshi Nomoto, Takahiro Takase, Kazuno Omori, Mayuko Ono, So Nagai, Shinji Taneda, Hideaki Miyoshi, Tatsuya Atsumi

  Geriatrics & gerontology international 22 8 560 - 567 2022年06月30日 

  AIM: To investigate the achievement of individualized target HbA1c based on the Japanese guideline after geriatric assessment with the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) and to evaluate patient characteristics acting as barriers to achieving the target HbA1c in elderly outpatients with diabetes. METHODS: This cross-sectional study enrolled 303 Japanese outpatients aged ≥65 years with diabetes. Their health status was measured using the DASC-8. The target HbA1c was optimized for each patient by the guideline based on the DASC-8 score and use of drugs potentially associated with severe hypoglycemia. Patient characteristics related to the agreement between measured HbA1c and target HbA1c were extracted by multivariate logistic regression analysis. RESULTS: The mean age was 73.0 years and the mean body mass index (BMI) was 24.2 kg/m2 . The agreement between measured HbA1c and target HbA1c was 43.9% (95% confidence interval: 38.4%-50.0%). In multivariate logistic regression analysis, the agreement in patients with drugs potentially associated with severe hypoglycemia was significantly lower than in those without these drugs (37.8% vs. 60.5%, P = 0.0004). In patients with these drugs, higher BMI (P = 0.0271) and higher fasting plasma glucose (P = 0.0034) were independent related factors for measured HbA1c being higher than target HbA1c. Vulnerable elderly patients (P = 0.0116) and not taking sodium glucose co-transporter-2 (SGLT2) inhibitor (P = 0.0186) were independent related factors for inappropriately lower HbA1c. CONCLUSIONS: The agreement between measured HbA1c and target HbA1c was low in elderly patients with diabetes. Geriatr Gerontol Int 2022; ••: ••-••.
• Effects of obesity on CC16 and their potential role in overweight/obese asthma.

  Houman Goudarzi, Hirokazu Kimura, Hiroki Kimura, Hironi Makita, Munehiro Matsumoto, Nozomu Takei, Kaoruko Shimizu, Masaru Suzuki, Taku Watanabe, Eiki Kikuchi, Hiroshi Ohira, Ichizo Tsujino, Jun Sakakibara-Konishi, Naofumi Shinagawa, Noriharu Shijubo, Hirokazu Sato, Katsunori Shigehara, Kichizo Kaga, Yasuhiro Hida, Soichi Murakami, Yuma Ebihara, Akinobu Nakamura, Hideaki Miyoshi, Satoshi Hirano, Nobuyuki Hizawa, Tatsuya Atsumi, Shau-Ku Huang, Yoichi M Ito, Masaharu Nishimura, Satoshi Konno

  Respiratory research 23 1 174 - 174 2022年06月29日 

  INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.
• Diabetic Chorea.

  Kei Yokozeki, Hiroshi Nomoto, Tatsuya Atsumi

  Journal of general internal medicine 37 10 2573 - 2574 2022年05月19日
• Effects of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide on glucose metabolism in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, parallel-group comparison study (the SWITCH-SEMA 2 study).

  Hiroshi Nomoto, Sho Furusawa, Akinobu Nakamura, Jun Takeuchi, So Nagai, Hiroki Yokoyama, Ichiro Sakuma, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, Hideaki Miyoshi

  BMJ open 12 5 e056885  2022年05月18日 

  INTRODUCTION: Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%-9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters. ETHICS AND DISSEMINATION: This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020-013). TRIAL REGISTRATION NUMBER: UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.
• Diagnostic Value of Vessel Wall Imaging to Determine the Timing of Extracranial-Intracranial Bypass for Moyamoya Syndrome Associated with Active Sjögren's Syndrome: A Case Report.

  Takafumi Shindo, Masaki Ito, Taku Sugiyama, Tomohiro Okuyama, Michihito Kono, Tatsuya Atsumi, Miki Fujimura

  Journal of neurological surgery. Part A, Central European neurosurgery 2022年04月22日 

  BACKGROUND: Sjögren's syndrome is a chronic autoimmune disorder that predominantly affects exocrine organs. It is characterized by an organ-specific infiltration of lymphocytes. The involvement of the major cerebral arteries in Sjögren's syndrome has rarely been reported. A recent study reported a case of successful extracranial‒intracranial (EC‒IC) bypass without complications, even in the active inflammatory state, although the optimal timing of such a bypass remains unclear. CASE DESCRIPTION: We here report the case of a 43-year-old woman presenting with acute ischemic stroke due to progressive middle cerebral artery (MCA) occlusion and signs of primary Sjögren's syndrome. During intensive immunosuppressive therapy for active Sjögren's syndrome, the patient was monitored using contrast-enhanced magnetic resonance vessel wall imaging (MR-VWI). A couple of intravenous cyclophosphamide injections combined with a methylprednisolone pulse and antiplatelet therapy, resulted in clear resolution of vessel wall enhancement, which suggested remission of inflammatory vasculitis. Nevertheless, she still experienced a transient ischemic attack due to decreased regional cerebral blood flow by MCA occlusion, as demonstrated by the conventional time-of-flight MR angiography and single-photon emission computed tomography. Considering the increased risk of further stroke, the decision was made to perform EC-IC bypass as a treatment of hemodynamic impairment medically uncontrollable. Her postoperative course was uneventful without further repeated TIAs, and continued immunosuppressive therapy for Sjögren's syndrome provided effective management. CONCLUSIONS: Our findings emphasize the diagnostic value of contrast-enhanced MR-VWI in monitoring the effect of immunosuppressive therapy for the major cerebral artery vasculitis and in determining the timing of EC‒IC bypass as a 'rescue' treatment for Moyamoya syndrome associated with active Sjögren's syndrome.
• Disease activity as a risk factor for venous thromboembolism in rheumatoid arthritis analysed using time-averaged DAS28CRP: a nested case-control study.

  Masaru Yoshimura, Yuichiro Fujieda, Masanari Sugawara, Michihito Kono, Masaru Kato, Isao Yokota, Olga Amengual, Yoichi M Ito, Tatsuya Atsumi

  Rheumatology international 42 11 1939 - 1946 2022年04月06日 

  The objective of this study is to clarify the clinical features and risk factors of venous thromboembolism (VTE) in patients with rheumatoid arthritis (RA). We retrospectively reviewed the prevalence of VTE in RA patients who visited Hokkaido University Hospital from 2010 to 2019 and had more than 2 years of follow-up. To explore the risk to develop VTE, we selected 260 RA patients without VTE (non-VTE) via density sampling and identified the risk factors for VTE by multivariate logistic regression analysis. Univariate conditional logistic regression analysis showed older age (p < 0.0001, Odds Ratio [OR] 1.08, 95% Confidence Interval [CI] 1.04-1.14), increase of the body mass index (BMI) (p = 0.001, OR 1.17, 95% CI 1.06-1.31), higher prevalence of RA-associated lung disease (p = 0.002, OR 2.10, 95% CI 1.33-3.30) and more frequent glucocorticoid usage (p = 0.001, OR 2.09, 95% CI 1.34-3.51) in RA patients was associated with the development of VTE significantly. Furthermore, patients with higher time-averaged disease activity score 28 (DAS28) CRP were at elevated risk (p < 0.0001, OR 3.25, 95% CI 1.94-6.12). In conditional multivariate logistic regression analysis, time averaged DAS28CRP was significantly associated with the development of VTE (p = 0.0001, adjusted OR 3.40, 95% CI 1.77-7.85). Disease activity was identified as a major risk factor of VTE in patients with RA, suggesting that sustained clinical remission could be beneficial for decrease the risk of VTE.
• COVID-19ワクチン接種後に脳炎・副腎不全を呈した汎下垂体機能低下症の一例

  濱谷 柚香, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 穴田 麻眞子, 矢部 一郎, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 1 254 - 254 (一社)日本内分泌学会 2022年04月
• 高齢で診断され、skewed X inactivationが確認されたAVPR2遺伝子変異を有する腎性尿崩症の女性例

  中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 岡田 絵里, 野津 寛大, 渥美 達也

  日本内分泌学会雑誌 98 1 256 - 256 (一社)日本内分泌学会 2022年04月
• 細胞株、マウス、患者由来腺腫細胞を用いた、クッシング病に対するニューロメジンB受容体拮抗薬の増殖・ホルモン分泌抑制効果の検討

  関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 1 297 - 297 (一社)日本内分泌学会 2022年04月
• 2型糖尿病または耐糖能異常合併高血圧患者におけるエサキセレノンの効果

  桑原 咲, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 小梁川 直秀, 竹内 淳, 永井 聡, 三次 有奈, 和田 典男, 種田 紳二, 栗原 義夫, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 1 300 - 300 (一社)日本内分泌学会 2022年04月
• 減量・代謝改善手術による骨代謝の変化

  大江 悠希, 高瀬 崇宏, 曹 圭龍, 海老原 裕磨, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 平野 聡, 渥美 達也, 三好 秀明

  日本内分泌学会雑誌 98 1 308 - 308 (一社)日本内分泌学会 2022年04月
• COVID-19ワクチン接種後に脳炎・副腎不全を呈した汎下垂体機能低下症の一例

  濱谷 柚香, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 穴田 麻眞子, 矢部 一郎, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 1 346 - 346 (一社)日本内分泌学会 2022年04月
• SGLT2阻害薬はミトコンドリア機能の改善を介し膵β細胞量・機能を保護する

  山内 裕貴, 中村 昭伸, 横田 卓, 高橋 清彦, 川田 晋一朗, 土田 和久, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 安斉 俊久, 田中 伸哉, 寺内 康夫, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 1 361 - 361 (一社)日本内分泌学会 2022年04月
• グルコキナーゼ活性化薬の長期投与に伴う血糖降下作用の消失機序の解明

  川田 晋一朗, 中村 昭伸, 三好 秀明, 山内 裕貴, 土田 和久, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也

  日本内分泌学会雑誌 98 1 361 - 361 (一社)日本内分泌学会 2022年04月
• 2型糖尿病における副腎ステロイドホルモン合成亢進機序の解明とDHCR24阻害薬の効果の検討

  上垣 里紗, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 神 茂樹, 的場 光太郎, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 1 381 - 381 (一社)日本内分泌学会 2022年04月
• 高齢で診断され、skewed X inactivationが確認されたAVPR2遺伝子変異を有する腎性尿崩症の女性例

  中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 岡田 絵里, 野津 寛大, 渥美 達也

  日本内分泌学会雑誌 98 1 400 - 400 (一社)日本内分泌学会 2022年04月
• インスリンデグルデクとDPP-4阻害薬の併用からデグルデク/リラグルチド配合注への切替えは血糖変動とQOLを改善させる

  野本 博司, 大江 悠希, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 宮 愛香, 亀田 啓, 曹 圭龍, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 138 (一社)日本糖尿病学会 2022年04月
• 日本人肥満2型糖尿病における腹腔鏡下スリーブ状胃切除術が脂肪肝に及ぼす効果 前向きコホート研究

  大江 悠希, 高瀬 崇宏, 曹 圭龍, 小川 浩司, 海老原 裕磨, 吉川 仁人, 西田 睦, 宮 愛香, 野本 博司, 亀田 啓, 荘 拓也, 須田 剛生, 中村 昭伸, 倉島 庸, 阿保 大介, 工藤 與亮, 坂本 直哉, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 139 (一社)日本糖尿病学会 2022年04月
• 内臓脂肪面積は内因性インスリン分泌低下型の2型糖尿病において血糖変動の安定性を予測する

  宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 伊藤 陽一, 永井 聡, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 210 (一社)日本糖尿病学会 2022年04月
• 肥満糖尿病病態への介入による膵β細胞の細胞内代謝変化

  千葉 幸輝, 野本 博司, 泉原 里美, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 Suppl.1 S - 216 (一社)日本糖尿病学会 2022年04月
• 高中性脂肪血症合併2型糖尿病におけるペマフィブラートの効果 前向きコホート研究

  鬼頭 健一, 野本 博司, 佐久間 一郎, 曹 圭龍, 山下 久美子, 家坂 光, 大江 悠希, 山内 裕貴, 半田 喬久, 川田 晋一郎, 土田 和久, 柴山 唯, 大森 一乃, 大場 知穂, 宮 愛香, 亀田 啓, 竹内 淳, 永井 聡, 種田 紳二, 沖 一郎, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 221 (一社)日本糖尿病学会 2022年04月
• 2型糖尿病におけるDPP-4阻害薬から経口セマグルチド切り替えによる血糖コントロールへの影響 SWITCH SEMA-2 studyプロトコール

  古澤 翔, 野本 博司, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 竹内 淳, 永井 聡, 種田 紳二, 横山 宏樹, 佐久間 一郎, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 225 (一社)日本糖尿病学会 2022年04月
• 剖検膵を用いた日本人2型糖尿病膵β細胞における代謝リモデリングの検討

  泉原 里美, 野本 博司, 千葉 幸輝, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 水上 浩哉, 渥美 達也

  糖尿病 65 Suppl.1 S - 281 (一社)日本糖尿病学会 2022年04月
• 日本人肥満症合併2型糖尿病患者への減量・代謝改善手術により代謝疾患は改善し治療薬を減量し得る

  大藤 悠理, 曹 圭龍, 海老原 裕磨, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 288 (一社)日本糖尿病学会 2022年04月
• 耐糖能異常患者における腎移植後の耐糖能変化及びその関連因子

  久住 麻唯子, 中村 昭伸, 宮 愛香, 野本 博司, 亀田 啓, 曹 圭龍, 堀田 記世彦, 篠原 信雄, 三好 秀明, 渥美 達也

  糖尿病 65 Suppl.1 S - 290 (一社)日本糖尿病学会 2022年04月
• 左上下肢の不随意運動を契機に診断された糖尿病性舞踏病の一例

  横関 恵, 野本 博司, 桑原 咲, 宮 愛香, 亀田 啓, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 65 Suppl.1 S - 295 (一社)日本糖尿病学会 2022年04月
• リラグルチドおよびデュラグルチドからセマグルチド切り替えによる血糖コントロール及びQOLへの影響 SWITCH-SEMA1 study

  高橋 由華, 野本 博司, 横山 宏樹, 濱谷 柚香, 宮崎 あすか, 中田 健人, 泉原 里美, 上垣 里紗, 続木 惇, 宮 愛香, 亀田 啓, 曹 圭龍, 大場 知穂, 竹内 淳, 永井 聡, 土田 和久, 種田 紳二, 高野 善成, 木島 弘道, 山下 久美子, 栗原 義夫, 青木 伸, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 305 (一社)日本糖尿病学会 2022年04月
• 内臓脂肪面積は内因性インスリン分泌低下型の2型糖尿病において血糖変動の安定性を予測する

  宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 伊藤 陽一, 永井 聡, 渥美 達也, 三好 秀明

  糖尿病 65 Suppl.1 S - 210 (一社)日本糖尿病学会 2022年04月
• SGLT2阻害薬はミトコンドリア機能の改善を介し膵β細胞量・機能を保護する

  山内 裕貴, 中村 昭伸, 横田 卓, 高橋 清彦, 川田 晋一朗, 土田 和久, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 安斉 俊久, 田中 伸哉, 寺内 康夫, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 98 1 361 - 361 (一社)日本内分泌学会 2022年04月
• Lymphocytic panhypophysitis and anti-rabphilin-3A antibody with pulmonary sarcoidosis.

  Yuka Takahashi, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Hiroki Nishimura, Hirokazu Kimura, Masaru Suzuki, Satoshi Konno, Ai Shimizu, Yoshihiro Matsuno, Michinari Okamoto, Hiroaki Motegi, Naoko Iwata, Haruki Fujisawa, Atsushi Suzuki, Yoshihisa Sugimura, Hideaki Miyoshi, Tatsuya Atsumi

  Pituitary 25 2 321 - 327 2022年04月 

  PURPOSE: To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis. METHODS AND RESULTS: A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis. CONCLUSION: To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies.
• 減量代謝改善手術後の甲状腺機能の変化

  大江 悠希, 亀田 啓, 関崎 知紀, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也, 三好 秀明

  日本内分泌学会雑誌 97 5 1161 - 1161 (一社)日本内分泌学会 2022年03月
• ニューロメジンB受容体を標的としたACTH産生下垂体腺腫の新規治療法の探索

  関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 岡本 迪成, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 5 1244 - 1244 (一社)日本内分泌学会 2022年03月
• 腎癌に対する免疫チェックポイント阻害薬併用療法により糖尿病ケトアシドーシスを発症し、その入院中にACTH分泌低下症を発症した1例

  家坂 光, 亀田 啓, 宮 愛香, 野本 博司, ちょう 圭龍, 中村 昭伸, 安部 崇重, 篠原 信雄, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 5 1253 - 1253 (一社)日本内分泌学会 2022年03月
• 減量・代謝改善手術による代謝疾患治療薬の減量と総体重減少率の関連

  大藤 悠理, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  肥満研究 27 Suppl. 318 - 318 (一社)日本肥満学会 2022年03月
• 減量・代謝改善手術によるインスリン抵抗性と分泌能の変化

  久住 麻唯子, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  肥満研究 27 Suppl. 318 - 318 (一社)日本肥満学会 2022年03月
• 減量・代謝改善手術後の栄養動態変化

  横関 恵, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  肥満研究 27 Suppl. 322 - 322 (一社)日本肥満学会 2022年03月
• 耐糖能異常を伴う肥満患者の腹腔鏡下スリーブ状胃切除術の肝脂肪化および肝線維化に対する効果

  古澤 翔, 曹 圭龍, 大江 悠希, 高橋 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  肥満研究 27 Suppl. 347 - 347 (一社)日本肥満学会 2022年03月
• 腹腔鏡下スリーブ状胃切除術後の骨密度の変化

  濱谷 柚香, 曹 圭龍, 大江 悠希, 高瀬 崇宏, 宮 愛香, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  肥満研究 27 Suppl. 349 - 349 (一社)日本肥満学会 2022年03月
• ニューロメジンB受容体を標的としたACTH産生下垂体腺腫の新規治療法の探索

  関崎 知紀, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 岡本 迪成, 茂木 洋晃, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 5 1244 - 1244 (一社)日本内分泌学会 2022年03月
• ベーチェット病 機械学習を用いたBehcet病患者の免疫学的サブセットの検討

  平原 理紗, 桐野 洋平, 飯塚 友紀, 副島 裕太郎, 吉見 竜介, 藤枝 雄一郎, 渥美 達也, 東野 俊洋, 廣畑 俊成, 小林 大介, 中島 秀明

  日本リウマチ学会総会・学術集会プログラム・抄録集 66回 330 - 330 (一社)日本リウマチ学会 2022年03月
• Glycogen synthase kinase 3β/CCR6-positive bone marrow cells correlate with disease activity in multicentric Castleman disease-TAFRO.

  Nobuya Abe, Michihito Kono, Michihiro Kono, Naoki Ohnishi, Tomoya Sato, Masato Tarumi, Masaru Yoshimura, Taiki Sato, Kohei Karino, Yuka Shimizu, Yuichiro Fujieda, Masaru Kato, Rie Hasebe, Kenji Oku, Masaaki Murakami, Tatsuya Atsumi

  British journal of haematology 196 5 1194 - 1204 2022年03月 

  Multicentric Castleman disease-thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly (MCD-TAFRO)-is an emergent phenotype characterized by lymphoproliferation, fluid collection, hemocytopenia and multiple organopathy. Although studies have demonstrated an aberrant blood cytokine/chemokine profile referred to as "chemokine storm", the pathogenesis remains unclear. We aimed to identify pathogenic key molecules, potential diagnostic targets and therapeutic markers in MCD-TAFRO using serum cytokine/chemokine profiles. We performed the targeted cytokine/chemokine multiplex analysis in six cases of MCD-TAFRO with remission or non-remission status. We observed significant changes in serum concentrations of CCL2, CCL5, and Chitinase-3-like-1 in the MCD-TAFRO patients with active state compared to inactive state. Ingenuity pathway analysis revealed that glycogen synthase kinase 3 (GSK3) and CCR6, which is expressed in megakaryocytes, were detected as upstream positive regulators for activating MCD-TAFRO status. More GSK3β+ CCR6+ cells like megakaryocytes were detected in the bone marrow of patients with MCD-TAFRO than in those with systemic lupus erythematosus, MCD-not otherwise specified or autoimmune haemophagocytic lymphohistiocytosis. The cellularity of GSK3β+ CCR6+ cells was correlated with disease activity, including thrombocytopenia and anaemia. In conclusion, GSK3β and CCR6 of bone marrow cells were potentially involved in the pathogenesis of MCD-TAFRO and may act as diagnostic targets and therapeutic markers.
• Aberrant functional connectivity between anterior cingulate cortex and left insula in association with therapeutic response to biologics in inflammatory arthritis

  Nobuya Abe, Yuichiro Fujieda, Khin K. Tha, Hisashi Narita, Kuniyuki Aso, Kohei Karino, Masatoshi Kanda, Michihito Kono, Masaru Kato, Olga Amengual, Tatsuya Atsumi

  Seminars in Arthritis and Rheumatism 151994 - 151994 2022年03月
• Glucokinase activation leads to an unsustained hypoglycaemic effect with hepatic triglyceride accumulation in db/db mice.

  Shinichiro Kawata, Akinobu Nakamura, Hideaki Miyoshi, Kelaier Yang, Ikumi Shigesawa, Yuki Yamauchi, Kazuhisa Tsuchida, Kazuno Omori, Kiyohiko Takahashi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi

  Diabetes, obesity & metabolism 24 3 391 - 401 2022年03月 

  AIM: To investigate how subchronic administration of a glucokinase activator (GKA) results in attenuation of the hypoglycaemic effect in the diabetic condition. MATERIALS AND METHODS: Six-week-old db/db mice were fed standard chow containing a GKA or the sodium-glucose cotransporter 2 inhibitor ipragliflozin for 1, 6, 14 or 28 days. We performed histological evaluation and gene expression analysis of the pancreatic islets and liver after each treatment and compared the results to those in untreated mice. RESULTS: The unsustained hypoglycaemic effect of GKAs was reproduced in db/db mice in conjunction with significant hepatic fat accumulation. The initial reactions to treatment with the GKA in the liver were upregulation of the gene expression of carbohydrate response element-binding protein beta (Chrebp-b) and downregulation of phosphoenolpyruvate carboxykinase (Pepck) on day 1. Subsequently, the initial changes in Chrebp-b and Pepck disappeared and increases in the expression of genes involved in lipogenesis, including acetyl-CoA carboxylase and fatty acid synthase, were observed. There were no significant changes in the pancreatic β cells nor in hepatic insulin signalling. CONCLUSIONS: The GKA showed an unsustained hypoglycaemic effect and promoted hepatic fat accumulation in db/db mice. Dynamic changes in the expression of hepatic genes involved in lipogenesis and gluconeogenesis could affect the unsustained hypoglycaemic effect of the GKA despite no changes in pancreatic β-cell function and mass.
• Branched chain amino acids in the treatment of polymyositis and dermatomyositis: a phase II/III, multi-center, randomized controlled trial.

  Naoki Kimura, Takuya Kawahara, Yukari Uemura, Tatsuya Atsumi, Takayuki Sumida, Toshihide Mimura, Yasushi Kawaguchi, Hirofumi Amano, Yukiko Iwasaki, Yuko Kaneko, Toshihiro Matsui, Yoshinao Muro, Yoshitaka Imura, Takashi Kanda, Yoshiya Tanaka, Atsushi Kawakami, Masatoshi Jinnin, Tomonori Ishii, Keiju Hiromura, Yusuke Miwa, Hiroshi Nakajima, Masataka Kuwana, Yasuhiko Nishioka, Akio Morinobu, Hideto Kameda, Hitoshi Kohsaka

  Rheumatology (Oxford, England) 61 11 4445 - 4454 2022年02月18日 

  OBJECTIVES: To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. METHODS: Treatment naïve adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary end point was the change of the MMT score at 12 weeks. The secondary end points were the clinical response and the change of functional index (FI). RESULTS: Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) groups. The changes of MMT scores at 12 weeks were 0.70±0.19 (mean±SEM) and 0.69±0.18, respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group (27.9±5.67 vs. 12.8±5.67 for the right shoulder flexion, and 27.0±5.44 vs. 13.4±5.95 for the left shoulder [P < 0.05]). Frequencies of adverse events upto 12 weeks were similar. CONCLUSION: BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions. TRIAL REGISTRATION: UMIN-CTR Clinical Trial, https://center6.umin.ac.jp/, UMIN000016233.
• Selection of treatment regimens based on shared decision-making in patients with rheumatoid arthritis on remission in the FREE-J study.

  Yoshiya Tanaka, Ayako Yamaguchi, Toshiaki Miyamoto, Kazuhide Tanimura, Hideyuki Iwai, Yuko Kaneko, Tsutomu Takeuchi, Koichi Amano, Naoki Iwamoto, Atsushi Kawakami, Miho Murakami, Norihiro Nishimoto, Tatsuya Atsumi, Takayuki Sumida, Koichiro Ohmura, Tsuneyo Mimori, Hisashi Yamanaka, Keishi Fujio, Yoshihisa Fujino, Kazuyoshi Saito, Kazuhisa Nakano, Shintaro Hirata, Shingo Nakayamada

  Rheumatology (Oxford, England) 61 11 4273 - 4285 2022年02月08日 

  OBJECTIVE: To compare the outcome of various treatment de-escalation regimens in patients with RA who achieved sustained remission. METHODS: At period 1, 436 RA patients who were treated with MTX and bDMARDs and had maintained DAS28(ESR) at < 2.6 were divided into five groups based on shared patient/physician decision-making; continuation, dose-reduction and discontinuation of MTX or bDMARD. At end of year 1, patients who achieved DAS28(ESR)<3.2 were allowed to enrol in period 2 for treatment using the de-escalation regimens for another year. The primary and secondary endpoints were the proportion of patients with DAS28(ESR)<2.6 at year 1 and 2, respectively. RESULTS: Based on shared decision-making, 81.4% elected de-escalation of treatment and 48.4% selected de-escalation of MTX. At end of period 1, similar proportions of patients maintained DAS28(ESR)<2.6 (continuation, 85.2%; MTX-dose-reduction, 79.0%; MTX-discontinuation, 80.0%; bDMARD-dose-reduction, 73.9%), although the rate was significantly different between the continuation and bDMARD-discontinuation. At end of period 2, similar proportions of patients of the MTX groups maintained DAS28(ESR)<2.6 (continuation or de-escalation), but the rates were significantly lower in the bDMARD-discontinuation group. However, half of the latter group satisfactorily discontinued bDMARD. Adverse events were numerically lower in MTX and bDMARD-de-escalation groups during period 1 and 2, compared with the continuation group. CONCLUSIONS: After achieving sustained remission by combination treatment of MTX/bDMARDs, disease control was achieved comparably by continuation, dose-reduction or discontinuation of MTX and dose-reduction of bDMARD at end of year 1. Subsequent de-escalation of MTX had no impacts on disease control but decreased adverse events in year 2.
• Abatacept Ameliorates Both Glandular and Extraglandular Involvements in Patients With Sjögren's Syndrome Associated with Rheumatoid Arthritis: Findings from an Open-Label, Multicenter, 1-Year, Prospective Study: the ROSE (Rheumatoid Arthritis with Orencia Trial Toward Sjögren's Syndrome Endocrinopathy) and ROSE II trials.

  Hiroto Tsuboi, Hirofumi Toko, Fumika Honda, Saori Abe, Hiroyuki Takahashi, Mizuki Yagishita, Shinya Hagiwara, Ayako Ohyama, Yuya Kondo, Kazuhisa Nakano, Yoshiya Tanaka, Toshimasa Shimizu, Hideki Nakamura, Atsushi Kawakami, Yuichiro Fujieda, Tatsuya Atsumi, Yasunori Suzuki, Mitsuhiro Kawano, Naoshi Nishina, Yuko Kaneko, Tsutomu Takeuchi, Hitomi Kobayashi, Masami Takei, Michihiro Ogasawara, Naoto Tamura, Yoshinari Takasaki, Kazuhiro Yokota, Yuji Akiyama, Toshihide Mimura, Kosaku Murakami, Tsuneyo Mimori, Shiro Ohshima, Naoto Azuma, Hajime Sano, Susumu Nishiyama, Isao Matsumoto, Takayuki Sumida

  Modern rheumatology 33 1 160 - 168 2022年02月04日 

  OBJECTIVE: To clarify the efficacy and safety of abatacept for glandular and extraglandular involvements in Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). PATIENTS AND METHODS: We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials) for SS with RA. The primary endpoint was the remission rate as measured by SDAI at 52 weeks after initiation of intravenous abatacept. The secondary endpoints included the changes in the Saxon's test, Schirmer's test, ESSDAI and ESSPRI. Adverse events and adherence rates during the study period were also analyzed. RESULTS: 68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled in this study. The mean SDAI decreased significantly from 23.6±13.2 (±SD) at baseline to 9.9±9.5 at 52 weeks (P<0.05). Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly from 2015.1±1695.4 (0 weeks) to 2311.3±1804.4 (24 weeks) mg/2 min (n=66, P<0.05). Tear volume increased significantly from 5.0±6.0 (0 weeks) to 5.6±6.3 (52 weeks) mm/5 min (n=52, P<0.05). Both ESSDAI and ESSPRI scores were significantly decreased at 12 weeks, and these responses were maintained up to 52 weeks. The rate of adherence to abatacept over the 52-week period was 83.8%. Twenty-two adverse events occurred in 15 patients, and 9 of these events were infections. CONCLUSION: Abatacept ameliorated both glandular and extraglandular involvements, as well as the systemic disease activities and patient-reported outcomes based on composite measures, in patients with SS associated with RA.
• Anti-Ganglionic Nicotinic Acetylcholine Receptor Α3 Subunit Antibody as a Potential Biomarker Associated With Lupus Enteritis.

  Kuniyuki Aso, Michihito Kono, Nobuya Abe, Yuichiro Fujieda, Masaru Kato, Tatsuya Atsumi

  Modern rheumatology 33 1 154 - 159 2022年02月02日 

  OBJECTIVES: We aimed to identify the clinical significance of anti-ganglionic nicotinic acetylcholine receptor α3 subunit (gAChRα3) antibodies (Abs) in patients with systemic lupus erythematosus (SLE). METHODS: This retrospective study comprised adult patients with SLE who visited our hospital from 2006 through 2019. Anti-gAChRα3 Abs were measured in the sera of patients with SLE using a luciferase immunoprecipitation system assay. The clinical features of the patients with or without anti-gAChRα3 Abs were compared. We evaluated whether the Abs predict a specific manifestation and affect its development or relapse rate. RESULTS: Among 144 patients, anti-gAChRα3 Abs were detected in 29 patients. Lupus enteritis (LE) was more frequently seen in anti-gAChRα3 Ab-positive patients than negative patients. The levels of anti-gAChRα3 Abs were significantly higher in patients with LE than those with other lupus manifestations. Logistic regression analysis revealed the anti-gAChRα3 Abs were independent predictors for LE (odds ratio 6.2, 95% confidence interval 1.9-20.3, p = 0.002). Kaplan-Meier analysis showed the rate of LE development or relapse from the time of sera collection was higher in anti-gAChRα3 Ab-positive patients than in negative patients (p < 0.001). CONCLUSION: Anti-gAChRα3 Abs could be a predictive biomarker for the development or relapse of LE.
• Autosplenectomy.

  Shuhei Takeyama, Nobuya Abe, Tatsuya Atsumi

  European journal of internal medicine 96 109 - 110 2022年02月
• Letter to the Editor: False Hypercortisolemia Due to Abnormal Albumin-Cortisol Binding in a Patient with Familial Dysalbuminemic Hyperthyroxinemia

  Koki Chiba, Hiraku Kameda, Aika Miya, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Shigeki Jin, Kotaro Matoba, Hideaki Miyoshi, Tatsuya Atsumi

  Thyroid 32 2 219 - 220 2022年02月01日
• Impact of low-starch high-fiber pasta on postprandial blood glucose.

  Chiho Oba-Yamamoto, Jun Takeuchi, Akinobu Nakamura, Hiroshi Nomoto, Hiraku Kameda, Kyu Y Cho, Tatsuya Atsumi, Hideaki Miyoshi

  Nutrition, metabolism, and cardiovascular diseases : NMCD 32 2 487 - 493 2022年02月 

  BACKGROUND AND AIMS: Almost all of the energy in noodle dishes is derived from carbohydrates, particularly starch. Recently, we invented a pasta with reduced starch content to about 50% and increased dietary fiber content, designated low-starch high-fiber pasta (LSHFP). In this study, we investigated the ingestion of LSHFP on the postprandial glucose response as a breakfast meal. METHODS AND RESULT: This was a randomized, single-blinded, crossover study. The postprandial glucose area under the curve for 4 h (4h-gluAUC), as the primary outcome, and the extent of postprandial glucose elevation (maxΔBG) were evaluated using a continuous glucose monitoring system in healthy volunteers and patients with type 2 diabetes (T2DM) after intake of LSHFP, standard pasta (SP), and rice. The amount of total carbohydrate was matched between LSHFP and SP. Ten individuals with T2DM and 10 individuals who did not have T2DM and were otherwise healthy were enrolled in this crossover study. The 4h-gluAUC for LSHFP (137.6 ± 42.2 mg/dL・h) was significantly smaller than the 4h-gluAUC for rice (201.7 ± 38.7 mg/dL・h) (p = 0.001) and SP (178.5 ± 59.2 mg/dL・h) (p = 0.020). The maxΔBG for rice (118.6 ± 24.2 mg/dL) was significantly higher than those for SP (87.5 ± 19.9 mg/dL) (p < 0.001) and LSHFP (72.7 ± 26.2 mg/dL) (p = 0.001), while the maxΔBG for LSHFP (p = 0.047) was significantly lower than that for SP, in T2DM patients as well as in healthy participants. CONCLUSIONS: This study demonstrated that LSHFP can reduce postprandial glucose elevation compared with SP in both healthy participants and patients with T2DM.
• Cytokine and chemokine multiplex analysis-based exploration for potential treatment and prognostic prediction in large-vessel vasculitis: A preliminary observational study.

  Nobuya Abe, Michihiro Kono, Michihito Kono, Takayuki Katsuyama, Kazumasa Ohmura, Taiki Sato, Kohei Karino, Yuichiro Fujieda, Masaru Kato, Rie Hasebe, Masaaki Murakami, Tatsuya Atsumi

  Frontiers in immunology 13 1066916 - 1066916 2022年 

  Large-vessel vasculitis (LVV) is subclassified into two phenotypes; Takayasu arteritis and giant cell arteritis. Although the pathogenesis of LVV is not fully established, IL-6-IL-17 axis and IL-12-IFN-γ axis play critical roles in the disease development. We aimed to clarify the association between the disease state and cytokine/chemokine levels, to assess disease course as prognosis and to predict regulators in patients with LVV using the blood profiles of multiple cytokines/chemokines. This retrospective analysis comprised 35 LVV patients whose blood were collected, and multiplex cytokine/chemokine analysis with 28 analytes was performed. The differences of cytokines/chemokines corresponding disease status, upstream regulator analysis, pathway analysis and cluster analysis were conducted using the cytokines/chemokines profile. Relapse-free survival rate was calculated with Kaplan-Meier analysis in the classified clusters. In the robust analysis, IL-4, CCL2/MCP-1, TNFSF13/APRIL, TNFSF13B/BAFF, CHI3L1 and VEGF-A levels were significantly changed after treatment. Untreated LVV patients demonstrated activation of NFκB-related molecules and these patients are potentially treated with JAK/STAT inhibitors, anti-TNF-α inhibitors and IL-6 inhibitors. Cluster analysis in active LVV patients revealed two clusters including one with high blood levels of IL-1β, IL-6, IL-17, IL-23 and CCL20/MIP-3. A subgroup of the LVV patients showed activated IL-17 signature with high relapse frequency, and JAK/TyK2 inhibitors and IFN-γ inhibitors were detected as potentially upstream inhibitors. Blood cytokine/chemokine profiles would be useful for prediction of relapse and potentially contributes to establish therapeutic strategy as precision medicine in LVV patients.
• Soluble Interleukin-2 Receptor Predicts Treatment Outcome in Patients With Autoimmune Tubulointerstitial Nephritis. A Preliminary Study.

  Satoka Shiratori-Aso, Daigo Nakazawa, Saori Nishio, Yusho Ueda, Mina Eguchi, Ai Yokoyama, Junpei Yoshikawa, Takashi Kudo, Kanako Watanabe-Kusunoki, Sayo Takeda-Otera, Junya Yamamoto, Naoko Matsuoka, Nobuharu Kaneshima, Fumihiko Hattanda, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Tatsuya Atsumi

  Frontiers in medicine 9 827388 - 827388 2022年 

  Background: Autoimmune tubulointerstitial nephritis (TIN) is characterized by immune-mediated tubular injury and requires immunosuppressive therapy. However, diagnosing TIN and assessing therapeutic response are challenging for clinicians due to the lack of useful biomarkers. Pathologically, CD4+ T cells infiltrate to renal tubulointerstitium, and soluble interleukin-2 receptor (sIL-2R) has been widely known as a serological marker of activated T cell. Here, we explored the usefulness of serum sIL-2R to predict the treatment outcome in patients with autoimmune TIN. Methods: Study Design: Single-center retrospective observational study. Participants: 62 patients were diagnosed of TIN from 2005 to April 2018 at Hokkaido University Hospital. Among them, 30 patients were diagnosed with autoimmune TIN and treated with corticosteroids. We analyzed the association between baseline characteristics including sIL-2R and the change of estimated glomerular filtration rate (eGFR) after initiation of corticosteroids. Results: The serum sIL-2R level in patients with autoimmune TIN was significantly higher than that in chronic kidney disease patients with other causes. Mean eGFR in autoimmune TIN patients treated with corticosteroids increased from 43.3 ± 20.4 mL/min/1.73 m2 (baseline) to 50.7 ± 19.9 mL/min/1.73 m2 (3 months) (ΔeGFR; 22.8 ± 26.0%). Multivariate analysis revealed that higher sIL-2R (per 100 U/mL, β = 1.102, P < 0.001) level was independently associated with the renal recovery. In ROC analysis, sIL-2R had the best area under the curve value (0.805) and the cutoff point was 1182 U/mL (sensitivity = 0.90, 1-specificity = 0.45). Conclusions: Our study showed that elevated serum sIL-2R levels might become a potential predictive marker for therapeutic response in autoimmune TIN.
• Switching from Insulin Degludec plus Dipeptidyl Peptidase-4 Inhibitor to Insulin Degludec/Liraglutide Improves Glycemic Variability in Patients with Type 2 Diabetes: A Preliminary Prospective Observation Study.

  Yuki Oe, Hiroshi Nomoto, Akinobu Nakamura, Saki Kuwabara, Yuka Takahashi, Ayano Yasui, Rimi Izumihara, Aika Miya, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of diabetes research 2022 5603864 - 5603864 2022年 

  Incretins reduce glycemic variability (GV) in patients with type 2 diabetes, but it is unknown whether switching from a combination of basal insulin and a DPP-4 inhibitor to insulin degludec/liraglutide (IDegLira) improves GV. We performed an exploratory prospective observational study to compare the effect of IDegLira and the combination on GV. We recruited hospitalized patients with type 2 diabetes who had stable glycemic control with insulin degludec (≤16 units/day) and taking a DPP-4 inhibitor. GV was analyzed using continuous glucose monitoring (CGM) before and after switching the medication to IDegLira. The principal endpoint was the change in mean amplitude of glycemic excursions (MAGE). Other indices of GV and CGM parameters were analyzed as the secondary endpoints. Fifteen participants were enrolled and 12 completed the study. In these participants, the DPP-4 inhibitor and insulin degludec were discontinued, and the equivalent dose of IDegLira was commenced. Switching to IDegLira significantly improved MAGE from 74.9 (60.3, 97.7) mg/dL to 64.8 (52.0, 78.2) mg/dL (P < 0.05), as well as other indices of GV and 24-hour mean blood glucose concentration. Analysis of the ambulatory glucose profile showed marked reductions in postprandial glucose concentration. Nocturnal glucose concentration was similar under the two treatment regimens. IDegLira improved GV as well as the mean and the postprandial glucose concentration by switching from insulin degludec plus DPP-4 inhibitor combination. IDegLira might be beneficial for patients being treated with low-dose basal insulin.
• Lupus-induced autoimmune chloride channelopathy-like myotonia congenita, successfully treated with immunosuppression.

  Nobuya Abe, Michihito Kono, Ikuko Iwata, Tatsuya Atsumi

  Rheumatology (Oxford, England) 61 1 e4-e5  2021年12月24日
• Comparison of administration of single- and triple-course steroid pulse therapy combined with tonsillectomy for immunoglobulin A nephropathy.

  Kanako Watanabe-Kusunoki, Daigo Nakazawa, Junya Yamamoto, Naoko Matsuoka, Nobuharu Kaneshima, Tasuku Nakagaki, Rie Yamamoto, Tomochika Maoka, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Naoki Nishimoto, Saori Nishio, Tatsuya Atsumi

  Medicine 100 50 e27778  2021年12月17日 

  Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis that can cause end-stage renal disease. Recently, tonsillectomy combined with corticosteroid pulse (TSP) has been shown to be effective for achieving clinical remission and favorable renal outcome in patients with IgAN. However, the standard regimen of corticosteroid use in TSP has not been established. Herein, we compared the effect of single- or triple-course steroid pulse therapy combined with tonsillectomy in patients with IgAN.This retrospective, observational cohort study included 122 patients with IgAN enrolled from January 2004 to December 2018 at 2 independent institutions. We divided the patients into 2 groups; single-course (TSP1: n = 70) and triple-course (TSP3: n = 52) of corticosteroid pulse therapy (1 course comprised 3 consecutive days' infusion of 0.5 g methylprednisolone) combined with tonsillectomy. The primary outcome for renal survival was defined as the first occurrence of ≧30% decrease in estimated glomerular filtration rate from baseline. Secondary outcomes included the incidence of clinical remission and recurrence of the disease.Regarding clinical parameters and findings at baseline, there were no significant differences between the 2 groups. The 8-years renal survival in the 2 groups was not significantly different according to Kaplan-Meier curves (TSP1; 82.5% vs TSP3; 69.2%, log-rank test P = .39). The cumulative incidence rates of remission of hematuria (94.4% vs 85.4%, P = .56) and clinical remission (85.0% vs 64.8%, P = .07) were comparable in both groups, while those of proteinuria showed higher rates in TSP1 than TSP3 (88.4% vs 65.4%, P = .02). The cumulative incidence of relapse of hematuria (5.6% vs 2.3%, P = .42) and proteinuria (7.1% vs 3.3%, P = .41) showed no significant differences in the 2 groups. Cox regression analyses showed that the number of courses of corticosteroid pulse therapy was not significantly associated with renal outcome (TSP1 vs TSP3; Hazard ratios 0.69, 95% confidence intervals 0.29-1.64, P = .39).The effect of single-course corticosteroid pulse therapy is not statistically, significantly different from triple-course in TSP protocol for improving renal outcome and preventing relapse in patients with IgAN. Single-course corticosteroid pulse therapy may become a treatment option for patients with IgAN.
• パシレオチド投与後に著明な高血糖を呈した先端巨大症の1例

  大藤 悠理, 亀田 啓, 桑原 咲, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 4 658 - 658 (一社)日本内分泌学会 2021年12月
• IgG4関連疾患治療中に尿崩症を呈しIgG4関連漏斗下垂体炎を発症した1例

  中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 4 658 - 658 (一社)日本内分泌学会 2021年12月
• 原発性アルドステロン症を合併した中枢性尿崩症の1例

  宮崎 あすか, 亀田 啓, 亀田 玲奈, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 4 658 - 658 (一社)日本内分泌学会 2021年12月
• 対側病変の原発性アルドステロン症を合併した副腎性Cushing症候群に対して副腎部分切除を施行した1例

  横関 恵, 亀田 啓, 千葉 幸輝, 桑原 咲, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 安倍 崇重, 篠原 信雄, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 4 660 - 660 (一社)日本内分泌学会 2021年12月
• 慢性心房細動に対する抗凝固療法中に指摘された両側副腎血腫の1例

  濱谷 柚香, 亀田 啓, 安井 彩乃, 大江 悠希, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 4 660 - 660 (一社)日本内分泌学会 2021年12月
• 悪性腹膜中皮腫の治療中に著しい高LDLコレステロール血症を指摘された1例

  久住 麻唯子, 亀田 啓, 千葉 幸輝, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 大原 克仁, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 4 660 - 660 (一社)日本内分泌学会 2021年12月
• Do the benefits of sodium-glucose cotransporter 2 inhibitors exceed the risks in patients with type 1 diabetes?

  Hikaru Kamoshima, Hiroshi Nomoto, Kumiko Yamashita, Yuka Takahashi, Kazuhisa Tsuchida, Saki Kuwabara, Aika Miya, Kyu Yong Cho, Hiraku Kameda, Akinobu Nakamura, Tatsuya Atsumi, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Yuri Ono, Hideaki Miyoshi

  Endocrine journal 69 5 495 - 509 2021年11月25日 

  Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are well-established means of improving glycemia and preventing cardio-renal events in patients with type 2 diabetes. However, their efficacy and safety have yet to be fully characterized in patients with type 1 diabetes (T1D). We studied patients with T1D who regularly attended one of five diabetes centers and treated with an SGLT2i (ipragliflozin or dapagliflozin) for >52 weeks, and the changes in HbA1c, body mass, insulin dose, and laboratory data were retrospectively evaluated and adverse events (AEs) recorded during December 2018 to April 2021. A total of 216 patients with T1D were enrolled during the period. Of these, 42 were excluded owing to short treatment periods and 15 discontinued their SGLT2i. The mean changes in glycated hemoglobin (HbA1c), body mass, and insulin dose were -0.4%, -2.1 kg, and -9.0%, respectively. The change in HbA1c was closely associated with the baseline HbA1c (p < 0.001), but not with the baseline body mass or renal function. The basal and bolus insulin doses decreased by 18.2% and 12.6%, respectively, in participants with a baseline HbA1c <8%. The most frequent AE was genital infection (2.8%), followed by diabetic ketoacidosis (DKA; 1.4%). None of the participants experienced severe hypoglycemic events. In conclusion, the administration of an SGLT2i in addition to intensive insulin treatment in patients with T1D improves glycemic control and body mass, without increasing the incidence of hypoglycemia or DKA.
• Favorable effects of burosumab on tumor-induced osteomalacia caused by an undetectable tumor: A case report.

  Yuki Oe, Hiraku Kameda, Hiroshi Nomoto, Keita Sakamoto, Takeshi Soyama, Kyu Yong Cho, Akinobu Nakamura, Koji Iwasaki, Daisuke Abo, Kohsuke Kudo, Hideaki Miyoshi, Tatsuya Atsumi

  Medicine 100 46 e27895  2021年11月19日 

  RATIONALE: Tumor-induced osteomalacia (TIO) is curable by tumor resection, but detection of the tumor can be challenging. Overproduction of fibroblast growth factor 23 (FGF23) by the tumor causes hypophosphatemia and consequently induces inappropriate bone turnover. Conventionally oral phosphate supplementation was the only treatment for TIO, but had risks of hypercalciuria and nephrocalcinosis. Burosumab, a human monoclonal anti-FGF23 antibody, was recently post-marketed in Japan against for FGF23-related hypophosphatemia. Herein, we present a case of TIO with undetectable tumor that was successfully treated with burosumab. PATIENT CONCERNS: A 47-year-old woman was forced to use a wheelchair because of pain in both feet. DIAGNOSIS: Laboratory findings showed hypophosphatemia, elevated bone markers, and high serum FGF23 without renal tubular defects. Imaging studies revealed bone atrophy in the feet, decreased bone density, and multiple pseudofractures in the talar, sacral, and L5 vertebral regions. After excluding drug-induced and hereditary osteomalacia, we diagnosed her as TIO. INTERVENTIONS: Comprehensive imaging studies and stepwise venous sampling failed to localize the tumor, and we started to administer subcutaneous burosumab. OUTCOMES: After administration of burosumab, her serum phosphate was normalized without phosphate supplementation within 2 months. Improvement of pseudofractures, relief of pain evaluated by a visual analog scale, and normalization of bone biomarkers were observed. The patient was able to stand by herself after 6 months administration of burosumab. LESSONS: This is the first report in clinical practice to demonstrate favorable effects of burosumab, including not only normalization of serum phosphate but also improvements of pseudofractures and subjective pain, in a patient with TIO and undetectable tumor.
• A Nationwide Questionnaire Survey on the Prevalence of Ankylosing Spondylitis and Non-Radiographic Axial Spondyloarthritis in Japan.

  Yuri Matsubara, Yosikazu Nakamura, Naoto Tamura, Hideto Kameda, Kotaro Otomo, Mitsumasa Kishimoto, Yuho Kadono, Shigeyoshi Tsuji, Tatsuya Atsumi, Hiroaki Matsuno, Michiaki Takagi, Shigeto Kobayashi, Keishi Fujio, Norihiro Nishimoto, Nami Okamoto, Ayako Nakajima, Kiyoshi Matsui, Masahiro Yamamura, Yasuharu Nakashima, Atsushi Kawakami, Masaaki Mori, Tetsuya Tomita

  Modern rheumatology 32 5 960 - 967 2021年11月10日 

  OBJECTIVE: This nationwide study aimed to reveal the prevalence of ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-ax SpA), and the positive rate of human leukocyte antigen (HLA) among these patients in Japan. METHODS: The first survey was conducted in 2221 randomly selected facilities (26.3%) in September, 2018, where the patients with AS/nr-ax SpA were taken care of from January to December, 2017. We estimated the total number of these patients using response and extraction rate. A second survey was conducted in 117 facilities (49.8%) to assess for HLA-B 27 positivity rate and clinical features. RESULTS: The estimated total number of the patients with AS and nr-ax SpA were 3200 (95% confidence interval [CI]: 2400-3900) and 800 (530-1100), suggesting that the prevalence of AS and nr-ax SpA in general population were 2.6/100,000 (0.0026%) and 0.6/100,000 (0.0006%), respectively. Although 55.5 % (76/137) of patients with AS were HLA-B27 positive, those whose age of onset was estimated to be over 50 years tended to undergo less HLA-B27 testing. CONCLUSION: This study revealed the lower prevalence of AS/nr-ax SpA in Japan, compared to those in other countries. Further studies are required to reveal the association of HLA-B27 with the clinical features.
• Prediction of the intolerance or non-responder to Janus kinase inhibitors in patients with rheumatoid arthritis: a preliminary retrospective study with integrative cluster analysis.

  Masanari Sugawara, Yuichiro Fujieda, Atsushi Noguchi, Shun Tanimura, Yuka Shimizu, Ikuma Nakagawa, Masaru Yoshimura, Nobuya Abe, Michihito Kono, Masaru Kato, Kenji Oku, Olga Amengual, Isao Yokota, Hiroki Takahashi, Tatsuya Atsumi

  Clinical and experimental rheumatology 2021年11月03日 

  OBJECTIVES: To identify the subpopulation of rheumatoid arthritis (RA) non-responders to Janus kinase inhibitors (JAKis) using cluster analysis. METHODS: This retrospective study enrolled RA patients who had been treated with JAKis (tofacitinib or baricitinib) between July 2013 and September 2019 in six centres. The endpoint was set as inadequate response to JAKis (JAKis-IR), defined as either non-response to JAKis or their intolerance. Non-response to JAKis was defined as achieving neither American College of Rheumatology 20% response nor Disease Activity Score (ΔDAS28-CRP) >1.2 at 12 weeks. Withdrawal time point included earlier than after 12 weeks from baseline. A hierarchical cluster analysis was performed with variables related with clinical and serological parameters at baseline. RESULTS: The 132 RA patients enrolled were classified into four groups (Group A-D). Groups consisted of three components defined at baseline, as seropositivity, advanced joint destruction, interstitial lung disease presumably associated with RA (RA-ILD). Group A (n=32): seronegative, presence of advanced joint destruction, absence of RA-ILD. Group B (n=35): seropositive, absence of advanced joint destruction and RA-ILD. Group C (n=20): seropositive, absence of advanced joint destruction, presence of RA-ILD. Group D (n=45): seropositive, presence of advanced joint destruction and RA-ILD. The rate of JAKis-IR in four groups was as follows: A, 34.3%; B, 17.1%; C, 20.0%; and D, 8.9%. The difference in JAKis-IR rate between group A and D was statistically significant. CONCLUSIONS: A subpopulation of RA patients with a combination of the following three components, seronegativity, advanced joint destruction and absence of RA-ILD, was identified as being prone to JAKis-IR.
• 妊娠中の高血圧緊急症から診断されたパラガングリオーマの一例

  中田 健人, 亀田 啓, 桑原 咲, 安井 彩乃, 高橋 由華, 高瀬 崇宏, 西尾 太郎, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 安部 崇重, 篠原 信雄, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 2 485 - 485 (一社)日本内分泌学会 2021年10月
• 常染色体優性多発性嚢胞腎を合併した嚢胞性GH産生下垂体腺腫

  桑原 咲, 亀田 啓, 関崎 知紀, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 岡本 迪成, 茂木 洋晃, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 2 491 - 491 (一社)日本内分泌学会 2021年10月
• ライム病を契機に診断されたACTH単独欠損症の一例

  各務 萌, 亀田 啓, 古澤 翔, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 2 496 - 496 (一社)日本内分泌学会 2021年10月
• 抗rabphilin-3A抗体が陽性であったリンパ球性汎下垂体炎の一例

  高橋 由華, 亀田 啓, 曹 圭龍, 中村 昭伸, 西村 弘基, 木村 孔一, 清水 亜衣, 岡本 迪成, 茂木 洋晃, 岩田 尚子, 藤沢 治樹, 鈴木 敦詞, 椙村 益久, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 2 495 - 495 (一社)日本内分泌学会 2021年10月
• 腫瘍性骨軟化症に対してブロスマブを使用した3例

  宮崎 あすか, 亀田 啓, 大江 悠希, 泉原 里美, 重沢 郁美, 野本 博司, 曹 圭龍, 中村 昭伸, 坂本 圭太, 森田 亮, 曽山 武士, 阿保 大介, 工藤 與亮, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 2 521 - 521 (一社)日本内分泌学会 2021年10月
• Lowering of blood pressure and pulse rate by switching from DPP-4 inhibitor to luseogliflozin in patients with type 2 diabetes complicated with hypertension: A multicenter, prospective, randomized, open-label, parallel-group comparison trial (LUNA study).

  Reina Hashimoto-Kameda, Kyu Yong Cho, Hiroshi Nomoto, Akinobu Nakamura, Kazuno Omori, So Nagai, Sachiko Edagawa, Shinichiro Kawata, Jun Takeuchi, Hiraku Kameda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi

  Diabetes research and clinical practice 180 109069 - 109069 2021年09月23日 

  AIMS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces clinic blood pressure (BP), but the effects on BP circadian rhythm remain unclear. The present study aimed to determine the nighttime antihypertensive effect of SGLT2i compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) in patients with type 2 diabetes and hypertension. MATERIALS AND METHODS: In this randomized, open-label, parallel-group trial, patients treated with DPP-4i were either switched to luseogliflozin 2.5 mg/day (Luseo group;n = 30) or continued DPP-4i (DPP-4i group;n = 26). The patients undertook 24-h ambulatory BP monitoring before and 8 weeks after the group allocation. The primary endpoint was mean change in nighttime systolic BP (SBP). RESULTS: Nighttime SBP, as well as daytime SBP, was significantly reduced in the Luseo group compared with the DPP-4i group (nighttime, -4.0 ± 11.4 vs. 3.6 ± 10.7 mmHg,P = 0.01; daytime, -4.4 ± 10.9 vs. 3.7 ± 11.9 mmHg,P = 0.01). Similarly, nighttimepulse rate(PR) was significantly reduced in the Luseo group (-2.0 ± 4.8 vs. 0.9 ± 4.8 bpm,P = 0.03). The proportion of patients with abnormal BP circadian rhythms (non-dipper pattern plus riser pattern) was significantly lower in the Luseo group (36.6% vs. 56.7%,P < 0.05). CONCLUSIONS: Switching from DPP-4i to luseogliflozin decreased nighttime SBP and PR; moreover, BP circadian rhythm was improved.
• 肥満糖尿病病態におけるHPA軸の活動性亢進機序

  関崎 知紀, 亀田 啓, 柴山 惟, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  ACTH RELATED PEPTIDES 31 5 - 6 間脳・下垂体・副腎系研究会 2021年09月
• 認知・生活機能質問票(DASC-8)を用いた目標HbA1cの達成に関連する患者背景因子の特定

  宮 愛香, 中村 昭伸, 横田 勲, 曹 圭龍, 亀田 啓, 野本 博司, 高瀬 崇宏, 大森 一乃, 永井 聡, 種田 紳二, 小野 真佑子, 渥美 達也, 三好 秀明

  糖尿病合併症 35 Suppl. 172 - 172 (一社)日本糖尿病合併症学会 2021年09月
• 認知・生活機能質問票(DASC-8)を用いた目標HbA1cの達成に関連する患者背景因子の特定

  宮 愛香, 中村 昭伸, 横田 勲, 曹 圭龍, 亀田 啓, 野本 博司, 高瀬 崇宏, 大森 一乃, 永井 聡, 種田 紳二, 小野 真佑子, 渥美 達也, 三好 秀明

  糖尿病合併症 35 Suppl. 172 - 172 (一社)日本糖尿病合併症学会 2021年09月
• Glucokinase is required for high-starch diet-induced β-cell mass expansion in mice.

  Kazuhisa Tsuchida, Akinobu Nakamura, Hideaki Miyoshi, Kelaier Yang, Yuki Yamauchi, Shinichiro Kawata, Kazuno Omori, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yusuke Seino, Yasuo Terauchi, Tatsuya Atsumi

  Journal of diabetes investigation 12 9 1545 - 1554 2021年09月 

  AIMS/INTRODUCTION: We aimed to determine whether glucokinase is required for β-cell mass expansion induced by high-starch diet (HSTD)-feeding, as has been shown in its high-fat diet-induced expansion. MATERIALS AND METHODS: Eight-week-old male wild-type (Gck+/+ ) or glucokinase haploinsufficient (Gck+/- ) mice were fed either a normal chow (NC) or an HSTD for 15 weeks. The bodyweight, glucose tolerance, insulin sensitivity, insulin secretion and β-cell mass were assessed. RESULTS: Both HSTD-fed Gck+/+ and Gck+/- mice had significantly higher bodyweight than NC-fed mice. Insulin and oral glucose tolerance tests revealed that HSTD feeding did not affect insulin sensitivity nor glucose tolerance in either the Gck+/+ or Gck+/- mice. However, during the oral glucose tolerance test, the 15-min plasma insulin concentration after glucose loading was significantly higher in the HSTD group than that in the NC group for Gck+/+ , but not for Gck+/- mice. β-Cell mass was significantly larger in HSTD-fed Gck+/+ mice than that in NC-fed Gck+/+ mice. In contrast, the β-cell mass of the HSTD-fed Gck+/- mice was not different from that of the NC-fed Gck+/- mice. CONCLUSIONS: The results showed that HSTD feeding would increase pancreatic β-cell mass and insulin secretion in Gck+/+ , but not Gck+/- mice. This observation implies that glucokinase in β-cells would be required for the increase in β-cell mass induced by HSTD feeding.
• von Willebrand病の診療ガイドライン 2021年版

  日笠 聡, 渥美 達也, 石黒 精, 金子 誠, 高橋 芳右, 野上 恵嗣, 藤井 輝久, 堀内 久徳, 松井 太衛, 毛利 博, 森下 英理子, 松下 正, 朝比奈 俊彦, 天野 景裕, 上田 恭典, 岡本 好司, 小亀 浩市, 佐道 俊幸, 瀧 正志, 長尾 梓, 西尾 健治, 西田 恭治, 西野 正人, 藤村 吉博, 松本 雅則, 宮川 義隆, 八木 秀男, 和田 英夫, von Willebrand病の診療ガイドライン作成委員会

  日本血栓止血学会誌 32 4 413 - 481 (一社)日本血栓止血学会 2021年08月
• Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor

  Chiho Oba-Yamamoto, Hiraku Kameda, Hideaki Miyoshi, Tomonori Sekizaki, Takahiro Takase, Tsuyoshi Yanagimachi, Yukihiro Fujita, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, So Nagai, Tatsuya Atsumi

  Internal Medicine 60 15 2375 - 2383 2021年08月01日
• Sjögren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development.

  Shuhei Shimoyama, Ikuma Nakagawa, Jing-Jing Jiang, Isao Matsumoto, John A Chiorini, Yoshinori Hasegawa, Osamu Ohara, Rie Hasebe, Mitsutoshi Ota, Mona Uchida, Daisuke Kamimura, Shintaro Hojyo, Yuki Tanaka, Tatsuya Atsumi, Masaaki Murakami

  International immunology 33 8 423 - 434 2021年07月23日 

  Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.
• Dipeptidyl peptidase-4 inhibitor might exacerbate Graves' disease: A multicenter observational case-control study.

  Tomonori Sekizaki, Hiraku Kameda, Hiroshi Nomoto, Kyu Yong Cho, Akinobu Nakamura, Kiyohiko Takahashi, Arina Miyoshi, Norio Wada, Jun Takeuchi, So Nagai, Hideaki Miyoshi, Tatsuya Atsumi

  Journal of diabetes investigation 12 11 1978 - 1982 2021年05月17日 

  Dipeptidyl peptidase-4 (DPP-4), namely CD26, is expressed on the surface of immune cells, suggesting that inhibition of DPP-4 might affect the immune system. The current multicenter observational case-control study was carried out to investigate the effects of DPP-4 inhibitor (DPP-4i) administration on Graves' disease (GD) activity. This study comprised patients with GD and type 2 diabetes, who were administered an oral hypoglycemic agent including DPP-4i. Exacerbation of GD was defined as an increase of antithyroid drug dose by 6 months after oral hypoglycemic agent administration. A total of 80 patients were enrolled and divided into an exacerbation group or a non-exacerbation group. The frequency of DPP-4i administration was significantly higher in the exacerbation group (88%) than that in the non-exacerbation group (31%). In multivariate logistic regression analysis, there was a significant association between DPP-4i administration and GD exacerbation (odds ratio 7.39). The current study suggests that DPP-4i administration is associated with GD exacerbation.
• The assessment of left heart disease in patients with systemic sclerosis and pulmonary hypertension.

  Keita Ninagawa, Masaru Kato, Hiroshi Ohira, Satonori Tsuneta, Hiroyuki Iwano, Michihito Kono, Yuichiro Fujieda, Kenji Oku, Ichizo Tsujino, Tatsuya Atsumi

  Clinical and experimental rheumatology 2021年05月12日 

  OBJECTIVES: Systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) is of clinical significance owing to its poor outcome. One of the explanations for the outcome is the co-presence of left heart disease (LHD). The aim of this study is to assess LHD phenotype in patients with SSc and pulmonary hypertension (PH). METHODS: This study included consecutive patients with SSc who underwent right heart catheterisation to diagnose PAH. Heart failure with preserved ejection fraction (HFpEF) was evaluated according to the recommendation of 6th WSPH and to the Framingham criteria. RESULTS: In total, 76 patients were enrolled in this study. Of them, 42 had PH (mPAP >20 mmHg) with a normal left ventricle ejection fraction (≥50%). Among the 42 patients, four and three patients were classified "HFpEF not excluded" and "HFpEF confirmed" whereas 10 had a clinical diagnosis of HFpEF according to 6th WSPH and Framingham criteria, respectively. These differences were due mainly to relatively low PAWP (<13 mmHg). By a combination of ROC curve and logistic regression analyses, left atrial dimension and left ventricular end-diastolic volume index assessed with echocardiography and cardiac MRI, respectively, had significantly higher predictive values for detecting the complication of HFpEF rather than PAWP. CONCLUSIONS: Morphological evaluation using echocardiography and cardiac MRI, compared with haemodynamic evaluation by PAWP, may better reflect the copresence of LHD phenotype in patients with SSc and PH. Our data would also indicate a limited elevation of PAWP in patients with SSc, PH and HFpEF.
• Favorable Effects of Burosumab on Fibroblast Growth Factor 23-Related Osteomalacia: A Case Report

  Yuki Oe, Hiraku Kameda, Hiroshi Nomoto, Keita Sakamoto, Takeshi Soyama, Kyu Yong Cho, Akinobu Nakamura, Daisuke Abo, Kohsuke Kudo, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of the Endocrine Society 5 Supplement_1 A194 - A194 2021年05月03日 

  Background: Fibroblast growth factor 23 (FGF23) decreases serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D level, thereby regulating phosphate metabolism. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by FGF23 overproduction by tumor tissue. Resecting the responsible tumor is a radical treatment for TIO. When the responsible tumor is undetectable, phosphate and active vitamin D administration is recommended. However, supplementation alone is frequently insufficient to maintain phosphate levels and it is difficult to prevent the complications associated with medical therapy, including hypercalciuria and nephrocalcinosis. Recently, burosumab, a human monoclonal anti-FGF23 antibody, has been approved in Japan as a therapeutic agent for FGF23-related hypophosphatemia. Here, we present a patient with TIO effectively treated with burosumab in the absence of identification of tumour location. Clinical case: A 47-year-old female developed pain and edema of the feet; however, the cause could not be determined at local hospitals. Afterwards, she developed marked bone atrophy in the feet and was referred to our hospital. Her age at symptom onset, hypophosphatemia (serum P, 1.9 mg/dl, 2.7 mg/dl &lt; n &lt; 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml &lt; n &lt; 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml &lt; n &lt; 60 pg/ml) indicated FGF23-related osteomalacia. She was not having any medication at the time of diagnosis, including saccharified iron oxide or iron polymaltose. Urinary phosphate excretion increased without renal tubular defect; therefore, hypophosphatemic osteomalacia was diagnosed. MRI showed high signal intensity in the talus, sacral, and L5 vertebral regions, indicating multiple pseudofractures. Comprehensive imaging studies, including systemic CT scan and 111In-pentetreotide scintigraphy, did not reveal any tumors despite the suspicion of TIO. Next, we performed systemic venous sampling, which revealed high FGF23 level in the left external iliac vein. Second venous sampling limited to the left lower limb exhibited high FGF23 level in the posterior tibial vein. However, an additional imaging study limited to the left foot could not identify any tumors. Genetic variation was negative for potentially responsible genes, including PHEX and FGF23. We decided to administer burosumab to normalize serum phosphate level without phosphate supplementation. Within 2 months, pain was relieved and the visual analog scale scores also improved from 10 to 6. Moreover, bone MRI showed improved pseudofractures. Conclusion: Burosumab administration was effective for TIO of unknown origin, and it improved not only laboratory findings but also clinical symptoms in this case.
• 膵特異的グルコキナーゼの抑制が2型糖尿病病態下の膵β細胞量を保持する

  大森 一乃, 中村 昭伸, 三好 秀明, 川田 晋一朗, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也

  糖尿病 64 Suppl.1 I - 3 (一社)日本糖尿病学会 2021年05月
• 肥満外科治療は糖尿病治療薬の減量・中止および2型糖尿病寛解の期待ができる

  千葉 幸輝, 大江 悠希, 高瀬 崇宏, 曹 圭龍, 野本 博司, 亀田 啓, 中村 昭伸, 渥美 達也, 三好 秀明

  糖尿病 64 Suppl.1 I - 3 (一社)日本糖尿病学会 2021年05月
• 糖代謝障害を伴った高度肥満症患者における腹腔鏡下スリーブ状胃切除術による糖・脂質代謝および肝臓への好影響

  安井 彩乃, 曹 圭龍, 大江 悠希, 野本 博司, 亀田 啓, 中村 昭伸, 海老原 裕磨, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 64 Suppl.1 I - 4 (一社)日本糖尿病学会 2021年05月
• リラグルチドおよびデュラグルチドからセマグルチド切り替えによる血糖コントロール及びQOLへの影響 SWITCH-SEMA1プロトコール

  高橋 由華, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 竹内 淳, 永井 聡, 種田 紳二, 横山 宏樹, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 64 Suppl.1 I - 2 (一社)日本糖尿病学会 2021年05月
• 2型糖尿病または耐糖能異常合併高血圧患者におけるエサキセレノンの効果

  桑原 咲, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 山本 浩平, 種田 紳二, 三次 有奈, 和田 典男, 小梁川 直秀, 竹内 淳, 永井 聡, 栗原 義夫, 三好 秀明, 渥美 達也

  糖尿病 64 Suppl.1 II - 3 (一社)日本糖尿病学会 2021年05月
• DPP-4阻害薬からSGLT2阻害薬への切替は、高血圧症を合併する2型糖尿病患者の夜間血圧・脈拍を低下させる

  亀田 玲奈, 曹 圭龍, 川田 晋一朗, 大森 一乃, 野本 博司, 亀田 啓, 竹内 淳, 永井 聡, 中村 昭伸, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 64 Suppl.1 III - 2 (一社)日本糖尿病学会 2021年05月
• 空腹時内因性インスリン分泌は不安定な血糖変動・低血糖の予測に役立つだけでなく血糖降下薬の選択においても有用である

  宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 永井 聡, 伊藤 陽一, 渥美 達也, 三好 秀明

  糖尿病 64 Suppl.1 III - 4 (一社)日本糖尿病学会 2021年05月
• インスリンデグルデクとDPP-4阻害薬の併用からデグルデク/リラグルチド配合注への切り替えは血糖変動を改善する

  大江 悠希, 野本 博司, 中村 昭伸, 桑原 咲, 高橋 由華, 安井 彩乃, 亀田 啓, 曹 圭龍, 渥美 達也, 三好 秀明

  糖尿病 64 Suppl.1 III - 3 (一社)日本糖尿病学会 2021年05月
• 耐糖能異常合併肥満症患者における腹腔鏡下スリーブ状胃切除後の骨密度低下

  上垣 里紗, 大江 悠希, 亀田 啓, 高瀬 崇宏, 野本 博司, 曹 圭龍, 中村 昭伸, 平野 聡, 渥美 達也, 三好 秀明

  糖尿病 64 Suppl.1 P - 6 (一社)日本糖尿病学会 2021年05月
• db/dbマウスを用いたグルコキナーゼ活性化薬の血糖降下作用消失機序の解明

  川田 晋一朗, 中村 昭伸, 三好 秀明, 重沢 郁美, 山内 裕貴, 土田 和久, 大森 一乃, 高橋 清彦, 北尾 直之, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也

  糖尿病 64 Suppl.1 P - 1 (一社)日本糖尿病学会 2021年05月
• 胸部CTでの定量的手法による1群又は3群強皮症性肺高血圧症の評価

  蜷川 慶太, 加藤 将, 河野 通仁, 藤枝 雄一郎, 大平 洋, 奥 健志, 杉森 博行, 辻野 一三, 渥美 達也

  日本肺高血圧・肺循環学会学術集会・日本小児肺循環研究会プログラム・抄録集 6回・27回 41 - 41 日本肺高血圧・肺循環学会・日本小児肺循環研究会 2021年05月
• SGLT2阻害薬はミトコンドリア機能の改善を介し膵β細胞を保護する

  山内 裕貴, 中村 昭伸, 横田 卓, 高橋 清彦, 川田 晋一朗, 土田 和久, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 安斉 俊久, 田中 伸哉, 寺内 康夫, 三好 秀明, 渥美 達也

  糖尿病 64 Suppl.1 III - 6 (一社)日本糖尿病学会 2021年05月
• [Neurological Manifestations in Antiphospholipid Syndrome].

  Nobuya Abe, Tatsuya Atsumi

  Brain and nerve = Shinkei kenkyu no shinpo 73 5 526 - 536 2021年05月 

  Antiphospholipid syndrome (APS) is an autoimmune disease characterized by persistent presence of positive antiphospholipid antibodies (aPLs). Historically, aPLs first attracted attention at the beginning of the 1970s, as a risk factor for the development of myelitis via cross-reaction with cephalin and sphingomyelin as neuronal tissue-enriched phospholipids. Primary APS manifestations include arteriovenous thrombosis and pregnancy complications; however, in rare cases, aPL-related neurological disorders including cognitive dysfunction, chorea, and transverse myelitis are observed." The pathogenesis and therapeutic strategies for thrombosis, including cerebral infarction in APS, have been established from basic and clinical research to date. However, pathological insights and clinical perspectives have not yet been well-defined for aPL-related cognitive dysfunction, chorea, and myelitis. Based on past experiences and findings of small observational studies, some patients with aPL-related neurological disorders recover following antiplatelet and anticoagulation therapy, but in some cases, multidisciplinary treatments with glucocorticoids and/or immunosuppressive agents, including cyclophosphamide, azathioprine, mycophenolate and rituximab, plasmapheresis, and psychoeducational support are required. A detailed research on pathophysiology and nationwide or international multicenter clinical trials for therapeutic strategies are vital for establishing sufficient basic and clinical understanding of aPL-related neurological manifestations.
• Efficacy and safety of sodium RISedronate for glucocorticoid-induced OsTeoporosis with rheumaTOid arthritis (RISOTTO study): A multicentre, double-blind, randomized, placebo-controlled trial.

  Yuichiro Fujieda, Tetsuya Horita, Naoki Nishimoto, Kazuhide Tanimura, Yoshiharu Amasaki, Hideki Kasahara, Shin Furukawa, Tsuyoshi Takeda, Shinji Fukaya, Kazuo Matsui, Akito Tsutsumi, Akira Furusaki, Akira Sagawa, Kou Katayama, Kaoru Takeuchi, Kazuaki Katsumata, Takashi Kurita, Peter Shane, Masaru Kato, Kenji Oku, Shinsuke Yasuda, Masahiko Takahata, Norimasa Iwasaki, Tatsuya Atsumi

  Modern rheumatology 31 3 593 - 599 2021年05月 

  OBJECTIVE: No evidence has shown the efficacy of Sodium Risedronate (Risedronate) for glucocorticoid-induced osteoporosis (GIO) in patients with Rheumatoid arthritis (RA). The aim of this study was to explore the effectiveness and safety of Risedronate for GIO complicated with RA. METHODS: This was a six-month randomized, double-blind, placebo-controlled trial of 95 patients with GIO complicated with RA from 19 centers. The primary endpoint was the change from baseline in lumbar spine bone mineral density (L-BMD). Secondary endpoints included changes in femoral neck and total hip BMD and bone turnover markers, as well as rheumatoid arthritis Disease Activity Score with 28-joint counts. Incident of non-traumatic spine fractures and adverse events were tracked as safety endpoints. RESULTS: Increase in L-BMD was significantly greater in the Risedronate group compared to the Placebo group (Risedronate: 3.49% [95% CI: 1.92-5.05] vs Placebo: 0.12% [95% CI: -2.07 to 2.30], p < .0001). No significant difference was found in the femoral neck and total hip BMD. Although adverse events were observed in 28 patients, none were considered serious. Non-traumatic vertebral fractures were identified in 10 patients. CONCLUSION: Risedronate was effective in increasing L-BMD and was well tolerated in patients with GIO complicated with RA.
• Log-linear relationship between endogenous insulin secretion and glycemic variability in patients with type 2 diabetes on continuous glucose monitoring.

  Aika Miya, Akinobu Nakamura, Takahisa Handa, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Yoichi M Ito, Hideaki Miyoshi, Tatsuya Atsumi

  Scientific reports 11 1 9057 - 9057 2021年04月27日 

  The contribution of endogenous insulin secretion to glycemic variability (GV) may differ between patients with impaired insulin secretion and those with preserved secretion. Our objective was to determine the linearity of the relationship between fasting C-peptide (CPR) as a marker of endogenous insulin secretion and GV in type 2 diabetes (T2DM), regardless of the type of antidiabetic treatment. We conducted a prospective observational study using continuous glucose monitoring obtained from 284 Japanese outpatients with T2DM with various HbA1c values and antidiabetic treatment. We constructed a prediction curve of base-line CPR versus coefficient of variation (CV) and identified the clinical factors associated with CV using multiple regression analysis. Fasting CPR showed a significant negative log-linear relationship with CV (P < 0.0001), and the latter being strikingly high in the low-CPR group. The multiple regression analysis showed that low CPR was an independent predictor of high CV (P < 0.0001). The significant correlations were sustained in both patients with/without insulin treatment. The contribution of endogenous insulin secretion to GV depends on the extent of insulin secretion impairment. Fasting CPR may represent a useful indicator of GV instability in T2DM.
• Severe infection including disseminated herpes zoster triggered by subclinical Cushing's disease: a case report.

  Yuki Yamauchi, Hiraku Kameda, Kazuno Omori, Michio Tani, Kyu Yong Cho, Akinobu Nakamura, Hideaki Miyoshi, Shinya Tanaka, Tatsuya Atsumi

  BMC endocrine disorders 21 1 84 - 84 2021年04月27日 

  BACKGROUND: Subclinical Cushing's disease (SCD) is defined by corticotroph adenoma-induced mild hypercortisolism without typical physical features of Cushing's disease. Infection is an important complication associated with mortality in Cushing's disease, while no reports on infection in SCD are available. To make clinicians aware of the risk of infection in SCD, we report a case of SCD with disseminated herpes zoster (DHZ) with the mortal outcome. CASE PRESENTATION: An 83-year-old Japanese woman was diagnosed with SCD, treated with cabergoline in the outpatient. She was hospitalized for acute pyelonephritis, and her fever gradually resolved with antibiotics. However, herpes zoster appeared on her chest, and the eruptions rapidly spread over the body. She suddenly went into cardiopulmonary arrest and died. Autopsy demonstrated adrenocorticotropic hormone-positive pituitary adenoma, renal abscess, and DHZ. CONCLUSIONS: As immunosuppression caused by SCD may be one of the triggers of severe infection, the patients with SCD should be assessed not only for the metabolic but also for the immunodeficient status.
• 高コルチゾール血症を呈したFamilial Dysalbuminemic Hyperthyroxinemiaの一例

  千葉 幸輝, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 1 225 - 225 (一社)日本内分泌学会 2021年04月
• 1型糖尿病の残存膵β細胞ではHIF1α/PFKFB3経路が活性化し解糖系が亢進する

  野本 博司, Tudzarova Slavica, Pei Lina, Montemurro Chiara, Gurlo Tatyana, Butler Peter C., 中村 昭伸, 渥美 達也

  日本内分泌学会雑誌 97 1 225 - 225 (一社)日本内分泌学会 2021年04月
• ニューロメジンB受容体はACTH産生下垂体腺腫の治療ターゲットとなりうる

  関崎 知紀, 亀田 啓, 中村 昭伸, 野本 博司, 曹 圭龍, 伊師 雪友, 茂木 洋晃, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 97 1 261 - 261 (一社)日本内分泌学会 2021年04月
• グルコキナーゼの抑制が2型糖尿病病態下の膵β細胞量に与える影響

  大森 一乃, 中村 昭伸, 三好 秀明, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也

  日本内分泌学会雑誌 97 1 275 - 275 (一社)日本内分泌学会 2021年04月
• COVID-19肺炎を合併し、ブロック&リプレースにより高コルチゾール血症のコントロールを行った活動性クッシング病の1例

  湯野 暁子, 高橋 由華, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 山下 優, 中久保 祥, 鎌田 啓佑, 鈴木 雅, 井下 尚子, 今野 哲, 三好 秀明, 渥美 達也, 澤村 豊, 島津 章

  日本内分泌学会雑誌 97 1 260 - 260 (一社)日本内分泌学会 2021年04月
• Combination of alcohol and glucose consumption as a risk to induce reactive hypoglycemia.

  Chiho Oba-Yamamoto, Jun Takeuchi, Akinobu Nakamura, Ryoko Takikawa, Ayano Ozaki, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of diabetes investigation 12 4 651 - 657 2021年04月 

  AIMS/INTRODUCTION: Alcohol consumption has been reported to cause hypoglycemia. However, the mechanism involved has not been unequivocally established. This study comprised healthy volunteers. We carried out a prospective trial to compare the effects of glucose and alcohol consumption, alone or in combination, on glucose and lipid metabolism. MATERIALS AND METHODS: A 75-g oral glucose tolerance test (OGTT), a combined 75-g glucose plus 20-g alcohol tolerance test (OGATT) and a 20-g alcohol tolerance test (OATT) were carried out in the participants. Plasma glucose, insulin, triglyceride and ethanol concentrations during each test were compared. RESULTS: We studied 10 participants. Their plasma glucose concentrations 15 and 30 min after the intake of 75 g of glucose were significantly higher during the OGATT than the OGTT. Hypoglycemia occurred in five participants after the OGATT, which was significantly more frequently than after the OGTT (P = 0.046). Hypoglycemia did not occur after the OATT, and the ethanol concentration was significantly lower after the OGATT than the OATT. The changes in triglyceride concentration from 30 min after the consumption of 75 g of glucose were significantly greater during the OGATT than the OGTT. The plasma insulin concentrations peaked after 60 min during both the OGTT and OGATT, and were significantly higher during the OGATT (P = 0.047). There were no differences between the two interventions in the Matsuda or disposition indexes. CONCLUSIONS: Hypoglycemia occurred more frequently after the simultaneous consumption of alcohol plus glucose than after the consumption of glucose alone, suggesting that alcohol in the combination of glucose induces reactive hypoglycemia.
• Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family

  Masaru Kato, Toshimi Michigami, Kanako Tachikawa, Momoko Kato, Ichiro Yabe, Tomohiro Shimizu, Takuya Asaka, Yoshimasa Kitagawa, Tatsuya Atsumi

  JOURNAL OF BONE AND MINERAL METABOLISM 2021年04月 

  Introduction Hypophosphatasia (HPP) is caused by mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase (TNSALP) and inherited in either an autosomal recessive or autosomal dominant manner. It is characterized clinically by defective mineralization of bone, dental problems, and low serum ALP levels. In the current report, we demonstrate a novel mutation in the ALPL gene (c.244G > A p.Gly82Arg) in a Japanese family with low serum ALP levels. Materials and methods The ALPL gene analysis using hybridization capture-based next-generation sequencing was performed. The expression plasmids of the wild type and mutated TNSALP were introduced into COS-7 cells. The enzymatic activity of ALP in the cell lysates was measured using p-nitrophenylphosphate as a substrate. Results TNSALP with the novel ALPL mutation (c.244G > A p.Gly82Arg) completely lost its enzymatic activity and suppressed that of wild-type TNSALP, corroborating its dominant negative effect. The diagnosis of autosomal dominant HPP was confirmed in three members of the family. Conclusion Our approach would help to avoid the inappropriate use of bone resorption inhibitors for currently mis- or under-diagnosed HPP, given that the presence of further, yet undetected mutations of the ALPL gene are plausible.
• The association between hypoglycemia and glycemic variability in elderly patients with type 2 diabetes: a prospective observational study.

  Takahisa Handa, Akinobu Nakamura, Aika Miya, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Narihito Yoshioka, Hideaki Miyoshi, Tatsuya Atsumi

  Diabetology & metabolic syndrome 13 1 37 - 37 2021年04月01日 

  BACKGROUND: This study aimed to explore predictive factors of time below target glucose range (TBR) ≥ 1% among patients' characteristics and glycemic variability (GV) indices using continuous glucose monitoring data in elderly patients with type 2 diabetes. METHODS: We conducted a prospective observational study on 179 (71 female) Japanese outpatients with type 2 diabetes aged ≥ 65 years. The characteristics of the participants with TBR ≥ 1% were evaluated by multivariate logistic regression analysis. Receiver-operating characteristic (ROC) curve analyses of GV indices, comprising coefficient of variation (CV), standard deviation, and mean amplitude of glycemic excursions, were performed to identify the optimal index for the identification of patients with TBR ≥ 1%. RESULTS: In the multivariate logistic regression analysis, none of the clinical characteristics, including HbA1c and C-peptide index, were independent markers for TBR ≥ 1%, while all three GV indices showed significant associations with TBR ≥ 1%. Among the three GV indices, CV showed the best performance based on the area under the curve in the ROC curve analyses. CONCLUSIONS: Among elderly patients with type 2 diabetes, CV reflected TBR ≥ 1% most appropriately among the GV indices examined. Trial registration UMIN-CTR: UMIN000029993. Registered 16 November 2017.
• The association between SLC16A11 haplotype and lipid metabolism in Japanese patients with type 2 diabetes.

  Yuki Kimura, Issei Higuchi, Masaki Kobayashi, Ayako Furugen, Katsuya Narumi, Yuya Suzuki, Hideaki Miyoshi, Akinobu Nakamura, Tatsuya Atsumi, Ken Iseki

  Drug metabolism and pharmacokinetics 37 100376 - 100376 2021年04月 

  Solute carrier (SLC) 16A11 has been reported as a risk gene for type 2 diabetes (T2D). However, the physiological function of SLC16A11 has not yet been clarified, and the relationship between SLC16A11 and T2D condition remains unclear. Therefore, we performed an association analysis between the SLC16A11 genotype and T2D pathology. The SLC16A11 genotype was determined by direct sequencing in 85 Japanese patients with T2D. The genotypes were analyzed by Mann-Whitney's U test and Chi-square test. Six single nucleotide polymorphisms (SNPs) were detected in the SLC16A11 gene, and five of them formed a haplotype (5SNP haplotype). The 5SNP haplotype carriers had significantly higher fasting plasma glucose (FPG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C) than the noncarriers. The SLC16A11 genotype affected the values of laboratory parameters for T2D, particularly of blood lipids. The function of SLC16A11 may be related to lipid metabolism.
• Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in db/db Mice.

  Kazuno Omori, Akinobu Nakamura, Hideaki Miyoshi, Yuki Yamauchi, Shinichiro Kawata, Kiyohiko Takahashi, Naoyuki Kitao, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi

  Diabetes 70 4 917 - 931 2021年04月 

  Efficacy of glucokinase activation on glycemic control is limited to a short-term period. One reason might be related to excess glucose signaling by glucokinase activation toward β-cells. In this study, we investigated the effect of glucokinase haploinsufficiency on glucose tolerance as well as β-cell function and mass using a mouse model of type 2 diabetes. Our results showed that in db/db mice with glucokinase haploinsufficiency, glucose tolerance was ameliorated by augmented insulin secretion associated with the increase in β-cell mass when compared with db/db mice. Gene expression profiling and immunohistochemical and metabolomic analyses revealed that glucokinase haploinsufficiency in the islets of db/db mice was associated with lower expression of stress-related genes, greater expression of transcription factors involved in the maintenance and maturation of β-cell function, less mitochondrial damage, and a superior metabolic pattern. These effects of glucokinase haploinsufficiency could preserve β-cell mass under diabetic conditions. These findings verified our hypothesis that optimizing excess glucose signaling in β-cells by inhibiting glucokinase could prevent β-cell insufficiency, leading to improving glucose tolerance in diabetes status by preserving β-cell mass. Therefore, glucokinase inactivation in β-cells, paradoxically, could be a potential strategy for the treatment of type 2 diabetes.
• Exploratory classification of clinical phenotypes in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis using cluster analysis.

  Haruki Watanabe, Ken-Ei Sada, Masayoshi Harigai, Koichi Amano, Hiroaki Dobashi, Yoshinari Takasaki, Shouichi Fujimoto, Tatsuya Atsumi, Kunihiro Yamagata, Sakae Homma, Yoshihiro Arimura, Hirofumi Makino

  Scientific reports 11 1 5223 - 5223 2021年03月04日 

  A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n = 8) and proteinase 3-ANCA-positive (n = 41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n = 47); cutaneous (n = 36); renal (n = 256), non-renal (n = 33); and both ENT and cutaneous symptoms (n = 6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n = 42), without s-Cr elevation (< 1.3 mg/dL) (n = 157), s-Cr elevation (≥ 1.3 mg/dL) with high CRP (> 10 mg/dL) (n = 71), or s-Cr elevation (≥ 1.3 mg/dL) without high CRP (≤ 10 mg/dL) (n = 157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.
• Lysosome-associated membrane protein 3 misexpression in salivary glands induces a Sjögren’s syndrome-like phenotype in mice

  Hiroyuki Nakamura, Tsutomu Tanaka, Thomas Pranzatelli, Youngmi Ji, Hongen Yin, Paola Perez, Sandra A Afione, Shyh-Ing Jang, Corrine Goldsmith, Chang Yu Zheng, William D Swaim, Blake M Warner, Noriyuki Hirata, Masayuki Noguchi, Tatsuya Atsumi, John A Chiorini

  Annals of the Rheumatic Diseases annrheumdis - 2020 2021年03月03日 

  Sjögren’s syndrome (SS) is an autoimmune sialadenitis with unknown aetiology. Although extensive research implicated an abnormal immune response associated with lymphocytes, an initiating event mediated by salivary gland epithelial cell (SGEC) abnormalities causing activation is poorly characterised. Transcriptome studies have suggested alternations in lysosomal function are associated with SS, but a cause and effect linkage has not been established. In this study, we demonstrated that altered lysosome activity in SGECs by expression of lysosome-associated membrane protein 3 (LAMP3) can initiate an autoimmune response with autoantibody production and salivary dysfunction similar to SS. Retroductal cannulation of the submandibular salivary glands with an adeno-associated virus serotype 2 vector encoding LAMP3 was used to establish a model system. Pilocarpine-stimulated salivary flow and the presence of autoantibodies were assessed at several time points post-cannulation. Salivary glands from the mice were evaluated using RNAseq and histologically. Following LAMP3 expression, saliva flow was significantly decreased and serum anti-Ro/SSA and La/SSB antibodies could be detected in the treated mice. Mechanistically, LAMP3 expression increased apoptosis in SGECs and decreased protein expression related to saliva secretion. Analysis of RNAseq data suggested altered lysosomal function in the transduced SGECs, and that the cellular changes can chemoattract immune cells into the salivary glands. Immune cells were activated via toll-like receptors by damage-associated molecular patterns released from LAMP3-expressing SGECs. These results show a critical role for lysosomal trafficking in the development of SS and establish a causal relationship between LAMP3 misexpression and the development of SS.
• JAK阻害剤-1:バリシチニブ 関節リウマチ患者に対するバリシチニブの安全性 特定使用成績調査(製造販売後全例調査)からの中間報告(2020年度)

  藤井 隆夫, 渥美 達也, 岡本 奈美, 高橋 伸典, 田村 直人, 中島 敦夫, 中島 亜矢子, 松野 博明, 辻本 直人, 西川 厚嗣, 石井 泰子, 竹内 勤, 桑名 正隆, 高木 理彰

  日本リウマチ学会総会・学術集会プログラム・抄録集 65回 344 - 344 (一社)日本リウマチ学会 2021年03月
• 中小型血管炎:ANCA関連血管炎(生物学的製剤) 好酸球性多発血管炎性肉芽腫症を対象としたメポリズマブ製造販売後調査の中間集計結果

  渥美 達也, 岡本 奈美, 高橋 伸典, 田村 直人, 中島 敦夫, 中島 亜矢子, 藤井 隆夫, 松野 博明, 向井 功, 石田 篤子, 那知 新也, 桑名 正隆, 高木 理彰, 竹内 勤

  日本リウマチ学会総会・学術集会プログラム・抄録集 65回 412 - 412 (一社)日本リウマチ学会 2021年03月
• ベーチェット病 Behcet病疾患レジストリ研究により明らかとなった疾患活動性残存の現状

  平原 理紗, 桐野 洋平, 副島 裕太郎, 岳野 光洋, 吉見 竜介, 藤枝 雄一郎, 渥美 達也, 東野 俊洋, 廣畑 俊成, 小林 大介, 中島 秀明

  日本リウマチ学会総会・学術集会プログラム・抄録集 65回 424 - 424 (一社)日本リウマチ学会 2021年03月
• 抗リン脂質抗体測定試薬「ステイシアMEBLuxテストβ2GPI」および「MESACUP-2テスト カルジオリピン」の基礎的性能および臨床的有用性の検討

  小川 昌起, 甲斐 宏一, 黒田 慶子, 奥 健志, 村島 温子, 田村 直人, 森下 英理子, 家子 正裕, 渥美 達也

  医学と薬学 78 4 447 - 459 (株)自然科学社 2021年03月 

  抗リン脂質抗体測定試薬「ステイシアMEBLuxテストβ2GPI」および「MESACUP-2テストカルジオリピン」の基礎的性能を評価し、臨床的有用性について検討した。臨床検体として、抗リン脂質抗体症候群(APS)患者61例、APSを合併していない全身性エリテマトーデス(SLE)患者26例、APSおよびSLE以外の自己免疫疾患患者69例の計156例を用いた。濃度の異なる血清4例を検体希釈液で10段階希釈し測定を行ったところ、各項目ともに測定上限値まで希釈直線性が得られた。本試薬の測定範囲はステイシアβ2GPI IgG:0.7〜150.0U/mL、ステイシアβ2GPI IgM:0.4〜300.0U/mL、MESACUP-2 CL IgG:4.0〜120.0U/mL、MESACUP-2 CL IgM:2.5〜80.0U/mLと設定され、濃度の異なる血清3例を各6重測定した時の同時再現性(CV%)はいずれも10%以内であった。また、臨床検体を測定した。その結果、MESACUP-2 CL IgG、IgMでは69%の感度であり、ステイシアβ2GPI IgG、IgMを加えて診断することで感度は77%へ上昇することが示された。
• 抗リン脂質抗体測定試薬「ステイシアMEBLuxテストβ2GPI」および「MESACUP-2テスト カルジオリピン」の基礎的性能および臨床的有用性の検討

  小川 昌起, 甲斐 宏一, 黒田 慶子, 奥 健志, 村島 温子, 田村 直人, 森下 英理子, 家子 正裕, 渥美 達也

  医学と薬学 78 4 447 - 459 (株)自然科学社 2021年03月
• Effects of Switching from Liraglutide or Dulaglutide to Subcutaneous Semaglutide on Glucose Metabolism and Treatment Satisfaction in Patients with Type 2 Diabetes: Protocol for a Multicenter, Prospective, Randomized, Open-Label, Blinded-Endpoint, Parallel-Group Comparison Study (The SWITCH-SEMA 1 Study).

  Hiroshi Nomoto, Chiho Oba-Yamamoto, Yuka Takahashi, Jun Takeuchi, So Nagai, Hiroki Yokoyama, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Tatsuya Atsumi, Hideaki Miyoshi

  Diabetes therapy : research, treatment and education of diabetes and related disorders 12 3 955 - 964 2021年03月 

  INTRODUCTION: Glucagon-like peptide (GLP)-1 receptor agonists exert potent hypoglycemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent manner. Once-weekly subcutaneous administration of the GLP-1 receptor agonist semaglutide has beneficial effects on glycemic and body weight control, but it is currently unclear if semaglutide provides superior glycemic control compared to conventional GLP-1 receptor agonists in the Japanese population. We aim to compare the effects of once-weekly subcutaneous semaglutide with those of liraglutide or dulaglutide administration in Japanese patients with T2D. METHODS: This study is a multicenter, prospective, randomized, open-label, blinded-endpoint, parallel-group trial. In total, 100 participants with T2D who have been treated with liraglutide (0.9-1.8 mg/day in plan A) or dulaglutide (0.75 mg/week in plan B) for more than 12 weeks and have a glycated hemoglobin (HbA1c) level of 6.0-9.9% and a body mass index (BMI) of ≥ 22 kg/m2 will be randomized to either continue using their existing GLP-1 receptor agonist or switch to subcutaneous semaglutide once weekly for 24 weeks. Biochemical analysis, physical assessment, and a quality-of-life questionnaire (DTSQ) will be completed at baseline and at the end of the study. The primary endpoint is the effect of semaglutide on the change in HbA1c. The secondary endpoints are the mean changes in total DTSQ score, body mass, abdominal circumference, systolic and diastolic blood pressure, pulse rate, factors associated with improvement in HbA1c and secondary endpoints, side effects, and other laboratory parameters. PLANNED OUTCOMES: The results of the study will provide useful information regarding the effects of switching to semaglutide from other GLP-1 receptor agonists on glycemic control in patients with T2D. ETHICS AND DISSEMINATION: The Hokkaido University Certified Review Board (CRB no. 1180001) has approved the protocol (no. 018-005). The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION: UMIN000042369 in the University Hospital Medical Information Network (UMIN); jRCT1011200008 in the Japan Registry of Clinical Trials (jRCT); pre-results.
• Vascular endothelial growth factor (VEGF)-A and VEGF-A165b are associated with time to remission of granulomatosis with polyangiitis in a nationwide Japanese prospective cohort study.

  Ryosuke Kikuchi, Naotake Tsuboi, Ken-Ei Sada, Masahiro Nakatochi, Yuki Yokoe, Atsuo Suzuki, Shoichi Maruyama, Toyoaki Murohara, Tadashi Matsushita, Koichi Amano, Tatsuya Atsumi, Yoshinari Takasaki, Satoshi Ito, Hitoshi Hasegawa, Hiroaki Dobashi, Takafumi Ito, Hirofumi Makino, Seiichi Matsuo

  Annals of clinical biochemistry 58 2 86 - 94 2021年03月 

  BACKGROUND: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A165b (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort. METHODS: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A165b concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA). RESULTS: Results revealed significant reductions in sVEGF-A and sVEGF-A165b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A165b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log2-transformed concentrations of sVEGF-A and sVEGF-A165b were inversely correlated with time to remission in granulomatosis with polyangiitis patients. CONCLUSION: These results suggest that sVEGF-A and -A165b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.
• Silent pituitary adenoma and metabolic disorders: obesity, abnormal glucose tolerance, hypertension and dyslipidemia.

  Natsuki Baba, Hiraku Kameda, Akinobu Nakamura, Kyu Yong Cho, Hiroshi Nomoto, Tomoko Mitsuhashi, Hideaki Miyoshi, Tatsuya Atsumi

  Endocrine journal 68 2 195 - 200 2021年02月28日 

  A silent pituitary adenoma (SPA) is characterized by the expression of pituitary hormones, detected by immunohistochemical staining, in the absence of clinical signs or symptoms of hormonal excess. Compared with functional pituitary adenomas, little is known regarding the involvement of SPAs in metabolic disorders. This study aimed to examine the correlations between SPAs and metabolic disorders, including obesity, abnormal glucose tolerance, hypertension and dyslipidemia. Seventy-four patients with nonfunctional pituitary adenomas who underwent a pituitary adenomectomy in Hokkaido University Hospital from 2008 to 2016 were retrospectively examined. Pituitary adenomas were immunohistochemically classified into pituitary hormone positive or negative groups. Twenty whole hormone-negative pituitary adenomas were excluded because we couldn't identify pituitary transcription factors which is necessary for the diagnosis of a null cell adenoma. The preoperative rates of obesity, abnormal glucose tolerance, hypertension and dyslipidemia were compared between each group. Twenty-seven GH positive adenomas (50.0%), 32 gonadotroph positive adenomas (59.3%), 28 TSH positive adenomas (51.9%) and 21 ACTH positive adenomas (38.9%) were identified. Evaluation of the preoperative clinical data showed 25 cases of obesity (46.2%), 16 cases of abnormal glucose tolerance (29.6%), 29 cases of hypertension (53.7%) and 35 cases of dyslipidemia (64.8%). The rate of hypertension was significantly lower in the GH positive group (37.0%) than the GH negative group (70.4%) (p = 0.0140). In the GH negative group, postoperative systolic and diastolic blood pressure levels were significantly lower than preoperative values. GH positive SPAs may affect the homeostasis of blood pressure.
• 血清サイトカイン・ケモカインのマルチプレックス解析を用いたTAFRO症候群における新規病態関連分子の検索

  垂水 政人, 阿部 靖矢, 河野 通仁, 藤枝 雄一郎, 加藤 将, 奥 健志, アメングアル・オルガ, 渥美 達也

  日本リウマチ学会北海道・東北支部学術集会抄録集 30回 58 - 58 (一社)日本リウマチ学会-北海道・東北支部 2021年02月
• Improved time in range and postprandial hyperglycemia with canagliflozin in combination with teneligliptin: Secondary analyses of the CALMER study

  Kyu Yong Cho, Hiroshi Nomoto, Akinobu Nakamura, Shinichiro Kawata, Hajime Sugawara, Jun Takeuchi, So Nagai, Kazuno Omori, Kazuhisa Tsuchida, Aika Miya, Ikumi Shigesawa, Kenichi Tsuchida, Shingo Yanagiya, Hiraku Kameda, Hiroki Yokoyama, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Naoki Nishimoto, Tatsuya Atsumi, Hideaki Miyoshi

  JOURNAL OF DIABETES INVESTIGATION 2021年02月 

  Aims/Introduction We recently reported the beneficial effect of the combination of sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor on daily glycemic variability in patients with type 2 diabetes mellitus. Additional favorable effects of combination therapy were explored in this secondary analysis.Materials and Methods The CALMER study was a multicenter, open-label, prospective, randomized, parallel-group comparison trial for type 2 diabetes mellitus involving continuous glucose monitoring under meal tolerance tests. Patients were randomly assigned to switch from teneligliptin to canagliflozin (SWITCH group) or to add canagliflozin to teneligliptin (COMB group). The continuous glucose monitoring metrics, including time in target range, were investigated.Results All 99 participants (mean age 62.3 years; mean glycated hemoglobin 7.4%) completed the trial. The time in target range was increased in the COMB group (71.2-82.7%, P < 0.001). The extent of the reduction in time above target range was significantly larger in the COMB group compared with the SWITCH group (-14.8% vs -7.5%, P < 0.01). Area under the curve values for glucose at 120 min after all meal tolerance tests were significantly decreased in the COMB group compared with the SWITCH group (P < 0.05).Conclusions Sodium-glucose cotransporter 2 inhibitor combined with dipeptidyl peptidase-4 inhibitor improved the quality of glycemic variability and reduced postprandial hyperglycemia compared with each monotherapy.
• Sodium-glucose cotransporter 2 inhibitors reduce day-to-day glucose variability in patients with type 1 diabetes.

  Koki Chiba, Hiroshi Nomoto, Akinobu Nakamura, Kyu Yong Cho, Kumiko Yamashita, Yui Shibayama, Aika Miya, Hiraku Kameda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of diabetes investigation 12 2 176 - 183 2021年02月 

  AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are used worldwide because of their multiple benefits for patients with type 2 diabetes. The purpose of this study was to determine the efficacy and safety of SGLT2i in patients with type 1 diabetes. MATERIALS AND METHODS: Patients with type 1 diabetes who had been treated with SGLT2i for >12 weeks were included in this retrospective observation study. We recorded the changes in body mass, insulin dose, blood and urine test data, and adverse events. The changes in day-to-day glucose variability, as the primary end-point, was evaluated using the interquartile range (P25/P75) of the ambulatory glucose data obtained using continuous glucose monitoring. RESULTS: A total of 51 patients (37 women; mean age 52.7 years) were included. Glycated hemoglobin and body mass significantly decreased by 0.4% and 1.6 kg, respectively. The total required insulin dose decreased by 9.4% (42.7 ± 26.6-38.7 ± 24.3 units/day). Continuous glucose monitoring data were obtained from 30 patients. P25/P75 decreased by 17.6 ± 20.7% during SGLT2i treatment (P < 0.001). The percentage of time per day within the target glucose range of 70-180 mg/dL significantly increased (from 42.2 to 55.5%, P < 0.001), without an increase in the percentage of time spent in the hypoglycemic range (<70 mg/dL). Urinary ketone bodies were detected in four patients (7.8%), but none developed ketoacidosis. CONCLUSIONS: SGLT2i improved day-to-day glucose variability and time in the target glucose range, without increasing frequency of hypoglycemia, in patients with type 1 diabetes, and reduced glycated hemoglobin, body mass and the required insulin dose.
• メドロキシプロゲステロンにより副腎皮質機能低下を呈した1例

  安井 彩乃, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 3 597 - 597 (一社)日本内分泌学会 2021年01月
• 悪性リンパ腫の両側副腎転移により副腎不全を呈した1例

  桑原 咲, 亀田 啓, 家坂 光, 泉原 里美, 大江 悠希, 上垣 里紗, 千葉 幸輝, 宮 愛華, 野本 博司, 曹 圭龍, 中村 昭伸, 安部 崇重, 篠原 信雄, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 3 598 - 598 (一社)日本内分泌学会 2021年01月
• Successful management of a patient with active Cushing’s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia

  Akiko Yuno, Yoshiyuki Kenmotsu, Yuka Takahashi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, Yu Yamashita, Junichi Nakamura, Sho Nakakubo, Keisuke Kamada, Masaru Suzuki, Hirokazu Sugino, Naoko Inoshita, Satoshi Konno, Hideaki Miyoshi, Tatsuya Atsumi, Yutaka Sawamura, Akira Shimatsu

  Endocrine Journal 68 4 477 - 484 2021年
• Impact of endogenous insulin secretion on the improvement of glucose variability in Japanese patients with type 2 diabetes treated with canagliflozin plus teneligliptin

  Aika Miya, Akinobu Nakamura, Kyu Yong Cho, Shinichiro Kawata, Hiroshi Nomoto, So Nagai, Hajime Sugawara, Shinji Taneda, Kazuhisa Tsuchida, Kazuno Omori, Hiroki Yokoyama, Jun Takeuchi, Shin Aoki, Yoshio Kurihara, Tatsuya Atsumi, Hideaki Miyoshi

  JOURNAL OF DIABETES INVESTIGATION 2021年01月 

  Aims/Introduction To identify the effect of combination therapy with a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter 2 inhibitor compared with switching from a dipeptidyl peptidase-4 inhibitor to a sodium-glucose cotransporter 2 inhibitor on improving the glucose variability in patients with or without impaired endogenous insulin secretion.Materials and Methods A secondary analysis regarding the relationship between endogenous insulin secretion and the change in mean amplitude of glycemic excursions (Delta MAGE) was carried out in a multicenter, prospective, randomized, parallel-group comparison trial that enrolled patients with type 2 diabetes who had been taking teneligliptin and were treated by switching to canagliflozin (SWITCH) or adding canagliflozin (COMB). Participants were categorized into the following four subgroups: SWITCH or COMB and high or low fasting C-peptide (CPR) divided at baseline by the median.Results Delta MAGE in the COMB group was greatly improved independent of a high or low CPR (-29.2 +/- 28.3 vs -20.0 +/- 24.6, respectively; P = 0.60). However, Delta MAGE was not ameliorated in the low CPR SWITCH group, and the Delta MAGE was significantly smaller than that in the high CPR COMB group (P < 0.01).Conclusions COMB would be a better protocol rather than switching teneligliptin to canagliflozin to improve daily glucose variability in patients with impaired endogenous insulin secretion.
• Favorable effect of sodium-glucose cotransporter 2 inhibitor, dapagliflozin, on non-alcoholic fatty liver disease compared with pioglitazone

  Kyu Yong Cho, Akinobu Nakamura, Kazuno Omori, Takahiro Takase, Aika Miya, Kohei Yamamoto, Hiroshi Nomoto, Hiraku Kameda, Shinji Taneda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi

  JOURNAL OF DIABETES INVESTIGATION 2020年12月 

  Aims/Introduction Sodium-glucose cotransporter 2 inhibitors, as well as thiazolidines, suppress nonalcoholic fatty liver disease (NAFLD); however, few comparative studies have been reported. Dapagliflozin has shown non-inferiority compared with pioglitazone for glycemic control, and superiority regarding weight reduction in patients with type 2 diabetes. We carried out a secondary analysis for the favorable effects of sodium-glucose cotransporter inhibitors for NAFLD.Materials and Methods In this multicenter, open-label, prospective, randomized, parallel-group comparison trial, patients taking pioglitazone for >= 12 weeks were randomly switched to dapagliflozin or continued pioglitazone for a further 24 weeks. The fatty liver index (FLI), consisting of body mass index, triglycerides, waist circumference and gamma-glutamyl transpeptidase, was used for the evaluation of NAFLD.Results A total of 53 participants with NAFLD (27 dapagliflozin; 26 pioglitazone) were included in this analysis. FLI decreased significantly in the dapagliflozin group (48.7 +/- 23.4 to 42.1 +/- 23.9) compared with the pioglitazone group (49.0 +/- 26.1 to 51.1 +/- 25.8; P < 0.01). Multiple linear regression analysis showed that the changes in FLI had a significantly positive correlation with changes in glycated hemoglobin (P = 0.03) and insulin level (P < 0.01) in the dapagliflozin group.Conclusion Dapagliflozin might be more beneficial than pioglitazone in patients with NAFLD. Improvements in FLI would be closely related to glycemic control.
• Beneficial effects of switching to denosumab from bisphosphonates or selective estrogen receptor modulators in postmenopausal women with type 2 diabetes and osteopenia/osteoporosis

  Arina Miyoshi, Hiraku Kameda, So Nagai, Akinobu Nakamura, Aika Miya, Takahiro Takase, Tatsuya Atsumi, Hideaki Miyoshi

  JOURNAL OF DIABETES INVESTIGATION 2020年12月 

  Aims/Introduction Patients with type 2 diabetes mellitus have a higher bone fracture risk than patients without diabetes. Although denosumab (Dmab) is a potent bone resorption inhibitor, its efficacy in patients with type 2 diabetes mellitus has not been elucidated. In this study, we investigated the effects of switching to Dmab from bisphosphonates (BP) or a selective estrogen receptor modulator (SERM) in postmenopausal type 2 diabetes mellitus patients.Materials and Methods This was a three medical institutions, prospective, observational study for postmenopausal patients with type 2 diabetes mellitus whose T-score of femoral neck or lumbar spine bone mineral density was under -1.0 standard deviation, even after >6 months of BP or SERM administration. After obtaining consent, participants were treated for osteopenia/osteoporosis by either continuing BP (BP-BP group)/SERM (SERM-SERM group), or by switching to Dmab (BP-Dmab or SERM-Dmab groups). Changes in bone mineral density and bone metabolism marker levels were evaluated after 6 months.Results A total of 48 patients were included in this study, and each group comprised 12 patients. No significant difference existed in baseline characteristics among the groups. The average age and glycated hemoglobin were 71 +/- 8 years and 7.2 +/- 0.9%, respectively. In the SERM-Dmab group, lumbar spine bone mineral density was significantly increased by 5.0% compared with the SERM-SERM group (P < 0.04). Serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b were significantly decreased in the BP-Dmab and SERM-Dmab groups compared with the BP-BP and SERM-SERM groups, respectively.Conclusions Switching to Dmab from BP or SERM is beneficial to prevent osteoporosis progression in postmenopausal patients with type 2 diabetes mellitus patients.
• Household income and the risk of incident hypertension in employees at multiple workplaces in Japan: J-HOPE.

  Shingo Yanagiya, Koshi Nakamura, Shigekazu Ukawa, Akizumi Tsutsumi, Tatsuya Atsumi, Akiko Tamakoshi

  Hypertension research : official journal of the Japanese Society of Hypertension 43 12 1445 - 1453 2020年12月 

  This cohort study aimed to investigate the association between household income and incident hypertension in a Japanese employed population. During 2012, a total of 4314 normotensive daytime employees (3153 men and 1161 women) were included in this study. Participants had a wide range of occupations and were employed at one of 12 workplaces from various economic sectors in Japan. After a 2-year follow-up, incident hypertension was compared among groups according to household income: <5.0, 5.0-7.9, 8.0-9.9, and ≥10.0 million Japanese yen (\)/year. A Cox proportional hazard model was used to calculate the hazard ratio for incident hypertension in each household income group, compared with the group earning <5.0 million \/year. The hazard ratios for men were 1.52 (95% confidence interval, 1.08-2.18) for 5.0-7.9 million \/year, 1.49 (0.98-2.27) for 8.0-9.9 million \/year, and 1.92 (1.23-3.01) for ≥10.0 million \/year after adjusting for age, baseline systolic blood pressure, worksite, type of occupation, number of family members, and smoking status. This positive relationship was attenuated but remained significant after further adjustment for alcohol consumption and body mass index, both of which were higher among men with higher household income. Conversely, there was no significant difference for women in the risk of incident hypertension among household income groups, although those with higher household income tended to have a lower risk of incident hypertension. Household income is positively associated with the onset of hypertension in Japanese employed men working daytime hours.
• COVID-19 pandemic in Japan.

  Olga Amengual, Tatsuya Atsumi

  Rheumatology international 2020年11月17日 

  The disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronavirus Disease-2019 (COVID-19), is a global emergency. The first case of COVID-19 was confirmed in Japan in January 2020, a second outbreak of infection occurred in mid-March and a third peak at the beginning of August. The COVID-19 phenotype was milder in Japan than in other countries, although the restrictive measures applied in the country have not been as strict as in other places. Factors related to a possible reduced susceptibility to the pulmonary manifestations of SARS-CoV-2 may have contributed to better outcomes and lower mortality in Japan.
• Impaired insulin secretion predicting unstable glycemic variability and time below range in type 2 diabetes patients regardless of glycated hemoglobin or diabetes treatment

  Aika Miya, Akinobu Nakamura, Takahisa Handa, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Hideaki Miyoshi, Tatsuya Atsumi

  JOURNAL OF DIABETES INVESTIGATION 2020年11月 

  Aims/Introduction To identify the coefficient of variation (CV) threshold for unstable glucose variability (GV) and hypoglycemia, and to characterize a patient population with unstable GV and hypoglycemia.Materials and Methods This was an observational study that enrolled 284 Japanese outpatients with type 2 diabetes who underwent continuous glucose monitoring. The C-peptide index (CPI = [(fasting serum C-peptide) / (plasma glucose)] x 100) was used as a marker of endogenous insulin secretion. The CV threshold between stable and unstable GV was defined as the upper limit of the CV distribution in the subgroup of patients who did not receive insulin nor insulin secretagogues (relatively stable GV subgroup, n = 104). The optimal CV range corresponding to time below target range >= 4% was determined for all patients using receiver operating characteristic curve analysis. Various characteristics of patients with unstable GV and hypoglycemia were extracted using multivariate logistic regression analysis.Results The upper limit of the CV in the relatively stable GV subgroup was 40. The optimal CV range corresponding to time below target range >= 4% was also defined as CV >= 40 (area under the curve 0.85) for all patients. The CPI was an independent risk for CV >= 40 (odds ratio 0.17, 95% confidence interval 0.04-0.50, P < 0.01). The optimal cut-off point for CPI to predict a CV cut-off value of 40 was equivalent to 0.81 (area under the curve 0.80).Conclusions A CV of 40 discriminates unstable GV and hypoglycemia from stable GV in Japanese outpatients with type 2 diabetes. Impaired insulin secretion might affect the stability of GV.
• 血糖管理 内因性インスリン分泌は2型糖尿病における血糖変動の不安定性を予測する

  宮 愛香, 中村 昭伸, 半田 喬久, 野本 博司, 亀田 啓, 曹 圭龍, 永井 聡, 三好 秀明, 渥美 達也

  糖尿病合併症 34 Suppl.1 168 - 168 (一社)日本糖尿病合併症学会 2020年11月
• 血糖管理 高齢2型糖尿病では、低血糖域の割合は変動係数と関連する

  半田 喬久, 宮 愛香, 中村 昭伸, 野本 博司, 亀田 啓, 曹 圭龍, 永井 聡, 三好 秀明, 吉岡 成人, 渥美 達也

  糖尿病合併症 34 Suppl.1 170 - 170 (一社)日本糖尿病合併症学会 2020年11月
• How should rheumatologists manage glucocorticoid-induced hyperglycemia?

  Hiroyuki Nakamura, Yuichiro Fujieda, Akinobu Nakamura, Tatsuya Atsumi

  Modern rheumatology 1 - 10 2020年10月07日 

  Glucocorticoid-induced hyperglycemia (GIH) is an important complication to be managed by rheumatologists as it can affect morbidity and mortality of patients. Before administration of glucocorticoids, risk for the development of GIH should be assessed in every patient. A meta-analysis identified male gender, older age, family history of diabetes mellitus, current smoking history, past history of hypertension, higher body mass index, higher fasting plasma glucose (PG) and higher hemoglobin A1c (HbA1c) levels as risk factors for GIH. Then, rheumatologists need to carefully monitored PG levels including 2-h after meals because glucocorticoids particularly affect postprandial glucose metabolism. Fasting PG level ≥ 126 mg/dL and/or post-meal PG level ≥ 200 mg/dL are considered as GIH regardless of HbA1c level. Treatment strategy for GIH should center on insulin injection since the effectiveness of oral hypoglycemic agents for GIH has been uncertain. But, rheumatologists may try oral hypoglycemic agents in advance of insulin therapy for mild GIH, whereas diabetologists should be consulted in case of intractable GIH. More strict control of GIH could be possible using intensive insulin protocol. Rheumatologists are encouraged to be interested in the management of GIH for providing patients superior care, working closely with diabetologists.
• COVID-19肺炎を合併したCushing病の一例

  高橋 由華, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 湯野 暁子, 澤村 豊, 島津 章, 山下 優, 中久保 祥, 鎌田 啓佑, 鈴木 雅, 今野 哲, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 2 504 - 504 (一社)日本内分泌学会 2020年10月
• 副甲状腺切除26年後に多発性内分泌腫瘍症1型と診断された1例

  泉原 里美, 亀田 啓, 家坂 光, 大江 悠希, 千葉 幸輝, 上垣 里紗, 重沢 郁美, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 2 548 - 548 (一社)日本内分泌学会 2020年10月
• 病理所見から原発性色素性結節状副腎皮質病変が疑われた一例

  上垣 里紗, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 清水 亜衣, 笹野 公伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 2 532 - 532 (一社)日本内分泌学会 2020年10月
• 抗FGF23抗体が奏功したFGF23関連低リン血症性骨軟化症の一例

  大江 悠希, 亀田 啓, 家坂 光, 泉原 里美, 上垣 里紗, 亀田 玲奈, 野本 博司, 坂本 圭太, 曽山 武士, 曹 圭龍, 中村 昭伸, 阿保 大介, 工藤 與亮, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 2 529 - 529 (一社)日本内分泌学会 2020年10月
• Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier.

  Yusuke Takada, Daisuke Kamimura, Jing-Jing Jiang, Haruka Higuchi, Daiki Iwami, Kiyohiko Hotta, Yuki Tanaka, Mitsutoshi Ota, Madoka Higuchi, Saori Nishio, Tatsuya Atsumi, Nobuo Shinohara, Yoshihiro Matsuno, Takahiro Tsuji, Tatsu Tanabe, Hajime Sasaki, Naoya Iwahara, Masaaki Murakami

  International immunology 32 10 653 - 662 2020年09月30日 

  Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.
• Morbidity and mortality in antiphospholipid syndrome based on cluster analysis: a 10-year longitudinal cohort study.

  Yusuke Ogata, Yuichiro Fujieda, Masanari Sugawara, Taiki Sato, Naoki Ohnishi, Michihito Kono, Masaru Kato, Kenji Oku, Olga Amengual, Tatsuya Atsumi

  Rheumatology (Oxford, England) 60 3 1331 - 1337 2020年09月18日 

  OBJECTIVE: Using cluster analysis, to identify the subgroup of patients with APS with the poorest prognosis and clarify the characteristics of that subgroup. METHODS: This is a longitudinal retrospective cohort study of APS patients. Using clinical data and the profile of aPL, cluster analysis was performed to classify the patients into subgroups. Events were defined as thrombosis, severe bleeding, and mortality. RESULTS: A total of 168 patients with APS were included. Cluster analysis classified the patients into three subgroups; Cluster A (n = 61): secondary APS, Cluster B (n = 56): accumulation of cardiovascular risks and arterial thrombosis, Cluster C (n = 61): triple positivity of aPL and venous thrombosis. Cluster B showed significantly higher frequency of the events and higher mortality compared with the other clusters (P = 0.0112 for B vs A and P = 0.0471 for B vs C). CONCLUSION: Using cluster analysis, we clarified the characteristics of the APS patients with the poorest prognosis. Risk factors for cardiovascular disease may further increase events in patients with APS.
• LAMP3 induces apoptosis and autoantigen release in Sjögren's syndrome patients.

  Tsutomu Tanaka, Blake M Warner, Toshio Odani, Youngmi Ji, Ying-Qian Mo, Hiroyuki Nakamura, Shyh-Ing Jang, Hongen Yin, Drew G Michael, Noriyuki Hirata, Futoshi Suizu, Satoko Ishigaki, Fabiola Reis Oliveira, Ana Carolina F Motta, Alfredo Ribeiro-Silva, Eduardo M Rocha, Tatsuya Atsumi, Masayuki Noguchi, John A Chiorini

  Scientific reports 10 1 15169 - 15169 2020年09月16日 

  Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by dysfunction of secretory epithelia with only palliative therapy. Patients present with a constellation of symptoms, and the diversity of symptomatic presentation has made it difficult to understand the underlying disease mechanisms. In this study, aggregation of unbiased transcriptome profiling data sets of minor salivary gland biopsies from controls and Sjögren's syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjögren's syndrome cases. Stratification of patients based on their clinical characteristics suggested an association between increased LAMP3 expression and the presence of serum autoantibodies including anti-Ro/SSA, anti-La/SSB, anti-nuclear antibodies. In vitro studies demonstrated that LAMP3 expression induces epithelial cell dysfunction leading to apoptosis. Interestingly, LAMP3 expression resulted in the accumulation and release of intracellular TRIM21 (one component of SSA), La (SSB), and α-fodrin protein, common autoantigens in Sjögren's syndrome, via extracellular vesicles in an apoptosis-independent mechanism. This study defines a clear role for LAMP3 in the initiation of apoptosis and an independent pathway for the extracellular release of known autoantigens leading to the formation of autoantibodies associated with this disease.ClinicalTrials.gov Identifier: NCT00001196, NCT00001390, NCT02327884.
• Non-tuberculosis Mycobacterium Tenosynovitis with Rice Bodies in a Patient with Systemic Lupus Erythematosus

  Yuichiro Fujieda, Keita Ninagawa, Yuichiro Matsui, Michihiro Kono, Tamotsu Kamishima, Norimasa Iwasaki, Tatsuya Atsumi

  Internal Medicine 59 18 2317 - 2320 2020年09月15日
• Low C4 as a risk factor for severe neuropsychiatric flare in patients with systemic lupus erythematosus.

  Kuniyuki Aso, Michihito Kono, Michihiro Kono, Toshiyuki Watanabe, Yuka Shimizu, Yusuke Ogata, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Olga Amengual, Shinsuke Yasuda, Tatsuya Atsumi

  Lupus 29 10 1238 - 1247 2020年09月 

  OBJECTIVE: This study aimed to explore the risk factors for 'severe' neuropsychiatric (NP) flare in patients with systemic lupus erythematosus (SLE). METHODS: This retrospective study comprised newly diagnosed 184 adult SLE patients who visited Hokkaido University Hospital between 2006 and 2017. In this study, severe NP flare was defined as the occurrence of at least one newly developed British Isles Lupus Assessment Group A score in the neurological domain. Overall severe NP flare-free survival was estimated by Kaplan-Meier analysis. Clinical and demographic profiles at SLE diagnosis were assessed as potential risk items in the adjusted multivariate Cox regression model. RESULTS: The median follow-up period was 7.9 years (interquartile range (IQR) 4.6-12.3) years. A total of 28 (15.2%) patients had one or more severe NP flares during the observation period. The median time from patient enrolment date to severe NP flare occurrence was 3.1 years (IQR 0.9-6.3 year). The 2- and 10-year severe NP flare-free survival rates were 92.7% and 86.0%, respectively. Among the manifestations of severe NP flare, psychosis was the most frequent (19.1%). In the multivariate model, low serum levels of C4 (hazard ratio (HR) = 3.67, p = 0.013) and severe NP manifestations at SLE diagnosis (HR = 7.11, p < 0.001) emerged as independent risk factors for developing severe NP flare. CONCLUSION: The first severe NP flare presented early in the course of SLE. Low C4 level and severe NP manifestations at SLE diagnosis could predict the development of severe NP flare.
• Effects of Palmaria palmata on lipid metabolism and glycemic control in participants with hypercholesterolemia in a randomized double-blind placebo-controlled trial.

  Takahiro Takase, Akinobu Nakamura, Hideaki Miyoshi, Minori Koga, Atsuhito Toyomaki, Ichiro Kusumi, Rikako Kino, Yasuyuki Konishi, Yoshinobu Kiso, Tatsuya Atsumi

  Phytotherapy research : PTR 34 9 2303 - 2312 2020年09月 

  BACKGROUND: Red algae have been reported to improve lipid and glucose metabolism in rats. We investigated the effects of Palmaria palmata (P. palmata), a red alga from northern Japan, on lipid metabolism and glycemic control in participants with hypercholesterolemia. METHODS: We conducted an 8-week, randomized, double-blind, placebo-controlled, and parallel-group comparison trial. The study enrolled Japanese participants with a serum low-density protein cholesterol (LDL-C) ≥120 mg/dL. The participants were randomly assigned to take either capsules containing P. palmata (2 g/day) or placebo capsules. The primary endpoint was the change in LDL-C from baseline to week 8 and the secondary endpoints were the changes in other lipid parameters and glycemic control. RESULTS: Of the 104 participants completed the study protocol. There were no significant differences in change in LDL-C, body mass index, waist circumference, or glycemic control between the two groups. However, serum triglyceride showed significantly greater improvement in women in the P. palmata group (-9.0 [-25.0, +5.0]) vs. those in the placebo group (-1.0 [-11.0, +19.0]; p = .03). CONCLUSIONS: The present study did not show that P. palmata had significant effect on serum LDL-C nor glycemic control, but hypertriglyceridemia could be ameliorated by administration of P. palmata in women.
• Intrafamilial phenotypic distinction of hypophosphatasia with identical tissue nonspecific alkaline phosphatase gene mutation: a family report.

  Masaru Kato, Toshiyuki Hattori, Tomohiro Shimizu, Keita Ninagawa, Rimi Izumihara, Hiroshi Nomoto, Kazuhide Tanimura, Tatsuya Atsumi

  Journal of bone and mineral metabolism 2020年08月08日 [査読有り][通常論文]
   

  Hypophosphatasia (HPP) is caused by mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene in an autosomal recessive or dominant manner and characterized by defective mineralization of bone and low serum ALP levels. In this report, we present a family with HPP mother (case 1) and HPP child (case 2) who have identical TNSALP gene mutation (c.1015G>A p.Gly339Arg heterozygous mutation) but distinct clinical phenotypes. Whereas case 1 appeared to be asymptomatic despite extremely low levels of serum ALP, case 2 had several HPP-related symptoms, such as tooth loss, fractures, short stature, with slightly decreased ALP levels. Upon the diagnosis of HPP, case 1 discontinued denosumab, which was used to treat her rheumatoid arthritis, concerning the risk of atypical femoral fractures. The clinical course of this family was suggestive in a genotype-phenotype imbalance in HPP, the underdiagnosis of HPP in adults, and the risk of atypical femoral fractures using bone resorption inhibitors.
• 転移性腎癌に対するニボルマブとイピリムマブの併用療法により破壊性甲状腺炎に続いて劇症1型糖尿病を発症した1例

  家坂 光, 亀田 啓, 安部 崇重, 亀田 玲奈, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 篠原 信雄, 三好 秀明, 渥美 達也

  糖尿病 63 Suppl.1 S - 173 (一社)日本糖尿病学会 2020年08月
• 1型糖尿病患者へのSGLT2阻害薬の投与は血糖変動を改善する

  泉原 里美, 亀田 啓, 千葉 幸輝, 野本 博司, 曹 圭龍, 中村 昭伸, 山下 久美子, 栗原 義夫, 渥美 達也, 三好 秀明

  糖尿病 63 Suppl.1 S - 193 (一社)日本糖尿病学会 2020年08月
• 欧米人2型糖尿病患者膵島ではHIF1α/PFKFB3経路が活性化することで膵島内代謝が解糖系へとシフトする

  野本 博司, Tudzarova Slavica, Pei Lina, Montemurro Chiara, Gurlo Tatyana, Butler Peter C., 中村 昭伸, 渥美 達也

  糖尿病 63 Suppl.1 S - 194 (一社)日本糖尿病学会 2020年08月
• 肥満外科治療は薬剤の減量・中止および糖尿病寛解を期待できる

  大江 悠希, 高瀬 崇宏, 曹 圭龍, 野本 博司, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 63 Suppl.1 S - 216 (一社)日本糖尿病学会 2020年08月
• SGLT2阻害薬ルセオグリフロジンによる膵β細胞保護作用の機序の解明

  山内 裕貴, 中村 昭伸, 三好 秀明, 関崎 知紀, 川田 晋一朗, 土田 和久, 柴山 惟, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也

  糖尿病 63 Suppl.1 S - 239 (一社)日本糖尿病学会 2020年08月
• グルコキナーゼ活性化薬の長期投与に伴う血糖降下作用の消失機序の解明

  川田 晋一朗, 中村 昭伸, 山内 裕貴, 関崎 知紀, 土田 和久, 柴山 惟, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 三好 秀明, 渥美 達也

  糖尿病 63 Suppl.1 S - 308 (一社)日本糖尿病学会 2020年08月
• 高血圧症合併2型糖尿病患者におけるDPP-4阻害薬からSGLT2阻害薬への切替による血圧・脈拍への影響に関する検討(プロトコール)

  曹 圭龍, 亀田 玲奈, 野本 博司, 中村 昭伸, 竹内 淳, 永井 聡, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 63 Suppl.1 S - 311 (一社)日本糖尿病学会 2020年08月
• 高炭水化物食長期摂取による膵β細胞量増加作用におけるグルコキナーゼの役割

  土田 和久, 中村 昭伸, 三好 秀明, Kelaier Yang, 関崎 知紀, 山内 裕貴, 川田 晋一朗, 柴山 惟, 大森 一乃, 野本 博司, 亀田 啓, 曹 圭龍, 清野 祐介, 寺内 康夫, 渥美 達也

  糖尿病 63 Suppl.1 S - 260 (一社)日本糖尿病学会 2020年08月
• 中小型血管炎(ANCA関連血管炎) ゲノムワイド関連解析と全ゲノムシークエンスによる日本人集団における抗好中球細胞質抗体の新規疾患関連候補遺伝子の同定

  針谷 正祥, 川崎 綾, 土屋 尚之, 佐田 憲映, 平野 史生, 杉原 毅彦, 天野 宏一, 山縣 邦弘, 土橋 浩章, 長坂 憲治, 渥美 達也, 本間 栄, 尾崎 承一, 丸山 彰一, 有村 義宏, 槇野 博史

  日本リウマチ学会総会・学術集会プログラム・抄録集 64回 506 - 506 (一社)日本リウマチ学会 2020年08月
• 地域一般集団での血清遊離脂肪酸とプロインスリンとの関連

  千葉 幸輝, 中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也

  糖尿病 63 Suppl.1 S - 130 (一社)日本糖尿病学会 2020年08月
• 血清高分子量アディポネクチンとプロインスリンとの関連 DOSANCO Health studyによる検討

  中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也

  糖尿病 63 Suppl.1 S - 134 (一社)日本糖尿病学会 2020年08月
• 地域住民横断調査におけるプロインスリンと肝の脂肪化との関連 DOSANCO Health Study

  宮 愛香, 中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也

  糖尿病 63 Suppl.1 S - 280 (一社)日本糖尿病学会 2020年08月
• 地域住民横断調査におけるプロインスリンと肝の脂肪化との関連 DOSANCO Health Study

  宮 愛香, 中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也

  糖尿病 63 Suppl.1 S - 280 (一社)日本糖尿病学会 2020年08月
• 中小型血管炎(ANCA関連血管炎) ゲノムワイド関連解析と全ゲノムシークエンスによる日本人集団における抗好中球細胞質抗体の新規疾患関連候補遺伝子の同定

  針谷 正祥, 川崎 綾, 土屋 尚之, 佐田 憲映, 平野 史生, 杉原 毅彦, 天野 宏一, 山縣 邦弘, 土橋 浩章, 長坂 憲治, 渥美 達也, 本間 栄, 尾崎 承一, 丸山 彰一, 有村 義宏, 槇野 博史

  日本リウマチ学会総会・学術集会プログラム・抄録集 64回 506 - 506 (一社)日本リウマチ学会 2020年08月
• Fluvastatin prevents the development of arthritis in env-pX rats via up-regulation of Rho GTPase-activating protein 12.

  Shun Tanimura, Mutsumi Nishida, Tatsunori Horie, Tamotsu Kamishima, Hitomi Matsumoto, Yutaka Morimura, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  Experimental and molecular pathology 115 104454 - 104454 2020年08月 

  The pleiotropic effects of statins, including an antiarthritic potential, have been noted. This study aimed to determine the efficacy of statins on rheumatoid arthritis (RA) and clarify how statins affect its pathogenesis. Fluvastatin (500 μg/kg/day) or vehicle was given per os to env-pX rats, which carry the human T-cell leukemia virus type I env-pX gene and spontaneously develop destructive arthritis mimicking RA, for 30 days. Blood sampling and ultrasonography (US) of the ankle joints were conducted on days 0, 10, 20, and 30. On day 30, all rats were euthanized, and the ankle joints were subjected to histological analysis. To clarify how fluvastatin affects the pathogenesis of RA, comprehensive serum exosomal microRNA (miRNA) analysis was performed. Gene expression in the primary culture of synovial fibroblasts derived from arthritic rat and human and non-arthritic rat periarticular tissues was determined quantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). As a result, the development of arthritis in env-pX rats was significantly suppressed by fluvastatin, which was evident from the viewpoints of serology, US imaging, and histology. Comprehensive serum exosomal miRNA analysis suggested that the expression of Rho GTPase-activating protein 12 (Arhgap12) was decreased in arthritic env-pX rats but increased with the administration of fluvastatin. Corresponding results were obtained by quantitative RT- PCR using primary culture of synovial fibroblasts. The collective findings suggest that fluvastatin prevents the development of arthritis in env-pX rats via the up-regulation of ARHGAP12. This study suggests that ARHGAP12 can be a possible therapeutic target of RA.
• 1型糖尿病の残存膵β細胞ではHIF1α/PFKFB3経路が活性化し解糖系が亢進する

  野本 博司, Tudzarova Slavica, Pei Lina, Montemurro Chiara, Gurlo Tatyana, Butler Peter C., 中村 昭伸, 渥美 達也

  日本内分泌学会雑誌 96 1 247 - 247 (一社)日本内分泌学会 2020年08月
• 当院における免疫チェックポイント阻害薬による下垂体機能低下症の臨床的特徴

  泉原 里美, 亀田 啓, 家坂 光, 大江 悠希, 千葉 幸輝, 小野 渉, 上垣 里紗, 重沢 郁美, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 1 324 - 324 (一社)日本内分泌学会 2020年08月
• メチラポンの投与で自覚症状が改善した再発周期性クッシング病の一例

  上垣 里紗, 亀田 啓, 家坂 光, 泉原 里美, 大江 悠希, 千葉 幸輝, 小野 渉, 重沢 郁美, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 1 345 - 345 (一社)日本内分泌学会 2020年08月
• 新規TRβ遺伝子変遺を認め、心房細動と脳梗塞を発症した甲状腺ホルモン不応症の一例

  小野 渉, 亀田 啓, 家坂 光, 泉原 里美, 大江 悠希, 上垣 里紗, 千葉 幸輝, 亀田 玲奈, 野本 博司, 曹 圭龍, 中村 昭伸, 林 良敬, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 1 347 - 347 (一社)日本内分泌学会 2020年08月
• 高コルチゾール血症を呈したFamilial Dysalbuminemic Hyperthyroxinemiaの一例

  千葉 幸輝, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 神 繁樹, 的場 光太郎, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 96 1 366 - 366 (一社)日本内分泌学会 2020年08月
• Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study

  S. Fukui, K. Ichinose, K. E. Sada, J. Miyamoto, M. Harigai, K. Amano, T. Atsumi, Y. Takasaki, H. Dobashi, Y. Arimura, H. Hasegawa, Y. Yuzawa, K. Yamagata, N. Tsuboi, S. Maruyama, S. Matsuo, H. Makino, T. Maeda, A. Kawakami

  Scandinavian Journal of Rheumatology 49 4 301 - 311 2020年07月03日 

  © 2020 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation. Objective: The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. Method: In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). Results: The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = −0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. Conclusions: The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.
• A comparative study of PF-06438179/GP1111 (an infliximab biosimilar) and reference infliximab in patients with moderate to severe active rheumatoid arthritis: A subgroup analysis.

  Hideto Kameda, Eishi Uechi, Tatsuya Atsumi, Carlos Abud-Mendoza, Kazumasa Kamei, Tsugumi Matsumoto, Dario Ponce de Leon, Muhammad I Rehman, Min Zhang, Sebastiao C Radominski

  International journal of rheumatic diseases 23 7 876 - 881 2020年07月 

  AIM: PF-06438179/GP1111 (PF-SZ-IFX) is a biosimilar of reference infliximab (Remicade® ). This analysis compared the efficacy of PF-SZ-IFX and reference infliximab sourced from the European Union (IFX-EU) in patient subgroups from a randomized, comparative study of PF-SZ-IFX versus IFX-EU. METHODS: Patients with rheumatoid arthritis were randomized 1:1 to PF-SZ-IFX (n = 324) or IFX-EU (n = 326); study drug (3 mg/kg) was administered intravenously at weeks 0, 2, and 6, then every 8 weeks thereafter. Subgroup analyses of efficacy endpoints such as American College of Rheumatology criteria for ≥20% clinical improvement (ACR20), change in high-sensitivity C-reactive protein (hs-CRP), and change in Disease Activity Score in 28 joints, four components based on hs-CRP (DAS28-CRP) at weeks 14 and 30 were performed by age, gender, race, region, immunogenicity status, and treatment history. RESULTS: Overall, ACR20 response rates as well as changes in DAS28-CRP and hs-CRP at week 14 were similar between PF-SZ-IFX and IFX-EU within the subgroups of age, gender, race, region, treatment history, and immunogenicity status. Results to week 30 support overall similarity in efficacy between the two treatment arms in all subgroups. CONCLUSION: Overall, PF-SZ-IFX and IFX-EU were similar in efficacy within the analyzed subgroups of age, gender, race, region, treatment history, and immunogenicity status. The efficacy results from these subgroup analyses were aligned with the previously described results for the overall population up to week 30.
• Inverse correlation between serum high-molecular-weight adiponectin and proinsulin level in a Japanese population: the DOSANCO Health Study.

  Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi

  Journal of diabetes investigation 12 1 63 - 66 2020年06月12日 [査読有り][通常論文]
   

  Serum high-molecular-weight adiponectin (HMWA) has a positive correlation with insulin secretion in a Japanese population. To validate this correlation, we investigated the correlation between serum HMWA and proinsulin, a marker of beta-cell dysfunction, in this population. 488 participants (53.9% females) aged 35 to 79 years without having oral hypoglycemic agents and/or insulin were enrolled. HMWA was significantly and inversely correlated with proinsulin adjusted for age and sex (partial regression coefficient: β= -0.37; 95% confidence interval: -0.46 to -0.28). When the participants were divided into two groups by median values of body mass index (23.2 kg/m2 ), serum insulin (4.3 µU/mL), or homeostasis model assessment of insulin resistance (1.0), similar inverse correlations were observed adjusted for age and sex in both groups. Our results demonstrated that the HMWA level was inversely correlated with the proinsulin level in a general Japanese population.
• トランジション後に糖尿病性ケトアシドーシスを発症した小児発症1型糖尿病の1例

  宮 愛香, 亀田 啓, 中村 昭伸, 馬場 菜月, 平田 恵里奈, 柴山 惟, 宮野 有希恵, 亀田 玲奈, 三好 秀明, 渥美 達也

  糖尿病 63 5 357 - 357 (一社)日本糖尿病学会 2020年05月
• 1型糖尿病患者へのSGLT-2阻害薬投与の有効性と安全性

  千葉 幸輝, 亀田 啓, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 山下 久美子, 栗原 義夫, 渥美 達也, 三好 秀明

  糖尿病 63 5 352 - 352 (一社)日本糖尿病学会 2020年05月
• 1型糖尿病患者におけるSensor Augmented Pump療法(SAP)への変更の効果

  川田 晋一朗, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 63 5 353 - 353 (一社)日本糖尿病学会 2020年05月
• 糖尿病合併肥満症患者に対する腹腔鏡下スリーブ状胃切除術への術前寛解予測スコアの検討

  小野 渉, 中村 昭伸, 海老原 裕磨, 曹 圭龍, 亀田 玲奈, 亀田 啓, 野本 博司, 渥美 達也, 三好 秀明, 平野 聡

  糖尿病 63 5 354 - 354 (一社)日本糖尿病学会 2020年05月
• Impact of adding tacrolimus to initial treatment of interstitial pneumonitis in polymyositis/dermatomyositis: a single-arm clinical trial.

  Kazuki Takada, Yoshinori Katada, Satoshi Ito, Taichi Hayashi, Jun Kishi, Kenji Itoh, Hiroyuki Yamashita, Michito Hirakata, Kimito Kawahata, Atsushi Kawakami, Norihiko Watanabe, Tatsuya Atsumi, Yoshinari Takasaki, Nobuyuki Miyasaka

  Rheumatology (Oxford, England) 59 5 1084 - 1093 2020年05月01日 [査読有り][通常論文]
   

  OBJECTIVE: Interstitial pneumonia is common and has high short-term mortality in patients with PM and DM despite glucocorticoid (GC) treatment. Retrospective studies suggested that the early use of immunosuppressive drugs with GCs might improve its short-term mortality. METHODS: A multicentre, single-arm, 52-week-long clinical trial was performed to test whether the initial combination treatment with tacrolimus (0.075 mg/kg/day, adjusted for the target whole-blood trough levels between 5 and 10 ng/ml) and GCs (0.6-1.0 mg/kg/day of prednisolone followed by a slow taper) improves short-term mortality of PM/DM-interstitial pneumonia patients. The primary outcome was overall survival. We originally intended to compare, by using propensity-score matching, the outcome data of clinical trial patients with that of historical control patients who were initially treated with GCs alone. RESULTS: The 52-week survival rate with the combination treatment (N = 26) was 88.0% (95% CI, 67.3, 96.0). Safety profiles of the combination treatment were consistent with those known for tacrolimus and high-dose GCs individually. Serious adverse events occurred in 11 patients (44.0%), which included four opportunistic infections. Only 16 patients, including only 1 deceased patient, were registered as historical controls, which precluded meaningful comparative analysis against the clinical trial patients. CONCLUSION: Our study provided findings which suggest that initial treatment with tacrolimus and GCs may improve short-term mortality of PM/DM-interstitial pneumonia patients with manageable safety profiles. This was the first prospective clinical investigation conducted according to the Good Clinical Practice Guideline of the International Conference on Harmonization for the treatment of this potentially life-threatening disease. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00504348.
• Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.

  Dinesh Khanna, Yannick Allanore, Christopher P Denton, Masataka Kuwana, Marco Matucci-Cerinic, Janet E Pope, Tatsuya Atsumi, Radim Bečvář, László Czirják, Eric Hachulla, Tomonori Ishii, Osamu Ishikawa, Sindhu R Johnson, Ellen De Langhe, Chiara Stagnaro, Valeria Riccieri, Elena Schiopu, Richard M Silver, Vanessa Smith, Virginia Steen, Wendy Stevens, Gabriella Szücs, Marie-Elise Truchetet, Melanie Wosnitza, Kaisa Laapas, Janethe de Oliveira Pena, Zhen Yao, Frank Kramer, Oliver Distler

  Annals of the rheumatic diseases 79 5 618 - 625 2020年05月 [査読有り][通常論文]
   

  OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.
• グルコキナーゼ活性化薬の長期投与に伴う血糖降下作用の消失機序の解明

  川田 晋一朗, 中村 昭伸, 三好 秀明, 山内 裕貴, 土田 和久, 大森 一乃, 高橋 清彦, 野本 博司, 亀田 啓, 曹 圭龍, 寺内 康夫, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 57回 56 - 56 日本臨床分子医学会 2020年04月
• MTXと生物学的製剤で寛解達成した関節リウマチ治療における減量・休薬の展望 FREE-J試験より

  山口 絢子, 平田 信太郎, 宮本 俊明, 谷村 一秀, 岩井 秀之, 金子 祐子, 竹内 勤, 天野 宏一, 岩本 直樹, 川上 純, 村上 美帆, 西本 憲弘, 渥美 達也, 住田 孝之, 三森 経世, 山中 寿, 藤尾 圭志, 中野 和久, 田中 良哉

  九州リウマチ 40 1 S20 - S20 九州リウマチ学会 2020年03月
• Factors associated with successful discontinuation of certolizumab pegol in early rheumatoid arthritis.

  Yoshiya Tanaka, Tatsuya Atsumi, Kazuhiko Yamamoto, Tsutomu Takeuchi, Hisashi Yamanaka, Naoki Ishiguro, Katsumi Eguchi, Akira Watanabe, Hideki Origasa, Toshiharu Shoji, Nobuyuki Miyasaka, Takao Koike

  International journal of rheumatic diseases 23 3 316 - 324 2020年03月 

  AIM: The Certolizumab-Optimal Prevention of joint damage for Early Rheumatoid Arthritis (C-OPERA) study demonstrated that in methotrexate (MTX)-naïve early RA patients with poor prognostic factors, 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year optimized MTX therapy brings radiographic and clinical benefits through 2 years even after stopping CZP. This exploratory analysis aimed to identify factors at baseline and at CZP discontinuation associated with successful CZP discontinuation. METHODS: MTX-naïve early RA patients with poor prognostic factors entered C-OPERA (NCT01451203), a multicenter, randomized controlled trial. Patients were randomized to CZP + MTX (n = 159) or PBO + MTX (n = 157); those who completed the 1-year, double-blind period received MTX alone in Year 2 (CZP + MTX→MTX, n = 108; PBO + MTX→MTX, n = 71). Association between factors at baseline or at discontinuation of CZP and clinical/radiographic outcomes were evaluated by multiple logistic regression analysis. Predictive value cut-offs were calculated using receiver operating characteristic analysis. RESULTS: Sex (male) and low baseline Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR) were associated with simple disease activity index (SDAI) remission (≤3.3), whereas high baseline DAS28-ESR and modified total Sharp score (mTSS) were associated with clinically relevant radiographic progression (yearly progression mTSS > 3) at Week 104 (across both treatment arms). Low DAS28-ESR (<2.1) and rheumatoid factor (RF; <74 IU/mL) at discontinuation of CZP were associated with SDAI remission at Week 104. At Week 104, SDAI remission was achieved by 75.0% (42/56) of patients with low DAS28-ESR and RF at discontinuation, compared to 15.4% (2/13) of patients with high DAS28-ESR and RF. CONCLUSION: Patients with low RF and low disease activity after treatment with CZP + MTX may be able to discontinue CZP without risk of loss of response.
• MicroRNA-9 ameliorates destructive arthritis through down-regulation of NF-κB1-RANKL pathway in fibroblast-like synoviocytes.

  Wen Shi Lee, Shinsuke Yasuda, Michihiro Kono, Yuki Kudo, Sanae Shimamura, Michihito Kono, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Tomohiro Shimizu, Tomohiro Onodera, Norimasa Iwasaki, Tatsuya Atsumi

  Clinical immunology (Orlando, Fla.) 212 108348 - 108348 2020年03月 [査読有り][通常論文]
   

  We investigated the effect of miR-9 on fibroblast-like synoviocytes (FLS) from RA patients and animal arthritis model. The binding of miR-9 to NF-κB1 3'UTR was analyzed by luciferase reporter assay and immunoprecipitation. ChIP assay and luciferase promoter assay were performed to identify the binding of NF-κB1 to RANKL promoter and its activity. FLS were treated with miR-9/anti-miR-9 to evaluate cell proliferation and the expression of RANKL. Therapeutic effect of intra-articular miR-9 was evaluated in type-II collagen-induced arthritis in rats. miR-9 bound to the 3'-UTR of NF-κB1 and downregulated NF-κB1. NF-κB1 bound to RANKL promoter and increased the promoter activity of RANKL. RANKL was downregulated by miR-9. Proliferation of FLS was increased by miR-9 inhibitor. miR-9 dampened experimental arthritis by lowering inflammatory state, reducing RANKL and osteoclasts formation. Our findings revealed miR-9-NF-κB1-RANKL pathway in RA-FLS, further, miR-9 ameliorated inflammatory arthritis in vivo which propose therapeutic implications of miR- 9 in RA.
• First external validation of sensitivity and specificity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies with a Japanese cohort.

  Masatoshi Jinnin, Akiko Ohta, Shoichiro Ishihara, Hirofumi Amano, Tatsuya Atsumi, Manabu Fujimoto, Takashi Kanda, Yasushi Kawaguchi, Atsushi Kawakami, Akio Mimori, Tsuneyo Mimori, Toshihide Mimura, Yoshinao Muro, Hajime Sano, Jun Shimizu, Tsutomu Takeuchi, Yoshiya Tanaka, Kazuhiko Yamamoto, Takayuki Sumida, Hitoshi Kohsaka

  Annals of the rheumatic diseases 79 3 387 - 392 2020年03月 [査読有り][通常論文]
   

  OBJECTIVE: To externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort. METHODS: This study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees. RESULTS: When the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto's criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter's criteria to diagnose those diseases except for ADM (88.4%/88.3%). CONCLUSIONS: Our study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients.
• Calcineurin inhibitors for adult-onset Still's disease: a multicentre retrospective cohort study.

  Hiroyuki Nakamura, Yuichiro Fujieda, Masato Tarumi, Hirohiko Kitakawa, Ryo Hisada, Ikuma Nakagawa, Atsushi Noguchi, Takashi Kurita, Hiroshi Kataoka, Hideki Kasahara, Yoshiharu Amasaki, Isao Yokota, Tatsuya Atsumi

  Clinical and experimental rheumatology 2020年02月19日 [査読有り][通常論文]
   

  OBJECTIVES: To clarify the efficacy and safety of calcineurin inhibitors (CNI) for treating adult-onset Still's disease (AOSD). METHODS: This multicentre historical cohort study enrolled the consecutive patients with AOSD according to Yamaguchi classification criteria. The endpoints were set as the time from the initiation of treatment to events, the persistency rate of CNI and safety. Based on the recurrent event data analysis, these endpoints were evaluated for each event. We divided the events into two groups according to the treatment that included CNI or conventional therapy without CNI. RESULTS: One hundred seventy-eight patients with 247 events were analysed. CNI were predominantly used in 72 events with a recurrent history, typical skin rash, high ferritin levels, and/or severe complications such as macrophage activation syndrome, disseminated intravascular coagulation, serositis, meningitis. CNI led to a significantly longer event-free survival (hazard ratio: 0.57, 95% confidential interval: 0.32-0.99) after adjustment of concomitant medications. Subgroup analysis showed that CNI were effective for AOSD patients with high ALT level (hazard ratio: 0.11, 95% confidential interval: 0.02-0.59) and severe complications (hazard ratio: 0.11, 95% confidential interval: 0.01-0.94). The persistency rate of CNI was 71% at 5th year. Adverse events occurred more frequently in the CNI group (18% versus 8%, p=0.02); however, CNI did not involve in increased risk of adverse events, including nephrotoxicity, after adjustment (p=0.23). CONCLUSIONS: Our retrospective analysis suggested that CNI could be an effective and safe option for treating AOSD.
• Incidence and risk of antiresorptive agent-related osteonecrosis of the jaw (ARONJ) after tooth extraction in patients with autoimmune disease.

  Yuichiro Fujieda, Mototsugu Doi, Takuya Asaka, Masahiro Ota, Ryo Hisada, Naoki Ohnishi, Michihiro Kono, Hiraku Kameda, Daigo Nakazawa, Masaru Kato, Olga Amengual, Masahiko Takahata, Shinsuke Yasuda, Yoshimasa Kitagawa, Tatsuya Atsumi

  Journal of bone and mineral metabolism 2020年02月19日 [査読有り][通常論文]
   

  INTRODUCTION: Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a rare but serious complication in patients receiving antiresorprtive agents (AR). However, the incidence of ARONJ after tooth extraction in patients with autoimmune disease (AID) remains unclear. The present study aimed to clarify the high-risk population of ARONJ in patients with AID. MATERIALS AND METHODS: The study population comprised 232 patients treated with AR, AID or non-AID, who had undergone dental extraction from January 2011 to September 2017. The incidence and risk factors of ARONJ were analysed retrospectively. Additionally, the relationship between ARONJ and osteoporotic fracture (OF) and AR discontinuation during dental procedures was investigated. RESULTS: Of 232 patients, 10 developed ARONJ within 1 year of dental extraction. The incidence of ARONJ in patients with AID was higher than that in non-AID patients (2.0/100 person-year vs 0.5/100 person-year; p = 0.03). Among the AID patients, RA patients had strikingly high incidence of ARONJ (3.6/100 person-year). The incidence of neither ARONJ nor OF significantly differed between patients who continued and discontinued AR in the perioperative period. CONCLUSION: Patients with AID who undergo dental extraction are at high risk of ARONJ. Discontinuation of AR would not significantly contribute to reduce the incidence of ARONJ in those patients.
• Correlation between serum proinsulin levels and fatty liver: The Dynamics of Lifestyle and Neighborhood Community on Health Study Health Study.

  Aika Miya, Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi

  Journal of diabetes investigation 11 4 964 - 970 2020年01月30日 [査読有り][通常論文]
   

  AIMS/INTRODUCTION: We explored the association between fatty liver and pancreatic β-cell dysfunction in a general population. MATERIALS AND METHODS: This cross-sectional study included 489 (53.8% women) community-dwelling Japanese adults. The extent of fatty liver was estimated using the fatty liver index (FLI). After all participants were divided into three groups - low (FLI <30), moderate (30 ≤FLI <60) or high (FLI ≥ 60) degree of fatty liver - serum proinsulin levels transformed into natural logarithms were compared among the three groups. To determine whether obesity modified the association of interest, the participants were stratified into two groups according to the median body mass index. Next, to determine whether hyperinsulinemia modified the association of interest, a similar stratified analysis was carried out using the median serum insulin level. RESULTS: Logarithm (proinsulin) was significantly higher in the high FLI group than in the moderate and low groups, and it was significantly higher in the moderate group than in the low group after adjustment for age and sex (P < 0.05). Logarithm (proinsulin) was significantly higher in the high FLI group than in the low FLI group, regardless of body mass index, after adjustment for age and sex. A similar pattern was observed regardless of serum insulin levels. CONCLUSIONS: The degree of fatty liver was positively associated with proinsulin level, regardless of the presence of obesity or hyperinsulinemia, suggesting that fatty liver reflects pancreatic β-cell dysfunction.
• Long-term efficacy and safety of tocilizumab in refractory Takayasu arteritis: final results of the randomized controlled phase 3 TAKT study.

  Yoshikazu Nakaoka, Mitsuaki Isobe, Yoshiya Tanaka, Tomonori Ishii, Seido Ooka, Hiroaki Niiro, Naoto Tamura, Shogo Banno, Hajime Yoshifuji, Yasushi Sakata, Atsushi Kawakami, Tatsuya Atsumi, Shunsuke Furuta, Hitoshi Kohsaka, Katsuya Suzuki, Ryoki Hara, Yasuhiro Maejima, Hiroshi Tsukamoto, Yoshinari Takasaki, Katsuhisa Yamashita, Norihiro Okada, Shinji Yamakido, Syuji Takei, Shumpei Yokota, Norihiro Nishimoto

  Rheumatology (Oxford, England) 59 9 2427 - 2434 2020年01月17日 [査読有り][通常論文]
   

  OBJECTIVE: To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). METHODS: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. RESULTS: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference -0.120 mg/kg/day; 95% CI -0.154, -0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported. CONCLUSION: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. TRIAL REGISTRATION: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.
• 多施設共同疫学研究による体軸性脊椎関節炎の実態調査2018

  吉川 卓宏, 多田 久里守, 井上 久, 小林 茂人, 浦野 房三, 近藤 正一, 大西 直樹, 渥美 達也, 佐々木 貴紀, 竹内 勤, 公文 義雄, 梅田 雅孝, 川上 純, 田村 直人, 松井 聖

  日本脊椎関節炎学会誌 7 2 71 - 76 日本脊椎関節炎学会 2020年 

  2018年の、多施設共同疫学研究による本邦の体軸性脊椎関節炎(nr-axSpA)患者の実態調査を報告した。調査対象は10施設からの88症例で、登録時平均年齢44.3±11.4歳、登録時平均罹病期間26.5±15.2年、男性55例(62.5%)、診断までの期間の中央値5.0(0.33-10.0)年、HLA-B27陽性率41.3%であった。症状は症候性背部痛91.4%、関節炎70.0%、付着部炎45.9%、ぶどう膜炎18.8%を認め、NSAIDs反応性良好は80.0%であった。疾患活動性はBASDAI中央値4.5で、BASDAIが4を超える症例が多かった。HLA-B27陽性群は陰性群と比較して発症年齢が有意に低く、診断までの期間は短く、X線での仙腸関節炎所見やぶどう膜炎の既往が多い傾向を認めた。
• Thrombomodulin as a Physiological Modulator of Intravascular Injury.

  Kanako Watanabe-Kusunoki, Daigo Nakazawa, Akihiro Ishizu, Tatsuya Atsumi

  Frontiers in immunology 11 575890 - 575890 2020年 

  Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelial- and blood cell-derived damage-associated molecular patterns (DAMPs), and DAMP-mediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects.
• Case with long-standing gout showing various ultrasonographic features caused by monosodium urate monohydrate crystal deposition.

  Michito Murayama, Mutsumi Nishida, Yusuke Kudo, Takahiro Deguchi, Katsuji Marukawa, Yuichiro Fujieda, Nobuya Abe, Masaru Kato, Hitoshi Shibuya, Yoshihiro Matsuno, Tatsuya Atsumi

  Modern rheumatology case reports 4 1 110 - 115 2020年01月 

  Gout, which is characterized by the deposition of monosodium urate monohydrate (MSU) in the synovial fluid and other tissues, is the most common form of inflammatory arthritis. Unlike the easily recognized acute and monoarticular gouty arthritis, advanced gout induces multiple finger joint disorders and may sometimes mimic rheumatoid arthritis (RA) or vice versa. The gold standard for gout diagnosis is the identification of MSU crystals via aspiration in the symptomatic joints or nodules; however, its feasibility and specificity may be inadequate. Recently, there have been important advances in imaging techniques, assisting in the non-invasive diagnosis of gout. Ultrasonography (US) has been known to have the ability to detect deposition of MSU crystals in patients with gout. Herein, we report an evocative case of long-standing gout with precisely detected specific US features indicating MSU crystal deposition and inflammation in multiple joints. Comprehensive US assessment included the bone, hyaline cartilage, soft tissue, subcutaneous nodules and tendon; we also discriminated gouty arthritis from RA.
• Myofascia-dominant involvement on whole-body MRI as a risk factor for rapidly progressive interstitial lung disease in dermatomyositis.

  Karino K, Kono M, Kono M, Sakamoto K, Fujieda Y, Kato M, Amengual O, Oku K, Yasuda S, Atsumi T

  Rheumatology (Oxford, England) 2020年01月 [査読有り][通常論文]
  
• Proinsulin is sensitive to reflect glucose intolerance.

  Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi

  Journal of diabetes investigation 11 1 75 - 79 2020年01月 [査読有り][通常論文]
   

  AIMS/INTRODUCTION: We investigated associations between glucose tolerance and β-cell function using a series of estimation methods in a population-based study. MATERIALS AND METHODS: Data from the Dynamics of Lifestyle and Neighborhood Community on Health Study were analyzed. A total of 489 participants (263 women) were divided into three groups: normal glucose tolerance (NGT), prediabetes (PDM) and diabetes group. We estimated β-cell function by the homeostasis model assessment of β-cell function, proinsulin level (PI), C-peptide index, proinsulin-to-C-peptide ratio (PI/CPR) and proinsulin-to-insulin ratio. Because data on all five parameters of β-cell function showed skewed distributions, the values of these parameters were normalized by natural logarithmic (ln) transformation. Next, the association between glucose tolerance and β-cell function among participants without diabetes was examined. In this analysis, glucose tolerance was assessed based on glycated hemoglobin levels. RESULTS: In the crude analysis, ln(PI) and ln(PI/CPR) were significantly higher in the diabetes group than those in the PDM and NGT groups, and these parameters were significantly higher in the PDM group than in the NGT group. Only ln(PI) in the PDM group was significantly higher compared with that in the NGT group after adjustment for age, sex and body mass index (ln[PI]: PDM group 2.38 pmol/L, 95% confidence interval 2.29-2.47 pmol/L; NGT group 2.17 pmol/L, 95% confidence interval 2.12-2.22 pmol/L; P < 0.05). In addition, ln(PI) levels were significantly and positively correlated with glycated hemoglobin quartile in participants without diabetes. CONCLUSIONS: Our results showed that PI was the most sensitive to reflect glucose intolerance.
• Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial.

  Yoshiya Tanaka, Koji Oba, Takao Koike, Nobuyuki Miyasaka, Tsuneyo Mimori, Tsutomu Takeuchi, Shintaro Hirata, Eiichi Tanaka, Hidekata Yasuoka, Yuko Kaneko, Kosaku Murakami, Tomohiro Koga, Kazuhisa Nakano, Koichi Amano, Kazuyasu Ushio, Tatsuya Atsumi, Masayuki Inoo, Kazuhiro Hatta, Shinichi Mizuki, Shouhei Nagaoka, Shinichiro Tsunoda, Hiroaki Dobashi, Nao Horie, Norihiro Sato

  Annals of the rheumatic diseases 79 1 94 - 102 2020年01月 [査読有り][通常論文]
   

  OBJECTIVES: The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. METHODS: In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. RESULTS: A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. CONCLUSION: Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.
• The adjusted global antiphospholipid syndrome score (aGAPSS) and the risk of recurrent thrombosis: Results from the APS ACTION cohort

  Massimo Radin, Savino Sciascia, Doruk Erkan, Vittorio Pengo, Maria G. Tektonidou, Amaia Ugarte, Pierluigi Meroni, Lanlan Ji, H. Michael Belmont, Hannah Cohen, Guilherme Ramires de Jesus, D. Ware Branch, Paul R. Fortin, Laura Andreoli, Michelle Petri, Esther Rodriguez, Ignasi Rodriguez-Pinto, Jason S. Knight, Tatsuya Atsumi, Rohan Willis, Emilio Gonzalez, Rosario Lopez-Pedrera, Ana Paula Rossi Gandara, Margarete Borges Gualhardo Vendramini, Alessandra Banzato, Ecem Sevim, Medha Barbhaiya, Maria Efthymiou, Ian Mackie, Maria Laura Bertolaccini, Danieli Andrade, Guillermo Pons-Estel, Bill Giannakopoulos, Steve Krilis, Guilherme de Jesus, Roger Levy, Michelle Ugolini-Lopes, Renata Rosa, Danieli Andrade, Paul F. Fortin, Zhouli Zhang, Stephane Zuily, Denis Wahl, Maria Tektonidou, Cecilia Nalli, Laura Andreoli, Angela Tincani, Cecilia B. Chighizola, Maria Gerosa, Pierluigi Meroni, Alessandro Banzato, Vittorio Pengo, Savino Sciascia, Karel De Ceulaer, Stacy Davis, Olga Amengual, Tatsuya Atsumi, Imad Uthman, Maarten Limper, Ronald Derksen, Philip de Groot, Amaia Ugarte, Guillermo Ruiz Irastorza, Ignasi Rodriguez-Pinto, Ricard Cervera, Esther Rodriguez, Maria Cuadrado, Maria Angeles Aguirre Zamorano, Rosario Lopez-Pedrera, Bahar Artim-Esen, Murat Inanc, Ian Mackie, Maria Efthymiou, Hannah Cohen, Maria Laura Bertolaccini, Munther Khamashta, Giovanni Sanna, Jason S. Knight, Michelle Petri, Robert Roubey, Tom Ortel, Emilio Gonzalez, Rohan Willis, Steven Levine, Jacob Rand, H. Michael Belmont, Medha Barbhaiya, Doruk Erkan, Jane Salmon, Michael Lockshin, Ware Branch

  SEMINARS IN ARTHRITIS AND RHEUMATISM 49 3 464 - 468 2019年12月 

  Objectives: To assess whether patients with antiphospholipid syndrome (APS) and history of recurrent thrombosis have higher levels of adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) when compared to patients without recurrent thrombosis.Methods: In this cross-sectional study of antiphospholipid antibody (aPL)-positive patients, we identified APS patients with a history of documented thrombosis from the AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry"). Data on aPL-related medical history and cardiovascular risk factors were retrospectively collected. The aGAPSS was calculated at Registry entry by adding the points corresponding to the risk factors: three for hyperlipidemia, one for arterial hypertension, five for positive anticardiolipin antibodies, four for positive anti-beta(2) glycoprotein-1 antibodies and four for positive lupus anticoagulant test.Results: The analysis included 379 APS patients who presented with arterial and/or venous thrombosis. Overall, significantly higher aGAPSS were seen in patients with recurrent thrombosis (arterial or venous) compared to those without recurrence (7.8 +/- 3.3 vs. 6 +/- 3.9, p<0.05). When analyzed based on the site of the recurrence, patients with recurrent arterial, but not venous, thrombosis had higher aGAPSS (8.1 +/- SD 2.9 vs. 6 +/- 3.9; p<0.05).Conclusions: Based on analysis of our international large-scale Registry of aPL-positive patients, the aGAPSS might help risk stratifying patients based on the likelihood of developing recurrent thrombosis in APS. (C) 2019 Elsevier Inc. All rights reserved.
• 長期間経過していた原発性Sjoegren症候群に合併した血栓性血小板減少性紫斑病(TTP)の一例

  篠原 陸斗, 加藤 将, 渥美 達也, 菅原 正成, 吉村 大, 麻生 邦之, 佐藤 太貴, 蜷川 慶太, 阿部 靖矢, 狩野 皓平, 下山 修平, 尾形 裕介, 大西 直樹, 河野 通仁, 藤枝 雄一郎, 奥 健志, 保田 晋助

  日本リウマチ学会北海道・東北支部学術集会抄録集 29回 85 - 85 (一社)日本リウマチ学会-北海道・東北支部 2019年11月
• Flow cytometric identification and cell-line establishment of macrophages in naked mole-rats.

  Wada H, Shibata Y, Abe Y, Otsuka R, Eguchi N, Kawamura Y, Oka K, Baghdadi M, Atsumi T, Miura K, Seino KI

  Scientific reports 9 1 17981  2019年11月 [査読有り][通常論文]
   

  Naked mole rats (NMRs) have extraordinarily long lifespans and anti-tumorigenic capability. Recent studies of humans and mice have shown that many age-related diseases, including cancer, are strongly correlated with immunity, and macrophages play particularly important roles in immune regulation. Therefore, NMR macrophages may contribute to their unique phenotypes. However, studies of the roles of macrophages are limited by material restrictions and the lack of an established experimental strategy. In this study, we developed a flow cytometric strategy to identify NMR macrophages. The NMR macrophages were extractable using an off-the-shelf anti-CD11b antibody, M1/70, and forward/side scatter data obtained by flow cytometry. NMR macrophages proliferated in response to human/mouse recombinant M-CSF and engulfed Escherichia coli particles. Interestingly, the majority of NMR macrophages exhibited co-staining with an anti-NK1.1 antibody, PK136. NK1.1 antigen crosslinking with PK136 results in mouse NK cell stimulation; similarly, NMR macrophages proliferated in response to NK1.1 antibody treatment. Furthermore, we successfully established an NMR macrophage cell line, NPM1, by transduction of Simian virus 40 early region that proliferated indefinitely without cytokines and retained its phagocytotic capacity. The NPM1 would contribute to further studies on the immunity of NMRs.
• Factor Xa inhibitors for preventing recurrent thrombosis in patients with antiphospholipid syndrome: a longitudinal cohort study.

  Sato T, Nakamura H, Fujieda Y, Ohnishi N, Abe N, Kono M, Kato M, Oku K, Bohgaki T, Amengual O, Yasuda S, Atsumi T

  Lupus 28 13 1577 - 1582 2019年11月 [査読有り][通常論文]
  
• Relationships between plasma lactate, plasma alanine, genetic variations in lactate transporters and type 2 diabetes in the Japanese population.

  Higuchi I, Kimura Y, Kobayashi M, Narumi K, Furugen A, Miyoshi H, Nakamura A, Yamada T, Atsumi T, Iseki K

  Drug metabolism and pharmacokinetics 2019年10月 [査読有り][通常論文]
  
• Pre-conception status, obstetric outcome and use of medications during pregnancy of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) in Japan: Multi-center retrospective descriptive study.

  Sayaka Tsuda, Azusa Sameshima, Michikazu Sekine, Haruna Kawaguchi, Daisuke Fujita, Shintaro Makino, Akio Morinobu, Yohko Murakawa, Kiyoshi Matsui, Takao Sugiyama, Mamoru Watanabe, Yasuo Suzuki, Masakazu Nagahori, Atsuko Murashima, Tatsuya Atsumi, Kenji Oku, Nobuaki Mitsuda, Syuji Takei, Takako Miyamae, Naoto Takahashi, Ken Nakajima, Shigeru Saito

  Mod Rheumatol 1 - 10 2019年09月 [査読有り][通常論文]
   

  SLE, RA, CD, and UC complicated pregnancies were at high risks of obstetric adverse outcome. High ART rates necessitate pre-conception counseling in SLE, RA, and UC pregnancies.
• Autophagy promotes citrullination of VIM (vimentin) and its interaction with major histocompatibility complex class II in synovial fibroblasts.

  Sugawara E, Kato M, Kudo Y, Lee W, Hisada R, Fujieda Y, Oku K, Bohgaki T, Amengual O, Yasuda S, Onodera T, Hatakeyama S, Atsumi T

  Autophagy 1 - 10 2019年09月 [査読有り][通常論文]
  
• Quantitative power Doppler signal assessment in the subchondral bone region of the metacarpophalangeal joint is an effective predictor of radiographic progression in the hand of rheumatoid arthritis: a pilot study.

  Motoshi Fujimori, Tamotsu Kamishima, Akihiro Narita, Mihoko Henmi, Masaru Kato, Kenneth Sutherland, Mutsumi Nishida, Yuki Tanaka, Lu Yutong, Kazuhide Tanimura, Tatsuya Atsumi

  Rheumatology international 39 8 1413 - 1421 2019年08月 

  Ultrasonography is useful for assessment of synovitis in the hand of rheumatoid arthritis (RA) patients. The aim of this study was to investigate the predictive value of the quantitative power Doppler (PD) signal assessment in the subchondral bone region of the metacarpophalangeal (MCP) joint in patients with RA showing radiographic progression of the hand by comparing with those of previously reported scoring systems. Twenty-two patients (20 women) with RA who underwent power Doppler ultrasonography (PDUS) of the bilateral one to five MCP joints at baseline were included in the study. Radiography of both hands was performed at baseline and at 1 year. PDUS of the synovial space was evaluated according to semi-quantitative scoring (0-3) and quantitative measurement (0-100%). The PD signal in the subchondral bone region was qualitatively (0, 1) and quantitatively (mm2) assessed. The performance of PDUS assessment was compared using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and the risk ratio (RR). As a predictor for radiographic progression, the quantitative PD signal assessment in the subchondral bone region (AUC = 0.842, p < 0.01) was equivalent to quantitative vascularity (AUC = 0.817, p < 0.05) and semi-quantitative scoring (AUC = 0.754, p < 0.05). As for the RR of the PD signal in the subchondral bone region for radiographic progression, the quantitative PD signal assessment was 5.40 (p < 0.01), whereas the qualitative PD signal assessment was 1.60 (p = 0.204). Quantitative PD signal assessment in the subchondral bone region can predict radiographic progression in the hand of RA patients.
• Detection of Increased Vascular Signal in Arthritis-Prone Rats Without Joint Swelling Using Superb Microvascular Imaging Ultrasonography.

  Horie T, Nishida M, Tanimura S, Kamishima T, Tamai E, Morimura Y, Nishibata Y, Masuda S, Nakazawa D, Tomaru U, Atsumi T, Ishizu A

  Ultrasound in medicine & biology 45 8 2086 - 2093 2019年08月 [査読有り][通常論文]
   

  © 2019 World Federation for Ultrasound in Medicine & Biology This study aimed to determine whether ultrasonography (US) can detect increased vascular signal in the synovial tissue before overt synovitis in rheumatoid arthritis (RA). Env-pX rats that spontaneously develop RA-like synovitis were used. Ankle joints of 15 pre-morbid env-pX rats were observed with power Doppler and superb microvascular imaging (SMI) using an ultrahigh-frequency (8–24 MHz) probe. Signal values were counted as the number of pixels. The total number of vessels and vessel area in the synovial tissue were histologically evaluated. Dilated vessels were determined from the mean value of synovial vessels in three wild-type rats. In all env-pX rats, apparent synovial proliferation was not observed. However, vasodilation was evident. Only SMI values were significantly correlated with the number of dilated vessels (r = 0.585, p = 0.022) but not with the total number of vessels. US with SMI using ultrahigh-frequency probe can detect increased vascular signal in the synovial tissue of arthritis-prone rats.
• Right ventricular dimension index by cardiac magnetic resonance for prognostication in connective tissue diseases and pulmonary hypertension.

  Abe N, Kato M, Kono M, Fujieda Y, Ohira H, Tsujino I, Oyama-Manabe N, Oku K, Bohgaki T, Yasuda S, Atsumi T

  Rheumatology (Oxford, England) 2019年08月 [査読有り][通常論文]
  
• Gitelman's syndrome with hyperphosphatemia, effectively responding to single oral magnesium oxide administration: A case report.

  Aika Miya, Akinobu Nakamura, Hiraku Kameda, Kandai Nozu, Hideaki Miyoshi, Tatsuya Atsumi

  Medicine 98 28 e16408  2019年07月 

  RATIONALE: The Gitelman's syndrome (GS) is characterized by metabolic alkalosis, hypokalemia, hypomagnesemia, and hypocalciuria. However, the involvement of this deranged electrolyte balance in patients with GS in parathyroid hormone action has not been known. PATIENT CONCERNS: We report a 34-year-old woman with muscle weakness and tetany/seizures caused by electrolyte imbalance. She had hyperphosphatemia and hypocalciuric hypocalcemia in addition to severe hypomagnesemia with low potassium in the absence of metabolic alkalosis. We identified 2 heterozygous mutations in the solute carrier family 12 member 3 gene in this case (c.1732G>A, p.Val578Met and c.2537_38delTT, p.846fs) by targeted sequence for all causative genes of salt-losing tubulopathies. DIAGNOSES: A diagnosis of GS. Hypocalcemia and hyperphosphatemia were suggested to relate with the secondary obstruction of appropriate parathyroid hormone release following severe hypomagnesemia in GS. INTERVENTIONS: She was treated with single oral magnesium oxide administration. OUTCOMES: The electrolyte imbalance including hypocalcemia and hyperphosphatemia were resolved with a remission of clinical manifestations. LESSONS: These observations, in this case, suggest that even severe hypomagnesemia caused by GS was associated with resistance to appropriate parathyroid hormone secretion. Through this case, we recognize that secondary hypoparathyroidism would be triggered by severe hypomagnesemia in GS.
• The presence of anti-neutrophil extracellular trap antibody in patients with microscopic polyangiitis.

  Hattanda F, Nakazawa D, Watanabe-Kusunoki K, Kusunoki Y, Shida H, Masuda S, Nishio S, Tomaru U, Atsumi T, Ishizu A

  Rheumatology (Oxford, England) 58 7 1293 - 1298 2019年07月 [査読有り][通常論文]
   

  OBJECTIVE: Although ANCA is the major autoantibody in patients with ANCA-associated vasculitis, previous studies have suggested the presence of anti-neutrophil extracellular trap (NET) antibody in patients with microscopic polyangiitis (MPA), one type of ANCA-associated vasculitis. In this study, we aimed to determine the prevalence and pathogenic role of anti-NET antibody (ANETA) in MPA. METHODS: We examined the presence or absence of ANETA in sera obtained from 19 MPA patients by indirect immunofluorescence. We compared the clinical parameters, including age, sex, MPO-ANCA, creatinine, CRP, MPO-DNA complexes and vasculitis activity, in ANETA-positive and ANETA-negative MPA patients. We investigated the serum NET induction and degradation abilities of ANETA-positive and ANETA-negative MPA patients with reference to healthy controls (n = 8). Furthermore, we assessed the relationship between ANETA and the effect of IgG depletion on the serum NET degradation ability. RESULTS: ANETA was present in 10 of the 19 MPA patients. There was no significant difference in the clinical parameters in ANCA-positive and ANCA-negative MPA patients. Although the NET induction ability was higher and the NET degradation ability was lower in MPA sera than those in healthy controls, these abilities were not different between ANETA-positive and ANETA-negative MPA sera. Interestingly, the NET degradation ability in some sera with ANETA was markedly increased by IgG depletion. CONCLUSION: Some MPA patients produce ANETA and some ANETA possess an inhibitory function against the serum NET degradation ability. Although further studies are needed, ANETA is worthy of attention in order to understand the pathophysiology of MPA.
• Circulating plasmablasts contribute to antiphospholipid antibody production, associated with type I interferon upregulation.

  Hisada R, Kato M, Sugawara E, Kanda M, Fujieda Y, Oku K, Bohgaki T, Amengual O, Horita T, Yasuda S, Atsumi T

  Journal of thrombosis and haemostasis : JTH 17 7 1134 - 1143 2019年07月 [査読有り][通常論文]
  
• Reduced diffusing capacity for carbon monoxide predicts borderline pulmonary arterial pressure in patients with systemic sclerosis.

  Ninagawa K, Kato M, Nakamura H, Abe N, Kono M, Fujieda Y, Oku K, Yasuda S, Ohira H, Tsujino I, Atsumi T

  Rheumatology international 2019年07月 [査読有り][通常論文]
  
• Factors with remission of fatty liver in patients with type 2 diabetes treated with ipragliflozin.

  Yamauchi Y, Nakamura A, Takahashi K, Takase T, Yamamoto C, Yokota I, Atsumi T, Miyoshi H

  Endocrine journal 66 11 995 - 1000 2019年07月 [査読有り][通常論文]
   

  We investigated the factors associated with fatty liver remission via treatment with ipragliflozin. The analysis was obtained from our multi-center prospective observational study, including 200 Japanese patients with type 2 diabetes treated with ipragliflozin (50 mg/day) for 24 weeks. The extent of fatty liver was estimated using a fatty liver index (FLI). Based on the FLI after the treatment with ipragliflozin, patients were classified into remission group (FLI < 30) and non-remission group (FLI ≥ 30). After treatment with ipragliflozin for 24 weeks, FLI significantly improved from 64.5 ± 21.6 to 51.9 ± 26.5 (p < 0.01). Body weight, body mass index, waist circumference, aspartate aminotransferase, alanine aminotransferase, and FLI in the remission group were significantly lower compared with those of the non-remission group. Stepwise analysis showed that the baseline FLI (Odds ratio 0.86; 95% confidence interval 0.81-0.90, p < 0.01) was an independent factor associated with FLI remission. Using a receiver operating characteristic (ROC) analysis, the adequate cut-off value for the remission was 50. The area under the ROC curve was 0.93 with the sensitivity and specificity 84.6% and 90.1% respectively. In conclusion, ipragliflozin ameliorated fatty liver. These results suggest that patients with fatty liver with a lower FLI are more likely to attain remission by the treatment with ipragliflozin.
• Effects of dapagliflozin and/or insulin glargine on beta cell mass and hepatic steatosis in db/db mice.

  Omori K, Nakamura A, Miyoshi H, Takahashi K, Kitao N, Nomoto H, Kameda H, Cho KY, Takagi M Ag R, Hatanaka KC, Terauchi Y, Atsumi T

  Metabolism: clinical and experimental 2019年06月 [査読有り][通常論文]
  
• Nivolumab-induced hypophysitis causing secondary adrenal insufficiency after transient ACTH elevation.

  Sekizaki T, Kameda H, Oba C, Yong Cho K, Nakamura A, Miyoshi H, Osawa T, Shinohara N, Atsumi T

  Endocrine journal 2019年06月 [査読有り][通常論文]
  
• Impact of Weekly Teriparatide on the Bone and Mineral Metabolism in Hemodialysis Patients With Relatively Low Serum Parathyroid Hormone: A Pilot Study.

  Yamamoto J, Nakazawa D, Nishio S, Ishikawa Y, Makita M, Kusunoki Y, Nagai S, Fujieda Y, Takahata M, Yamada K, Yamamura T, Yotsukura A, Saito M, Shimazaki M, Atsumi T

  Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 2019年06月 [査読有り][通常論文]
  
• Efficacy of dual antiplatelet therapy for preventing recurrence of arterial thrombosis in patients with antiphospholipid syndrome.

  Ohnishi N, Fujieda Y, Hisada R, Nakamura H, Kato M, Oku K, Bohgaki T, Amengual O, Yasuda S, Atsumi T

  Rheumatology (Oxford, England) 58 6 969 - 974 2019年06月 [査読有り][通常論文]
   

  OBJECTIVE: Warfarin is regarded as the standard treatment for preventing thrombotic events in APS, but the recurrence rate is still high. Dual antiplatelet therapy (DAPT) has been shown to be effective for the prevention of acute coronary syndrome or stroke. The objective of this study was to evaluate the efficacy of DAPT for the prevention of thrombosis recurrence in APS patients with history of arterial thrombosis. METHODS: This retrospective cohort study of APS patients was conducted at Hokkaido University Hospital between 1990 and 2016. The secondary prophylactic effects and safety of warfarin monotherapy (Wf), antiplatelet monotherapy (AP), warfarin and antiplatelet combination therapy (Wf + AP) and DAPT were evaluated. The primary endpoints were set as thrombosis-free and adverse events-free survival period. Adverse events were defined as severe bleeding and death. RESULTS: A total of 90 APS patients were enrolled. Thrombotic recurrence was found in 40 patients (35 arterial and 5 venous thromboses) and serious adverse events in 20 patients (9 severe bleeding events and 14 deaths). Kaplan-Meier analysis demonstrated a 10-year recurrence-free survival rate of 62%. The recurrence rate per 100 patient-years was as follows: Wf: 11.6, AP: 5.5, Wf: + AP: 3.7, DAPT: 1.8. We demonstrated that DAPT significantly reduced the rate of recurrence compared with Wf (log-rank P = 0.001). There were no significant differences in the rate of serious adverse events among the groups. CONCLUSION: DAPT might be considered as an effective and safe option for the prophylaxis of recurrent arterial thrombosis in APS.
• Pathogenic roles of anti-C1q antibodies in recurrent pregnancy loss.

  Ohmura K, Oku K, Kitaori T, Amengual O, Hisada R, Kanda M, Shimizu Y, Fujieda Y, Kato M, Bohgaki T, Horita T, Yasuda S, Sugiura-Ogasawara M, Atsumi T

  Clinical immunology (Orlando, Fla.) 203 37 - 44 2019年06月 [査読有り][通常論文]
  
• Predictive value of serum amyloid a levels for requirement of concomitant methotrexate in tocilizumab initiation: A post hoc analysis of the SURPRISE study.

  Kato M, Kaneko Y, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, Miyata M, Murakawa Y, Yasuoka H, Hirata S, Nagasawa H, Tanaka E, Miyasaka N, Yamanaka H, Yamamoto K, Yokota I, Atsumi T, Takeuchi T

  Modern rheumatology 1 - 8 2019年06月 [査読有り][通常論文]
  
• Improvement in treatment satisfaction after switching from liraglutide to dulaglutide in patients with type 2 diabetes: A randomized controlled trial.

  Takahiro Takase, Akinobu Nakamura, Chiho Yamamoto, Hiroshi Nomoto, Aika Miya, Midori Dannoura, Kyu Yong Cho, Yoshio Kurihara, Naoki Manda, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of diabetes investigation 10 3 699 - 705 2019年05月 [査読有り][通常論文]
   

  AIMS/INTRODUCTION: We compared treatment satisfaction in type 2 diabetes patients taking daily and weekly glucagon-like peptide-1 receptor agonists. MATERIALS AND METHODS: The study was a 12-week, multicenter, open-label, prospective, randomized, parallel-group comparison trial. The participants were Japanese patients with type 2 diabetes being administered with the glucagon-like peptide-1 receptor agonist, liraglutide, daily for >3 months. Patients were randomly assigned to either continue taking liraglutide once daily (Lira group) or switch to dulaglutide once weekly (Dula group). The primary outcome was the change in the Diabetes Treatment Satisfaction Questionnaire score from baseline to week 12 in the two groups. The secondary outcomes comprised changes in the Diabetes Therapy-Related Quality of Life score, body mass and glycemic control. RESULTS: A total of 33 participants were initially enrolled in the trial, and 31 participants completed the protocol. The change in the Diabetes Treatment Satisfaction Questionnaire score in the Dula group was significantly greater than that in the Lira group (+0.1 ± 4.7 in the Lira group vs +4.9 ± 5.2 in the Dula group; P = 0.013). The change in Diabetes Therapy-Related Quality of Life score in the Dula group was significantly greater than that in the Lira group (-3.7 ± 6.9 vs +8.9 ± 15.1; P = 0.007). There were no significant differences between groups in the changes in body mass, plasma glucose or glycated hemoglobin. CONCLUSIONS: Weekly administration of dulaglutide was superior to liraglutide with regard to treatment satisfaction in patients with type 2 diabetes, in the absence of any negative effect on glycemic control.
• 常染色体優性多発性嚢胞腎に対するトルバプタン投与の長期成績

  山本 準也, 西尾 妙織, 楠 加奈子, 武田 紗夜, 中沢 大悟, 渥美 達也

  日本腎臓学会誌 61 3 353 - 353 (一社)日本腎臓学会 2019年05月
• 軟骨下骨領域におけるパワードプラ血流信号の定量評価 関節破壊の予後予測

  藤森 元嗣, 田中 悠貴, Lu Yutong, 勝海 友里, 中川 紗良, 神島 保, 成田 明宏, 邉見 美穂子, 谷村 一秀, 加藤 将, 渥美 達也, Sutherland Kenneth, 西田 睦

  北海道医学雑誌 94 1 58 - 59 北海道医学会 2019年05月
• The development of quality indicators for systemic lupus erythematosus using electronic health data: a modified RAND appropriateness method

  Nobuyuki Yajima, Yasushi Tsujimoto, Shingo Fukuma, Ken-ei Sada, Sayaka Shimizu, Kakuya Niihata, Ryo Takahashi, Yoshihide Asano, Teruhisa Azuma, Hideto Kameda, Masataka Kuwana, Hitoshi Kohsaka, Mayumi Sugiura-Ogasawara, Katsuya Suzuki, Tsutomu Takeuchi, Yoshiya Tanaka, Naoto Tamura, Toshihiro Matsui, Tsuneyo Mimori, Shunichi Fukuhara, Tatsuya Atsumi

  Modern Rheumatology 2019年05月 [査読有り][通常論文]
  
• Tumour necrosis factor alpha blockade for non-inflammatory pain: beyond inflammation?

  Abe N, Kato M, Fujieda Y, Narita H, Tha KK, Atsumi T

  Scandinavian journal of rheumatology 1 - 3 2019年05月 [査読有り][通常論文]
  
• 多彩な尿酸塩結晶沈着所見を呈した慢性痛風性関節炎の1例

  村山 迪史, 工藤 悠輔, 西田 睦, 佐藤 恵美, 表原 里実, 岩井 孝仁, 阿部 靖矢, 藤枝 雄一郎, 加藤 将, 澁谷 斉, 松野 吉宏, 渥美 達也

  超音波検査技術 44 Suppl. S225 - S225 (一社)日本超音波検査学会 2019年04月
• 感染症から死の転帰に至った高齢サブクリニカルクッシング病の一剖検例

  山内 裕貴, 亀田 啓, 馬場 菜月, 関崎 知紀, 平田 恵里奈, 大森 一乃, 高瀬 崇宏, 亀田 玲奈, 大場 知穂, 谷 道夫, 曹 圭龍, 中村 昭伸, 三好 秀明, 田中 伸哉, 渥美 達也

  日本内分泌学会雑誌 95 1 492 - 492 (一社)日本内分泌学会 2019年04月
• 著明な高Ca血症と骨量減少を呈したatypical parathyroid adenomaの一例

  大場 知穂, 亀田 啓, 桑原 健, 高桑 恵美, 馬場 菜月, 関崎 知紀, 山内 裕貴, 平田 恵里奈, 高瀬 崇宏, 亀田 玲奈, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 95 1 481 - 481 (一社)日本内分泌学会 2019年04月
• DPP-4阻害薬とSGLT2阻害薬併用による血糖変動平坦化の増強効果

  曹 圭龍, 中村 昭伸, 川田 晋一朗, 土田 和久, 大森 一乃, 菅原 基, 野本 博司, 本庄 潤, 竹内 淳, 永井 聡, 横山 宏樹, 萬田 直紀, 栗原 義夫, 青木 伸, 渥美 達也, 三好 秀明

  糖尿病 62 Suppl.1 S - 244 (一社)日本糖尿病学会 2019年04月
• 早期膵β細胞機能障害マーカーとしての血清プロインスリンの有用性

  中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也

  糖尿病 62 Suppl.1 S - 318 (一社)日本糖尿病学会 2019年04月
• 【診療力を上げる! 症例問題集】(第6章)膠原病・アレルギー 症例問題 遷延する発熱・咽頭痛・関節痛,その鑑別診断は?

  河野 通大, 渥美 達也

  内科 123 4 817 - 818 (株)南江堂 2019年04月 [査読有り][通常論文]
  
• Disseminated subcutaneous nodules and destructive polyarthritis.

  Abe N, Fujieda Y, Amengual O, Atsumi T

  BMJ (Clinical research ed.) 365 l1344  2019年04月 [査読有り][通常論文]
  
• Formation and Disordered Degradation of Neutrophil Extracellular Traps in Necrotizing Lesions of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

  Masuda S, Nonokawa M, Futamata E, Nishibata Y, Iwasaki S, Tsuji T, Hatanaka Y, Nakazawa D, Tanaka S, Tomaru U, Kawakami T, Atsumi T, Ishizu A

  The American journal of pathology 189 4 839 - 846 2019年04月 [査読有り][通常論文]
   

  Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the production of ANCAs and systemic necrotizing vasculitis in small vessels. Disordered regulation of neutrophil extracellular traps (NETs) is critically involved in the pathogenesis of AAV. NETs are web-like DNA decorated with antimicrobial proteins; they are extruded from activated neutrophils. The principal degradation factor of NETs in vivo is DNase I; however, NETs resistant to DNase I can persist in tissues and can lead to the production of ANCAs. Deposition of NETs has been demonstrated in glomerular crescents and necrotizing vasculitis in AAV. Here, the amount of NETs in formalin-fixed, paraffin-embedded tissue sections was examined, and the results for AAV were compared with the results for diseases that should be distinguished from AAV. NETs were more abundant in necrotizing vasculitis of AAV than in non-ANCA-associated vasculitis, or in granulomatous angiitis. Pulmonary granulomas in AAV and non-ANCA-associated diseases were further studied. The amount of NETs was significantly greater in necrotizing granulomas of AAV than in granulomas of sarcoidosis without necrosis. Although NETs were formed in necrotizing granulomas of tuberculosis equivalently to those formed in AAV, they were more susceptible to degradation by DNase I than were NETs in AAV. The formation and disordered degradation of NETs in necrotizing lesions are characteristics of AAV and are possibly related to its pathogenesis.
• Antiphospholipid score is a novel risk factor for idiopathic osteonecrosis of the femoral head in patients with systemic lupus erythematosus.

  Hisada R, Kato M, Ohnishi N, Sugawara E, Fujieda Y, Oku K, Bohgaki T, Amengual O, Yasuda S, Atsumi T

  Rheumatology (Oxford, England) 58 4 645 - 649 2019年04月 [査読有り][通常論文]
   

  OBJECTIVE: Idiopathic osteonecrosis of the femoral head (ION) is a common complication of SLE associated with CS therapy. Although the pathogenesis of ION involves local bone ischaemia favoured by thrombophilia, the involvement of aPL in lupus ION remains to be elucidated. We have previously reported the aPL score (aPL-S) as a quantitative marker of aPL and the development of thrombotic events in autoimmune diseases. The aim of this study was to identify the impact of aPL on the development of ION using aPL-S. METHODS: This was a single-centre retrospective study comprising 88 consecutive SLE patients who underwent MRI of the hip joints from January 2000 to March 2017. Baseline characteristics, pharmacotherapy and total hip arthroplasty performed during follow-up were evaluated. RESULTS: The presence of ION was confirmed by MRI scan in 38 patients (43.1%). Male gender, positivity of any aPL, aPL-S, high aPL-S (≥30) and high dose of CS were identified as risk factors for ION by univariate analysis. Multivariate analysis revealed high aPL-S (odds ratio 5.12, 95% CI 1.18-29.79) and use of high-dose CS (odds ratio 10.25, 95% CI 3.00-48.38) as independent variables. Kaplan-Meier analysis showed that patients with high aPL-S received total hip arthroplasty more frequently than those without aPL (P = 0.010). CONCLUSIONS: We newly identified high aPL-S as an important risk factor for ION development in SLE, suggesting the involvement of aPL-induced coagulopathy in the pathophysiology of lupus ION.
• A case report dysregulated neutrophil extracellular traps in a patient with propylthiouracil-induced anti-neutrophil cytoplasmic antibody-associated vasculitis.

  Watanabe-Kusunoki K, Abe N, Nakazawa D, Karino K, Hattanda F, Fujieda Y, Nishio S, Yasuda S, Ishizu A, Atsumi T

  Medicine 98 17 e15328  2019年04月 [査読有り][通常論文]
  
• Reduction in glucose fluctuations in elderly patients with type 2 diabetes using repaglinide: A randomized controlled trial of repaglinide vs sulfonylurea.

  Kazuno Omori, Hiroshi Nomoto, Akinobu Nakamura, Takahiro Takase, Kyu Yong Cho, Kota Ono, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of diabetes investigation 10 2 367 - 374 2019年03月 [査読有り][通常論文]
   

  AIMS/INTRODUCTION: Glinides are antidiabetic drugs that enhance the early phase of insulin secretion, but have been considered to be less effective at lowering blood glucose than sulfonylureas. However, glinides show a lower risk of hypoglycemia and a greater effect on postprandial hyperglycemia, and are particularly recommended for use in elderly patients with type 2 diabetes. We investigated the efficacy and safety of repaglinide compared with sulfonylurea for the treatment of elderly patients. MATERIALS AND METHODS: In the present multicenter, prospective, randomized, open-label, controlled trial, 57 elderly lean patients with type 2 diabetes who were being treated with sulfonylureas were studied. They were either switched to repaglinide (Repa group) or continued a sulfonylurea (SU group) for 12 weeks. The primary outcome comprised the change in glycemic control, and among the secondary outcomes was the presence of hypoglycemia and drug compliance. RESULTS: Although glycated hemoglobin (HbA1c) was not significantly different between the two groups (SU +0.02% vs Repa -0.07%), greater improvements in the glycated albumin (GA) and GA to HbA1c ratio (GA/HbA1c) were observed in the Repa group (ΔGA, SU +0.12% vs Repa -1.15%; ΔGA/HbA1c, SU +0.01 vs Repa -0.13; each P < 0.01) without increasing hypoglycemia. When the Repa group was subdivided according to whether GA improved, the SU dose before switching to repaglinide was significantly smaller and the homeostatic model assessment of β-cell function was significantly higher in the GA improvement subgroup. CONCLUSIONS: Switching from SU to Repa improved GA and GA/HbA1c, and had favorable effects on glucose fluctuation in elderly patients with type 2 diabetes.
• Should sulfonylurea be discontinued or maintained at the lowest dose when starting ipragliflozin? A multicenter observational study in Japanese patients with type 2 diabetes.

  Kiyohiko Takahashi, Kyu Yong Cho, Akinobu Nakamura, Aika Miya, Arina Miyoshi, Chiho Yamamoto, Hiroshi Nomoto, Hirokatsu Niwa, Kiyohito Takahashi, Naoki Manda, Yoshio Kurihara, Shin Aoki, Yoichi M Ito, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of diabetes investigation 10 2 429 - 438 2019年03月 [査読有り][通常論文]
   

  AIMS/INTRODUCTION: We investigated the difference in efficacy and safety between discontinuation and maintaining of sulfonylurea when adding a sodium-glucose cotransporter 2 inhibitor. MATERIALS AND METHODS: In the present multicenter, prospective observational study, 200 patients with type 2 diabetes treated with sulfonylurea and with a need to add ipragliflozin were enrolled and divided into two groups: discontinued sulfonylurea (Discontinuation group) or maintained sulfonylurea, but at the lowest dose (Low-dose group) when adding ipragliflozin. We compared the two groups after 24 weeks using propensity score matching to adjust for differences between the groups. RESULTS: In the matched cohort (58 patients in each group), baseline characteristics of both groups were balanced. The primary outcome of the proportion of patients with non-exacerbation in glycated hemoglobin after 24 weeks was 91.4% in the Low-dose group and 75.9% in the Discontinuation group, a significant difference (P = 0.024). However, bodyweight was significantly decreased in the Discontinuation group compared with the Low-dose group (-4.4 ± 2.1 kg vs -2.9 ± 1.9 kg, P < 0.01). Similarly, liver enzyme improvement was more predominant in the Discontinuation group. A logistic regression analysis showed that high-density lipoprotein cholesterol, age and sulfonylurea dose were independent factors associated with non-exacerbation of glycated hemoglobin in the Discontinuation group. CONCLUSIONS: The purpose of using ipragliflozin should be considered when making the decision to discontinue or maintain sulfonylurea at the lowest dose. Furthermore, low high-density lipoprotein cholesterol level, low dose of sulfonylurea and younger age were possible markers to not show worsening of glycemic control by discontinuing sulfonylurea.
• 強皮症-2 疾患特異的iPS細胞を用いた強皮症性肺動脈性肺高血圧症の病態解明

  工藤 友喜, 加藤 将, 柴田 悠平, 神田 真聡, リー・ウェンシー, 河野 通大, 菅原 恵理, 河野 通仁, 藤枝 雄一郎, 坊垣 暁之, アメングアル・オルガ, 奥 健志, 保田 晋助, 渥美 達也

  日本リウマチ学会総会・学術集会プログラム・抄録集 63回 539 - 539 (一社)日本リウマチ学会 2019年03月
• 関節リウマチの治療(前向き臨床研究) インフリキシマブによるプログラムドコントロール治療で導入された関節リウマチの寛解維持に関するランダム化比較試験(RRRR Study)における結果報告

  田中 良哉, 小池 隆夫, 宮坂 信之, 三森 経世, 竹内 勤, 平田 信太郎, 田中 榮一, 安岡 秀剛, 金子 祐子, 村上 孝作, 古賀 智裕, 中野 和久, 天野 宏一, 牛尾 一康, 渥美 達也, 猪尾 昌之, 八田 和大, 水木 伸一, 長岡 章平, 角田 慎一郎, 土橋 浩章

  日本リウマチ学会総会・学術集会プログラム・抄録集 63回 472 - 472 (一社)日本リウマチ学会 2019年03月
• ANCA関連血管炎の壊死性病変部における好中球細胞外トラップの存在と病的意義

  益田 紗季子, 西端 友香, 中沢 大悟, 外丸 詩野, 川上 民裕, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 63回 777 - 777 (一社)日本リウマチ学会 2019年03月
• ステロイド性骨粗鬆症 ステロイド性骨粗鬆症を合併する関節リウマチにおけるsodium risedronateの骨密度増加効果(RISOTTO試験) プラセボ対照多施設共同二重盲検比較研究

  藤枝 雄一郎, 堀田 哲也, 谷村 一秀, 天崎 吉晴, 笠原 英樹, 古川 真, 竹田 剛, 深谷 進司, 松井 和生, 佐川 昭, 片山 耕, 竹内 薫, 勝俣 一晃, 栗田 崇史, 加藤 将, 奥 健志, 保田 晋助, 岩崎 倫政, 渥美 達也

  日本リウマチ学会総会・学術集会プログラム・抄録集 63回 485 - 485 (一社)日本リウマチ学会 2019年03月 [査読有り][通常論文]
  
• Effect of switching from pioglitazone to the sodium glucose co-transporter-2 inhibitor dapagliflozin on body weight and metabolism-related factors in patients with type 2 diabetes mellitus: An open-label, prospective, randomized, parallel-group comparison

  Cho KY, Nakamura A, Omori K, Takase T, Miya A, Manda N, Kurihara Y, Aoki S, Atsumi T, Miyoshi H

  Diabetes, obesity & metabolism 21 3 710 - 714 2019年03月 [査読有り][通常論文]
   

  The effects of dapagliflozin (DAP) and pioglitazone (PIO) on body weight and glycaemic control were compared in patients with type 2 diabetes mellitus. Seventy-one patients on PIO were either switched to DAP (n = 36) at 5 mg per day or continued on PIO (n = 35). Primary endpoints were superiority of body weight loss and non-inferiority of HbA1c level after 24 weeks with DAP. Body weight decrease was greater with DAP than with PIO (75.3 +/- 14.9 to 71.3 +/- 15.1 kg vs. 74.7 +/- 13.8 to 75.2 +/- 13.9 kg; P < 0.01). Change in the HbA1c level was comparable (P = 0.64). The level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and urinary albumin : creatinine ratio (ACR) decreased only with DAP (NT-proBNP, P < 0.01; ACR, P = 0.02), and the change in NT-proBNP correlated negatively with baseline NT-proBNP level (rho = -0.68, P < 0.01) and log-converted ACR (rho = -0.35, P < 0.05). DAP promotes body weight loss in type 2 diabetes mellitus and may decrease fluid retention, thus reducing the occurrence of cardiovascular events.
• Clinical significance of anti-DNA/N-methyl-D-aspartate receptor 2 antibodies in de novo and post-steroid cases with neuropsychiatric systemic lupus erythematosus.

  Fujieda Y, Mader S, Jeganathan V, Arinuma Y, Shimizu Y, Kato M, Oku K, Minami A, Shimizu C, Yasuda S, Atsumi T

  International journal of rheumatic diseases 22 3 443 - 448 2019年03月 [査読有り][通常論文]
  
• Histopathological classification of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in a nationwide Japanese prospective 2-year follow-up cohort study.

  Yamagata K, Usui J, Nagata M, Sugiyama H, Sada KE, Muso E, Harigai M, Amano K, Atsumi T, Fujimoto S, Yuzawa Y, Kobayashi M, Saito T, Ito T, Hirawa N, Homma S, Dobashi H, Tsuboi N, Ishizu A, Arimura Y, Makino H, Matsuo S, Research Committee of, Intractable Renal Disease, the Research Committee of, Intractable Vasculitis Syndrome of the, Ministry of Health,Labour, Welfare of Japan

  Clinical and experimental nephrology 23 3 387 - 394 2019年03月 [査読有り][通常論文]
  
• Safety and tolerability of sifalimumab, an anti-interferon-α monoclonal antibody, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

  Takeuchi T, Tanaka Y, Matsumura R, Saito K, Yoshimura M, Amano K, Atsumi T, Suematsu E, Hayashi N, Wang L, Tummala R

  Modern rheumatology 1 - 8 2019年02月21日 [査読有り][通常論文]
  
• 【最近のループス腎炎治療】国内外の診療ガイドラインの現況 IVCY、MMFの使い方も含めて

  河野 通大, 渥美 達也

  日本医事新報 4947 28 - 35 (株)日本医事新報社 2019年02月 [査読有り][通常論文]
   

  ＜Point＞▼増殖性ループス腎炎における寛解導入治療において、ミコフェノール酸モフェチル(MMF)あるいはシクロホスファミド静注(IVCY)が免疫抑制薬の第一選択となる▼IVCY療法では、よりシクロホスファミド(CY)投与量を抑えたEuro-lupus式IVCYもNational Institute of Health(NIH)原法と同様に推奨される▼MMFはIVCYと同等もしくはそれ以上の効果が期待できる▼日本人に対するMMF治療では、感染症・血球減少が有害事象として最多であった(著者抄録)
• Case of fulminant type 1 diabetes induced by the anti-programmed death-ligand 1 antibody, avelumab.

  Shibayama Y, Kameda H, Ota S, Tsuchida K, Cho KY, Nakamura A, Miyoshi H, Atsumi T

  Journal of diabetes investigation 2019年02月 [査読有り][通常論文]
  
• Anti-cyclic citrullinated peptide antibody titers decrease in rheumatoid arthritis patients treated with tocilizumab: A pilot study.

  Noguchi A, Yasuda S, Hisada R, Kato M, Oku K, Bohgaki T, Suzuki M, Matsumoto Y, Atsumi T

  Modern rheumatology 30 2 1 - 6 2019年02月 [査読有り][通常論文]
   

  Objectives: To analyze the effects of tocilizumab on peripheral B-cell subpopulation and its ability to produce anti-cyclic citrullinated peptide (CCP) antibody in patients with rheumatoid arthritis (RA).Methods: Thirteen consecutive RA patients initiated with tocilizumab were enrolled in our prospective study. Anti-CCP antibody titers and clinical parameters were evaluated during treatment. Peripheral blood B-cell subsets were analyzed using flow cytometry according to the Human Immunology Project.Results: Disease activity was significantly improved and anti-CCP antibody titers significantly decreased at week 24 compared to baseline. The percentages of post-switch memory B cells in CD19+ cells transiently increased at week 12, but there was no significant difference in any of the investigated B-cell subpopulations at week 24 compared to baseline. The ratios of post-switch memory to naïve B cells (post-switch/naïve) correlated negatively with anti-CCP antibody titers regardless of the time-points.Conclusion: Our study indicated that tocilizumab has a potential to reduce anti-CCP antibody production presumably by affecting post-switch/naïve ratio, and that anti-CCP antibody titers reflect B-cell distribution/subpopulation. As anti-CCP antibodies are produced in lymph nodes or ectopic lymphoid structures in synovial tissues, not in circulation, transient increment of post-switch memory B cells after tocilizumab treatment may reflect the altered balance of B-cell distribution between circulation and arthritic joints, resulting in suppressed production of anti-CCP antibody in situ.
• Disseminated Cryptococcosis with Bronchiolitis and Cellulitis.

  Nobuya Abe, Yuichiro Fujieda, Kentaro Nagaoka, Misako Ohkusu, Shinsuke Yasuda, Katsuhiko Kamei, Tatsuya Atsumi

  American journal of respiratory and critical care medicine 199 2 235 - 236 2019年01月15日 [査読有り][通常論文]
  
• The Pathogenicity of BPI-ANCA in a Patient With Systemic Vasculitis.

  Sayo Takeda, Kanako Watanabe-Kusunoki, Daigo Nakazawa, Yoshihiro Kusunoki, Saori Nishio, Tatsuya Atsumi

  Frontiers in immunology 10 1334 - 1334 2019年 

  Objective: ANCA associated vasculitis (AAV) is characterized by systemic necrotizing vasculitis with the presence of ANCA. Although BPI-ANCA is one of the atypical ANCAs and is occasionally seen in patients with vasculitis, the pathogenicity of BPI-ANCA remains unclear. This study was performed to examine the pathogenic role of BPI-ANCA against neutrophils. Methods: A 76-year-old Japanese man showed BPI-ANCA positive systemic vasculitis with a medical history of Pseudomonas aeruginosa infection. BPI-ANCA IgGs were eluted from the patient serum using an immunoadsorbent column. In vitro experiment, healthy donor neutrophils were treated with BPI-AAV IgGs, MPO-AAV IgGs, healthy control IgGs under TNFα stimulation. After 3 h incubation, neutrophil extracellular trap (NET) was assessed by immunofluorescent imaging. To determine the pathogenicity of BPI-ANCA, TNFα-primed neutrophils were incubated with monoclonal BPI-ANCA in the presence or absence of recombinant BPI. Results: BPI-AAV IgGs-treated neutrophils showed NET formation with histone citrullination. Interestingly, the monoclonal BPI-ANCA did not induce NET, but the immune complexes (ICs) of recombinant BPI and BPI-ANCA induced TNFα-dependent NET formation with hypercitrullination. Furthermore, TNFα increased the expression of BPIs in neutrophils and the BPIs were translocated to cell surface. Conclusion: BPI-ANCA could affect neutrophils leading to NET formation and may play a role in the development of systemic vasculitis as pathogenic autoantibody.
• Clinical profiles and risk assessment in patients with antiphospholipid antibodies.

  Masaru Kato, Ryo Hisada, Tatsuya Atsumi

  Expert review of clinical immunology 15 1 73 - 81 2019年01月 

  INTRODUCTION: Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia associated with the presence of persistent antiphospholipid antibodies (aPL). Owing to recent studies, not only APS patients but also incidentally-identified, asymptomatic aPL carriers are able to be stratified in terms of the risk of future thrombotic events, according to the variety and the titer of positive aPL tests and to the non-thrombotic, aPL-associated clinical manifestations. Areas covered: Here, we critically review (1) criteria manifestations of APS, (2) non-criteria manifestations of APS, (3) risk assessment in patients with APS and in aPL carriers, and (4) the potential role of primary thrombosis prophylaxis in aPL carriers. In addition, we discuss what we are currently able to do and what we need to do in the future for primary prophylaxis against a first thrombotic event. Expert commentary: We suggest a comprehensive algorithm to stratify thrombotic risk in aPL carriers, including criteria aPL, non-criteria aPL, their scoring systems, and non-criteria manifestations. However, further studies, particularly prospective randomized controlled trials, are highly warranted to establish an effective and tolerable treatment regimen for high risk aPL carriers.
• 多彩な尿酸塩結晶沈着所見を呈した慢性痛風性関節炎の1例

  村山 迪史, 工藤 悠輔, 西田 睦, 佐藤 恵美, 表原 里実, 岩井 孝仁, 阿部 靖矢, 藤枝 雄一郎, 加藤 将, 澁谷 斉, 松野 吉宏, 渥美 達也

  超音波検査技術抄録集 44 S225 - S225 一般社団法人 日本超音波検査学会 2019年
• 多施設共同疫学研究による体軸性脊椎関節炎の実態調査2019 地域間での比較

  吉川 卓宏, 多田 久里守, 井上 久, 小林 茂人, 浦野 房三, 梅田 雅孝, 川上 純, 佐々木 貴紀, 竹内 勤, 大西 直樹, 渥美 達也, 平田 絢子, 亀田 秀人, 近藤 正一, 公文 義雄, 田村 直人, 松井 聖

  日本脊椎関節炎学会誌 Suppl. 42 - 42 日本脊椎関節炎学会 2019年
• Breakdown of Autonomously Functioning Thyroid Nodule Accompanied by Acromegaly After Octreotide Treatment.

  Nomoto H, Kameda H, Nakamura A, Tsuchida K, Nagai S, Atsumi T, Miyoshi H

  Frontiers in endocrinology 10 131  2019年 [査読有り][通常論文]
  
• Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.

  Chikashi Terao, Hajime Yoshifuji, Takayoshi Matsumura, Taeko K Naruse, Tomonori Ishii, Yoshikazu Nakaoka, Yohei Kirino, Keitaro Matsuo, Tomoki Origuchi, Masakazu Shimizu, Yasuhiro Maejima, Eisuke Amiya, Natsuko Tamura, Takahisa Kawaguchi, Meiko Takahashi, Kazuya Setoh, Koichiro Ohmura, Ryu Watanabe, Tetsuya Horita, Tatsuya Atsumi, Mitsuru Matsukura, Tetsuro Miyata, Yuta Kochi, Toshio Suda, Kazuo Tanemoto, Akira Meguro, Yukinori Okada, Akiyoshi Ogimoto, Motohisa Yamamoto, Hiroki Takahashi, Shingo Nakayamada, Kazuyoshi Saito, Masataka Kuwana, Nobuhisa Mizuki, Yasuharu Tabara, Atsuhisa Ueda, Issei Komuro, Akinori Kimura, Mitsuaki Isobe, Tsuneyo Mimori, Fumihiko Matsuda

  Proceedings of the National Academy of Sciences of the United States of America 115 51 13045 - 13050 2018年12月18日 [査読有り][通常論文]
   

  Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.
• Decreased Expression of Serine/Arginine-Rich Splicing Factor 1 in T Cells From Patients With Active Systemic Lupus Erythematosus Accounts for Reduced Expression of RasGRP1 and DNA Methyltransferase 1.

  Michihiro Kono, Takashi Kurita, Shinsuke Yasuda, Michihito Kono, Yuichiro Fujieda, Toshiyuki Bohgaki, Takayuki Katsuyama, George C Tsokos, Vaishali R Moulton, Tatsuya Atsumi

  Arthritis & rheumatology (Hoboken, N.J.) 70 12 2046 - 2056 2018年12月 [査読有り][通常論文]
   

  OBJECTIVE: T cells from systemic lupus erythematosus (SLE) patients have reduced protein levels of RasGRP1, a guanine nucleotide exchange factor for Ras, and increased transcript of alternatively spliced (AS) forms lacking exon 11. Serine/arginine-rich splicing factor 1 (SRSF1) binds pre-messenger RNA (pre-mRNA) to regulate AS forms of several genes, including CD3ζ in SLE T cells. This study was undertaken to assess whether SRSF1 controls the expression of RasGRP1 in T cells from patients with SLE. METHODS: We studied T cells from 45 SLE patients and 18 healthy subjects. Expression levels of SRSF1, wild-type (WT) RasGRP1, and DNA methyltransferase 1 (DNMT1) were assessed by quantitative polymerase chain reaction. Direct binding of SRSF1 to exon 11 of RasGRP1 mRNA was evaluated with an oligonucleotide-protein pulldown assay. Healthy T cells and SLE T cells were treated with SRSF1-specific small interfering RNA or SRSF1 expression vector, respectively, and then evaluated for mRNA/protein expression. RESULTS: SRSF1 expression levels were significantly lower in T cells from SLE patients compared to those from healthy subjects, and correlated inversely with disease activity and positively with levels of RasGRP1-WT and DNMT1. SRSF1 bound directly to exon 11 of RasGRP1 mRNA. Silencing of SRSF1 in human T cells led to increased ratios of RasGRP1-AS to RasGRP1-WT and decreased levels of RasGRP1 protein, whereas overexpression of SRSF1 in SLE T cells caused recovery of RasGRP1, which in turn induced DNMT1/interleukin-2 expression. CONCLUSION: SRSF1 controls the alternative splicing of RasGRP1 and subsequent protein expression. Our findings extend evidence that alternative splicing plays a central role in the aberrant T cell function in patients with SLE by controlling the expression of multiple genes.
• Ectopic RASGRP2 (CalDAG-GEFI) expression in rheumatoid synovium contributes to the development of destructive arthritis.

  Hiroyuki Nakamura, Sanae Shimamura, Shinsuke Yasuda, Michihito Kono, Michihiro Kono, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Tomohiro Shimizu, Norimasa Iwasaki, Tatsuya Atsumi

  Annals of the rheumatic diseases 77 12 1765 - 1772 2018年12月 [査読有り][通常論文]
   

  OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune polyarthritis, in which fibroblast-like synoviocytes (FLS) play a key role in cartilage and bone destruction through tumour-like proliferation and invasiveness. Considering still unsatisfactory remission rate in RA even under treatment with biological disease-modifying antirheumatic drugs, novel therapeutic strategy for treatment-resistant RA is still awaited. In this study, we analysed the expression and function of Ras guanine nucleotide-releasing proteins (RASGRPs), guanine exchange factors for small GTPase Ras, in FLS as a potential therapeutic target for RA. METHODS: The expression of RASGRPs mRNA was quantified by a real-time PCR assay in FLS isolated from synovial tissue samples. RASGRP2 protein was also evaluated immunohistochemically. Then, we transiently transfected FLS with RASGRP2 expression vector and assessed their proliferation, adhesion, migration and invasion by cellular functional assays and downstream signalling activation using immunoblot. Finally, the therapeutic effect of RASGRP2 silencing was evaluated in type-II collagen-induced arthritis rats. RESULTS: RASGRP2 was abundantly expressed in FLS from RA synovium, whereas scarcely found in those from osteoarthritis. Expression of RASGRP2 in RA-FLS was enhanced by transforming growth factor-beta. RASGRP2 activated RAP-1, subsequently affecting nuclear factor kappa-light-chain-enhancer of activated B cells pathway and actin dynamics in FLS. RASGRP2-overexpressed FLS had increased abilities of adhesion, migration and interleukin (IL)-6 production. Silencing of RASGRP2 using the intra-articular injection of Rasgrp2-specific siRNAs dampened experimental arthritis in rats by inhibiting pannus formation. CONCLUSIONS: RASGRP2 was identified to be involved in the pathogenesis of RA by promoting adhesion, migration and IL-6 production from FLS, proposed as a potential novel non-immunosuppressive therapeutic target for RA.
• ゲノムワイド関連解析を用いた産科抗リン脂質抗体症候群の新たな関連遺伝子の探索

  吉原 紘行, 大前 陽輔, 川嶋 実苗, 豊岡 理人, Khor Seik-Soon, 澤井 裕美, 堀田 哲也, 渥美 達也, 村島 温子, 藤田 太輔, 藤田 富雄, 森本 真司, 森下 英理子, 桂木 真司, 北折 珠央, 片野 衣江, 尾崎 康彦, 徳永 勝士, 杉浦 真弓

  日本生殖医学会雑誌 63 4 524 - 525 (一社)日本生殖医学会 2018年12月
• Anti-TIF1γ antibody predicted malignancy of thymic tumor with dermatomyositis as an "autoimmune tumor marker": A case report.

  Karino K, Fujieda Y, Kawamura T, Abe N, Shimoyama S, Kono M, Kato M, Yasuda S, Atsumi T

  Medicine 97 49 e13563  2018年12月 [査読有り][通常論文]
  
• Potential therapeutics for antiphospholipid antibody associated thrombocytopenia: a systematic review and meta-analysis.

  Abe N, Oku K, Amengual O, Fujieda Y, Kato M, Bohgaki T, Yasuda S, Mori R, Morishita E, Suzuki-Inoue K, Atsumi T

  Modern rheumatology 30 1 1 - 21 2018年12月 [査読有り][通常論文]
   

  Objectives: Thrombocytopenia is frequently observed in antiphospholipid antibody (aPL) carriers. Due to the paradoxical risks of thrombosis and hemorrhage, the management of aPL-associated thrombocytopenia (APAT) is often deductive. We aimed to investigate the efficacy and safety of therapeutic approaches for APAT through a systematic review. Methods: Four therapeutic approaches for APAT, including antiplatelet agents, glucocorticoids, splenectomy and thrombopoietin receptor agonists, were selected. Clinical trials evaluating therapeutic outcomes including the remission, complications, mortality and relapse, were searched in MEDLINE, EMBASE and CENTRAL from the inception dates to 28 November 2016. A meta-analysis was performed to calculate risk ratios (RRs) and 95% confidence intervals (CIs) using random-effects models. Results: Out of 1407 papers, eight controlled clinical trials were included. In patients with APAT, the remission rates were higher in patients on glucocorticoids (RR 8.33 [95% CI 3.07-22.6]) or splenectomy (RR 8.37 [95% CI 1.61-43.7]) than in patients without those treatments. There was no significant association between glucocorticoids and thrombosis (RR 1.57 [95% CI, 0.17-14.9]) or between splenectomy and hemorrhage (RR 0.17 [95% CI 0.02-1.28]). The extracted data of mortality and relapse rate were not available for synthesis. Conclusion: Glucocorticoids or splenectomy seemed suitable therapeutic approaches for APAT.
• Detection of Autoreactive Type II NKT Cells: A Pilot Study of Comparison Between Healthy Individuals and Patients with Vasculitis.

  Yusuke Nishioka, Takaomi Sonoda, Haruki Shida, Yoshihiro Kusunoki, Fumihiko Hattanda, Shun Tanimura, Ryo Uozumi, Mai Yamada, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  Cytometry. Part A : the journal of the International Society for Analytical Cytology 93 11 1157 - 1164 2018年11月 [査読有り][通常論文]
   

  NKT cells are defined as T cells that recognize hydrophobic antigens presented by class I MHC-like molecules, including CD1d. Among CD1d-restricted NKT cells, type I and type II subsets have been noted. CD1d-restricted type I NKT cells are regarded as pro-inflammatory cells in general. On the contrary, accumulated evidence has demonstrated an anti-inflammatory property of CD1d-restricted type II NKT cells. In our earlier study using a rat model with vasculitis, we demonstrated the pro-inflammatory function of CD1d-restricted type II NKT cells and identified that one such cell recognized P518-532 of rat sterol carrier protein 2 (rSCP2518-532 ), which appeared on vascular endothelial cells presented by CD1d. Based on this evidence, we attempted to detect human CD1d-restricted type II NKT cells in peripheral blood using hSCP2518-532 , the human counterpart of rSCP2518-532, together with a CD1d tetramer in flow cytometry. First, we determined the binding of hSCP2518-532 to CD1d. Next, we detected CD3-positive hSCP2518-532 -loaded CD1d (hSCP2518-532 /CD1d) tetramer-binding cells in peripheral blood of healthy donors. The abundance of TGF-β-producing cells rather than TNF-α-producing cells in CD3-positive hSCP2518-532 /CD1d tetramer-binding cells suggests the anti-inflammatory property of SCP2-loaded CD1d (SCP2/CD1d) tetramer-binding type II NKT cells in healthy individuals. Furthermore, we compared cytokine profile between healthy individuals and patients with vasculitis in a pilot study. Interestingly, the percentage of TGF-β-producing cells in SCP2/CD1d tetramer-binding type II NKT cells in vasculitic patients was significantly lower than that in healthy controls despite the greater number of these cells. Although further studies to clarify the mechanism and significance of this phenomenon are needed, SCP2/CD1d tetramer-binding type II NKT cells in peripheral blood should be examined in more detail to understand the pathophysiology of vasculitides in humans. © 2018 International Society for Advancement of Cytometry.
• 関節リウマチの関節破壊進行予測におけるパワードプラ超音波検査の定量的評価の有用性

  瀬野 結実香, 勝海 友里, 藤森 元嗣, 堀江 達則, 西田 睦, 神島 保, 加藤 將, 保田 晋助, 渥美 達也

  北海道医学雑誌 93 2 123 - 123 北海道医学会 2018年11月
• 【徹底ガイド DICのすべて 2019-20】(X章)類似病態、鑑別すべき病態 APS(抗リン脂質抗体症候群)

  堀田 哲也, 渥美 達也

  救急・集中治療 30 臨増 420 - 424 (株)総合医学社 2018年11月 [査読有り][通常論文]
   

  ＜point＞▼APSは、血中に抗リン脂質抗体が検出され、各種動静脈血栓症や妊娠合併症をきたす自己免疫性疾患である。▼SLEなどの膠原病に合併する二次性APSと、基礎疾患をもたない原発性APSに分類される。▼若年性の脳梗塞や習慣流産をきたす患者をみた場合や、検査値異常としてAPTTの延長や血小板減少がみられた場合は、抗リン脂質抗体を検査してみる必要がある。▼急性期の血栓症に対しては、それぞれの血栓症の標準的治療が推奨され、慢性期には再発予防が重要であり、抗血小板療法、抗凝固療法が考慮される。妊娠合併症の治療には、少量アスピリンやヘパリンの投与が考慮される。▼短期間に多臓器の血栓症を発症するCAPSという病型があり、抗血栓療法や免疫抑制療法を含む集学的な治療を行っても致死率が高い。(著者抄録)
• Relationship Between Visceral Fat and Plasma Aldosterone Concentration in Patients With Primary Aldosteronism.

  Shibayama Y, Wada N, Baba S, Miyano Y, Obara S, Iwasaki R, Nakajima H, Sakai H, Usubuchi H, Terae S, Nakamura A, Atsumi T

  Journal of the Endocrine Society 2 11 1236 - 1245 2018年11月 [査読有り][通常論文]
  
• Association Between Reappearance of Myeloperoxidase-Antineutrophil Cytoplasmic Antibody and Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Subgroup Analysis of Nationwide Prospective Cohort Studies.

  Watanabe H, Sada KE, Matsumoto Y, Harigai M, Amano K, Dobashi H, Fujimoto S, Usui J, Yamagata K, Atsumi T, Banno S, Sugihara T, Arimura Y, Matsuo S, Makino H, Japan Research Committee of, the, Ministry of Health,Labour, d Welfare for Intractable Vasculitis, the Research Committee of, Intractable Renal, Disease of, the, Ministry of Health,Labour, Welfare of Japan

  Arthritis & rheumatology (Hoboken, N.J.) 70 10 1626 - 1633 2018年10月 [査読有り][通常論文]
   

  OBJECTIVE: To evaluate clinical links between levels of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and relapse in patients with ANCA-associated vasculitis (AAV) using a data set from 2 nationwide prospective cohort studies. METHODS: From the cohort studies, MPO-ANCA-positive patients who achieved remission during the 6 months after remission induction therapy were enrolled. We measured MPO-ANCA levels at months 0, 3, 6, 12, 18, 24, and at the time of relapse. The primary outcome measure was relapse. A nested case-control analysis and multivariable analysis were performed to investigate the relationship between ANCA reappearance and relapse. RESULTS: Of 271 patients, 183 were classified as having microscopic polyangiitis, 34 as having granulomatosis with polyangiitis, 15 as having eosinophilic granulomatosis with polyangiitis, and 39 were unclassifiable. The median age was 73 years, and 165 (61%) were female. In 195 patients (72%), MPO-ANCA levels decreased to normal levels within 6 months after commencement of treatment, and MPO-ANCA reappeared in 73 of 181 patients (40%) with complete follow-up data. Reappearance of MPO-ANCA was more frequent in patients with relapse than in 75 age- and sex-matched control patients without relapse (odds ratio 26.2 [95% confidence interval 8.2-101], P < 0.0001) after adjustment for confounding factors. CONCLUSION: Reappearance of MPO-ANCA could be a clinically useful biomarker for predicting relapse in patients with MPO-ANCA-positive AAV in remission. This suggests that routine MPO-ANCA monitoring should be implemented in this patient population.
• 服薬アドヒアランスの悪い高齢者2型糖尿病に週1回GLP-1受容体作動薬が有用であった1例

  高瀬 崇宏, 三好 秀明, 大森 一乃, 高橋 清彦, 北尾 直之, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也

  日本老年医学会雑誌 55 4 699 - 699 (一社)日本老年医学会 2018年10月
• 【関節リウマチと骨粗鬆症 今後の展開】関節リウマチと骨障害・骨粗鬆症に対するバイオマーカー

  河野 通大, 渥美 達也

  分子リウマチ治療 11 4 177 - 180 (株)先端医学社 2018年10月 [査読有り][通常論文]
   

  関節リウマチ(RA)診療において、生物学的製剤を含めた治療の進歩により高率に臨床的寛解の達成が可能となった。一方で、臨床的寛解を達成していても骨破壊・骨粗鬆症が進行する症例が存在することから、骨障害・骨粗鬆症を予測できるバイオマーカーの普及が期待される。RA患者では、破骨細胞の活性化による骨吸収の亢進が骨破壊・骨粗鬆症病態における中心的な役割を演じており、破骨細胞機能を反映する種々の骨吸収マーカーは、現段階で最も有用なバイオマーカーと考えられている。実際にさまざまな骨吸収マーカーがRA患者における骨破壊評価・進行予測に有用であるという報告が散見されるものの、日常診療における有用性に関して一定した見解は得られていない。RA患者の臨床現場における骨吸収マーカーの評価方法・時期・有用性の確立に向け、今後、更なる症例の蓄積が期待される。(著者抄録)
• 【話題のリウマチ・膠原病治療薬:その基礎と臨床評価】ミコフェノール酸モフェチル

  河野 通大, 渥美 達也

  炎症と免疫 26 6 505 - 510 (株)先端医学社 2018年10月 [査読有り][通常論文]
   

  ミコフェノール酸モフェチル(MMF)は、T、Bリンパ球の増殖を選択的に抑制する新たな作用機序を有する免疫抑制薬である。ループス腎炎の寛解導入治療および維持治療につき海外を中心に有効性・安全性が多数報告され、MMFはループス腎炎における標準治療の一つとされている。当院でも中等量ステロイド併用MMFは、ループス腎炎の寛解導入治療として良好な成績を示した。しかし、ループス腎炎をはじめとする多くの膠原病疾患で、日本人におけるMMFの有効性・安全性に関する報告は限られており、今後のさらなる症例の集積が望まれる。(著者抄録)
• Pathogenesis of Antiphospholipid syndrome:and update

  アメングアル オルガ

  Lupus 2018年10月 [査読有り][招待有り]
  
• Quantification of hand synovitis in rheumatoid arthritis: Arterial mask subtraction reinforced with mutual information can improve accuracy of pixel-by-pixel time–intensity curve shape analysis in dynamic MRI

  Yuto Kobayashi, Tamotsu Kamishima, Hiroyuki Sugimori, Shota Ichikawa, Atsushi Noguchi, Michihito Kono, Toshitake Iiyama, Kenneth Sutherland, Tatsuya Atsumi

  Journal of Magnetic Resonance Imaging 48 3 687 - 694 2018年09月 [査読有り][通常論文]
   

  © 2018 International Society for Magnetic Resonance in Medicine Background: Synovitis, which is a hallmark of rheumatoid arthritis (RA), needs to be precisely quantified to determine the treatment plan. Time–intensity curve (TIC) shape analysis is an objective assessment method for characterizing the pixels as artery, inflamed synovium, or other tissues using dynamic contrast-enhanced MRI (DCE-MRI). Purpose/Hypothesis: To assess the feasibility of our original arterial mask subtraction method (AMSM) with mutual information (MI) for quantification of synovitis in RA. Study Type: Prospective study. Subjects: Ten RA patients (nine women and one man; mean age, 56.8 years; range, 38–67 years). Field Strength/Sequence: 3T/DCE-MRI. Assessment: After optimization of TIC shape analysis to the hand region, a combination of TIC shape analysis and AMSM was applied to synovial quantification. The MI between pre- and postcontrast images was utilized to determine the arterial mask phase objectively, which was compared with human subjective selection. The volume of objectively measured synovitis by software was compared with that of manual outlining by an experienced radiologist. Simple TIC shape analysis and TIC shape analysis combined with AMSM were compared in slices without synovitis according to subjective evaluation. Statistical Tests: Pearson's correlation coefficient, paired t-test and intraclass correlation coefficient (ICC). Results: TIC shape analysis was successfully optimized in the hand region with a correlation coefficient of 0.725 (P < 0.01) with the results of manual assessment regarded as ground truth. Objective selection utilizing MI had substantial agreement (ICC = 0.734) with subjective selection. Correlation of synovial volumetry in combination with TIC shape analysis and AMSM with manual assessment was excellent (r = 0.922, P < 0.01). In addition, negative predictive ability in slices without synovitis pixels was significantly increased (P < 0.01). Data Conclusions: The combination of TIC shape analysis and image subtraction reinforced with MI can accurately quantify synovitis of RA in the hand by eliminating arterial pixels. Level of Evidence: 2. Technical Efficacy: Stage 2. J. Magn. Reson. Imaging 2018;48:687–694.
• Remission of Nephrotic Syndrome After Therapy for Chronic Hepatitis C Virus Infection in a Patient With Systemic Lupus Erythematosus.

  Nakamura H, Fujieda Y, Yasuda S, Nakai M, Atsumi T

  Annals of internal medicine 169 5 352 - 353 2018年09月 [査読有り][通常論文]
  
• The Effect of Everolimus on Refractory Hypoglycemia in a Patient with Inoperable Metastatic Insulinoma Evaluated by Continuous Glucose Monitoring.

  Shingo Yanagiya, Kyu Yong Cho, Akinobu Nakamura, Hiroshi Nomoto, Yasuyuki Kawamoto, Kazumichi Kawakubo, Yoshito Komatsu, Tomoko Mitsuhashi, Hideaki Miyoshi, Tatsuya Atsumi

  Internal medicine (Tokyo, Japan) 57 17 2527 - 2531 2018年09月01日 [査読有り][通常論文]
   

  An 84-year-old Japanese woman with metastatic insulinoma suffered from frequent hypoglycemic events. Continuous glucose monitoring (CGM) confirmed severe and frequent symptomatic/asymptomatic hypoglycemia. After the initiation of everolimus treatment, the hypoglycemic events were rapidly eliminated. CGM revealed that her blood glucose levels were maintained without hypoglycemia throughout the day. Furthermore, everolimus reduced the duration of time above the upper limit (>180 mg/dL) along with the standard deviation and mean amplitude of glycemic excursions. This case shows the potential effects of everolimus on hypoglycemia and glycemic control in a patient with inoperable metastatic insulinoma evaluated by CGM.
• Systemic lupus erythematosus: nothing stale her infinite variety.

  Oku K, Atsumi T

  Modern rheumatology 28 5 758 - 765 2018年09月 [査読有り][通常論文]
  
• Factors Associated with First Thrombosis in Patients Presenting with Obstetric Antiphospholipid Syndrome in APS Alliance For Clinical Trials & International Networking (APS ACTION) Clinical Database And Repository: a retrospective study.

  de Jesús GR, Sciascia S, Andrade D, Nascimento IS, Rosa R, Barbhaiya M, Tektonidou M, Banzato A, Pengo V, Ji L, Meroni PL, Ugarte A, Cohen H, Branch DW, Andreoli L, Belmont HM, Fortin PR, Petri M, Rodriguez E, Cervera R, Knight JS, Atsumi T, Willis R, Erkan D, Levy RA, APS ACTION

  BJOG : an international journal of obstetrics and gynaecology 2018年09月 [査読有り][通常論文]
  
• Sustained Clinical Remission after Discontinuation of Infliximab with a Raising Dose Strategy in Patients with Rheumatoid Arthritis (RRRR study): A Randomized Controlled Trial

  Tanaka Yoshiya, Oba Koji, Koike Takao, Miyasaka Nobuyuki, Mimori Tsuneyo, Takeuchi Tsutomu, Hirata Shintaro, Tanaka Eiichi, Yasuoka Hidekata, Kaneko Yuko, Murakami Kosaku, Koga Tomohiro, Nakano Kazuhisa, Amano Koichi, Ushio Kazuyasu, Atsumi Tatsuya, Inoo Masayuki, Hatta Kazuhiro, Mizuki Shinichi, Nagaoka Shohei, Tsunoda Shinichiro, Dobashi Hiroaki, Horie Nao, Sato Norihiro

  ARTHRITIS & RHEUMATOLOGY 70 2018年09月 [査読有り][通常論文]
  
• Malignancy in Japanese Patients with Rheumatoid Arthritis Treated with Tofacitinib: Interim Analysis of All-Case Post-Marketing Surveillance

  Tamura Naoto, Kuwana Masataka, Atsumi Tatsuya, Takei Syuji, Harigai Masayoshi, Fujii Takao, Matsuno Hiroaki, Mimori Tsuneyo, Momohara Shigeki, Yamamoto Kazuhiko, Takasaki Yoshinari, Nomura Kazuto, Endo Yutaka, Hirose Tomohiro, Morishima Yosuke, Sugiyama Naonobu, Yoshii Noritoshi, Takagi Michiaki

  ARTHRITIS & RHEUMATOLOGY 70 2018年09月 [査読無し][通常論文]
  
• Infection Events in Japanese Patients with Rheumatoid Arthritis Treated with Tofacitinib: Interim All-Case Post-Marketing Surveillance

  Tamura Naoto, Kuwana Masataka, Atsumi Tatsuya, Takei Syuji, Harigai Masayoshi, Fujii Takao, Matsuno Hiroaki, Mimori Tsuneyo, Momohara Shigeki, Yamamoto Kazuhiko, Takasaki Yoshinari, Nomura Kazuto, Endo Yutaka, Hirose Tomohiro, Morishima Yosuke, Sugiyama Naonobu, Yoshii Noritoshi, Takagi Michiaki

  ARTHRITIS & RHEUMATOLOGY 70 2018年09月 [査読無し][通常論文]
  
• Clinical significance of plasma presepsin levels in patients with systemic lupus erythematosus.

  Shun Tanimura, Yuichiro Fujieda, Michihiro Kono, Yuhei Shibata, Ryo Hisada, Eri Sugawara, Hiroyuki Nakamura, Kazumasa Ohmura, Sanae Shimamura, Asako Mitani, Haruki Shida, Toshiyuki Watanabe, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Chikara Shimizu, Tatsuya Atsumi

  Modern rheumatology 28 5 865 - 871 2018年09月 [査読有り][通常論文]
   

  OBJECTIVES: Presepsin (PSEP: soluble CD14 subtype) is produced from bacteria-stimulated monocytes or neutrophils, thus recognized as a biomarker of sepsis. Aberrant functions in monocyte or neutrophils are increasingly recognized in systemic lupus erythematosus (SLE). We investigated whether plasma PSEP reflects disease activity in patients with SLE. METHODS: This retrospective study comprised 35 patients with SLE and 72 with non-SLE autoimmune diseases who visited our facility during the period from August 2012 to September 2015. Plasma PSEP levels and laboratory data were compared between SLE and non-SLE. Clinical markers of SLE disease activity, including SLE disease activity index 2000 (SLEDAI-2K), serum complement concentrations and serum anti-ds-DNA antibodies were assessed in correlation with plasma PSEP levels. RESULTS: Plasma PSEP levels in SLE were higher than those in non-SLE. This phenomenon holds true when comparing SLE and non-SLE patients in the absence of infection (p = .0008). Plasma PSEP levels in SLE patients negatively correlated with C3 (r = -0.4454, p = .0430), CH50 (r = -0.4502, p = .0406) and positively with SLEDAI-2K (r = 0.4801, p = .0237). CONCLUSION: Elevated plasma PSEP levels were correlated with disease activity of SLE, suggesting inappropriate monocyte or neutrophil activation in the pathophysiology of SLE exacerbation.
• Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis in a real-world clinical setting.

  Tatsuya Atsumi, Keishi Fujio, Kunihiro Yamaoka, Minako Tomobe, Kazuyuki Kuroyanagi, Hideto Kameda

  Modern rheumatology 28 5 780 - 788 2018年09月 [査読有り][通常論文]
   

  OBJECTIVES: The objective of this study is to evaluate the safety and effectiveness of subcutaneous tocilizumab (TCZ-SC) in a real-world clinical setting in Japan. METHODS: This single arm, 26-week prospective observational study enrolled patients with RA who were either TCZ naïve or switched from TCZ-IV to TCZ-SC (TCZ-IV-SC group) (UMIN Clinical Trials Registry UMIN000011102). All patients received TCZ-SC 162 mg every 2 weeks and data were collected until week 26 or discontinuation. RESULTS: Overall 784 (78.1%) were TCZ naïve and 219 (21.8%) were in the TCZ-IV-SC group. 70.9% received disease-modifying antirheumatic drugs at baseline. Adverse events (AEs) and serious AEs occurred in 28.2% and 4.9% of patients, respectively (TCZ-naïve: 29.5% and 5.2%; TCZ-IV-SC: 23.2% and 4.1%). Infections and infestations were the most common AEs (7.4%) and serious AEs (1.7%). Two TCZ-naïve patients died. TCZ-naïve patients had an improvement in median Clinical Disease Activity Index (CDAI) score and mean Disease Activity Score in 28 joints as measured by erythrocyte sedimentation rate (DAS28-ESR) from baseline to week 26. The TCZ-IV-SC group had similar median CDAI scores and mean DAS28-ESR over 26 weeks. CONCLUSIONS: There were no unexpected safety signals with TCZ-SC. TCZ-SC was effective in reducing disease activity in TCZ-naïve patients and maintaining remission in TCZ-IV-SC patients.
• Serum adiponectin and insulin secretion: A direct or inverse association?

  Akinobu Nakamura, Hideaki Miyoshi, Shigekazu Ukawa, Koshi Nakamura, Takafumi Nakagawa, Yasuo Terauchi, Akiko Tamakoshi, Tatsuya Atsumi

  Journal of diabetes investigation 9 5 1106 - 1109 2018年09月 [査読有り][通常論文]
   

  We investigated the association between serum high molecular weight (HMW) adiponectin and insulin secretion in a population-based study, with or without adjustment for insulin sensitivity. A total of 488 participants (263 women) were included in the present study. Insulin secretion was estimated using the homeostasis model assessment of β-cell function ± adjustment for insulin resistance using the disposition index. Multivariate analysis showed that HMW adiponectin was significantly and inversely associated with homeostasis model assessment of β-cell function (partial regression coefficient -0.19, 95% confidence interval -0.28, -0.10, P < 0.0001). However, HMW adiponectin was significantly and positively associated with disposition index (partial regression coefficient 0.15, 95% confidence interval 0.06, 0.24, P = 0.0016). The present study showed that a positive association between HMW adiponectin levels and insulin secretion evaluated using an index incorporating adjustment for insulin resistance was identified, and vice versa using an index that did not adjust for insulin resistance.
• The role of glucokinase and insulin receptor substrate-2 in the proliferation of pancreatic beta cells induced by short-term high-fat diet feeding in mice.

  Naoyuki Kitao, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Kiyohiko Takahashi, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi

  Metabolism: clinical and experimental 85 48 - 58 2018年08月 [査読有り][通常論文]
   

  OBJECTIVE: We investigated whether glucokinase and insulin receptor substrate-2 were required for beta cell proliferation induced by short-term high-fat (HF) diet feeding, as has been shown for long-term HF diet. METHODS: Eight-week-old C57BL/6J mice were exposed to either a standard chow (SC) or HF diet. After 1 week on the diet, histopathological beta cell proliferation and gene expression in isolated islets were examined. Additionally, 8-week-old beta cell-specific glucokinase haploinsufficient (Gck+/-) and Irs2 knockout (Irs2-/-) mice were exposed to either an SC or HF diet. RESULTS: Immunohistochemical analysis revealed that short-term HF diet feeding resulted in a significant increase in BrdU incorporation rate compared with SC consumption in wild-type mice. Western blot analysis demonstrated that Irs2 expression levels did not differ between the two diets. Moreover, there was a significant increase in the BrdU incorporation rate in the HF diet group compared with the SC group in both Gck+/- and Irs2-/- mice. Gene expression profiling of isolated islets from mice fed an HF diet for 1 week revealed that the expression levels of downstream genes of Foxm1 were coordinately upregulated. One week of HF diet feeding stimulated beta cell proliferation with Foxm1 upregulation in 48-week-old mice as well as in 8-week-old. CONCLUSIONS: The mechanism of pancreatic beta cell proliferation induced by short-term HF diet feeding in mice could involve a glucokinase- and Irs2-independent pathway. Our results suggest that the pathways that induce beta cell proliferation in response to short-term HF diet feeding may differ from those in response to sustained HF diet feeding.
• The data of change in macrophage gene expression which induced by perilipin 1 overexpression.

  Kohei Yamamoto, Hideaki Miyoshi, Kyu Yong Cho, Akinobu Nakamura, Andrew S Greenberg, Tatsuya Atsumi

  Data in brief 19 179 - 182 2018年08月 [査読有り][通常論文]
   

  The data presented here are related to the research article entitled "Overexpression of Perilipin1 protects against atheroma progression in apolipoprotein E knockout mice" [1]. This paper describes data that were obtained from perilipin 1 (PLIN1) transgenic mice (Plin1Tg) regarding atherosclerosis. The main aim of collecting the data was to clarify the role of PLIN1 in the pathophysiology of atherosclerosis. The data were collected from C57BL/6J mice, apolipoprotein E knockout mice (ApoeKO) and Plin1Tg/ApoeKO. The atherosclerotic lesion areas of aorta were 3.3 ± 1.2% in C57BL/6J mice, 14.2 ± 3.2% in ApoeKO, and 5.6 ± 1.9% in Plin1Tg/ApoeKO. Body weight, gonadal adipose mass and plasma triglyceride concentrations were comparable among the three groups [1]. Furthermore, PLIN1 overexpression did not affect the gene expressions related to cholesterol influx and efflux in macrophage.
• Evaluation of the alternative classification criteria of systemic lupus erythematosus established by Systemic Lupus International Collaborating Clinics (SLICC).

  Kenji Oku, Tatsuya Atsumi, Yuji Akiyama, Hirofumi Amano, Naoto Azuma, Toshiyuki Bohgaki, Yu Funakubo Asanuma, Tetsuya Horita, Tadashi Hosoya, Kunihiro Ichinose, Masaru Kato, Yasuhiro Katsumata, Yasushi Kawaguchi, Atsushi Kawakami, Tomohiro Koga, Hitoshi Kohsaka, Yuya Kondo, Kanae Kubo, Masataka Kuwana, Akio Mimori, Tsuneyo Mimori, Toshihide Mimura, Kosaku Murakami, Kazuhisa Nakano, Shingo Nakayamada, Hiroshi Ogishima, Kazumasa Ohmura, Kazuyoshi Saito, Hajime Sano, Mihoko Shibuya, Yuko Takahashi, Yoshinari Takasaki, Tsutomu Takeuchi, Naoto Tamura, Yoshiya Tanaka, Hiroto Tsuboi, Shinichiro Tsunoda, Naoichiro Yukawa, Noriyuki Yamakawa, Kazuhiko Yamamoto, Takayuki Sumida

  Modern rheumatology 28 4 642 - 648 2018年07月 [査読有り][通常論文]
   

  OBJECTIVE: To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan. METHODS: This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses. RESULTS: Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p < .01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses. CONCLUSION: Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population.
• Interferon-inducible Mx1 protein is highly expressed in renal tissues from treatment-naïve lupus nephritis, but not in those under immunosuppressive treatment.

  Shimizu Y, Yasuda S, Kimura T, Nishio S, Kono M, Ohmura K, Shimamura S, Kono M, Fujieda Y, Kato M, Oku K, Bohgaki T, Fukasawa Y, Tanaka S, Atsumi T

  Modern rheumatology 28 4 661 - 669 2018年07月 [査読有り][通常論文]
   

  OBJECTIVES: The aim of this study was to clarify the consequences of Mx1, one of the IFN-inducible proteins, in the peripheral blood as well as in renal tissues in patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Mx1 protein concentrations in (PBMCs) from 18 SLE patients mostly in their stable disease status, 11 IgA nephropathy (IgAN) patients, 5 ANCA-associated vasculitis (AAV) patients and 16 healthy controls were measured using enzyme-linked immunosorbent assay (ELISA). Mx1 expression in renal specimens from 18 patients with lupus nephritis (LN), 18 with IgAN and 10 with AAV were evaluated using immunohistochemistry. RESULTS: Mx1 protein concentrations in lysates of PBMCs were significantly higher in SLE patients compared with those in other three groups. Mx1-positive area in renal tissues was significantly dominant in both glomeruli and renal tubules of LN compared with other renal diseases. Renal Mx1 protein levels were lower in LN after immunosuppressive treatment, compared with those from immunosuppressant-naïve patients. CONCLUSION: Mx1 levels were upregulated in lupus peripheral blood even when their disease activities were stable. On the other hand, Mx1 was highly expressed in kidneys from patients with LN before treatment, which was decreased after immunosuppressive treatment. These results suggest that Mx1 is a potential marker for the diagnosis of SLE in the peripheral blood and also for the activity of lupus nephritis in the kidney.
• Comment on "Elevation of Serum Carcinoembryonic Antigen Concentration Caused by Everolimus-Induced Lung Injury: A Case Report".

  Nomoto H, Miyoshi H, Sekizaki T, Atsumi T

  Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 24 3 165 - 166 2018年06月 [査読有り][通常論文]
  
• 抗C1qモノクローナル抗体による流産モデルマウスの検討

  大村 一将, 奥 健志, 吉田 美香, 内藤 澄悦, 高橋 伸彦, 渥美 達也, 家子 正裕

  日本検査血液学会雑誌 19 学術集会 S196 - S196 (一社)日本検査血液学会 2018年06月 [査読有り][通常論文]
  
• POST-MARKETING SURVEILLANCE OF TOFACITINIB IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS: AN INTERIM REPORT OF SAFETY DATA

  Tamura N, Kuwana M, Atsumi T, Takei S, Harigai M, Fujii T, Matsuno H, Mimori T, Momohara S, Yamamoto K, Nomura K, Endo Y, Sugiyama N, Hirose T, Morishima Y, Yoshii N, Takagi M

  ANNALS OF THE RHEUMATIC DISEASES 77 1408 - 1408 2018年06月 [査読無し][通常論文]
  
• Prodromal signs and symptoms of serious infections with tocilizumab treatment for rheumatoid arthritis: Text mining of the Japanese postmarketing adverse event-reporting database

  Tatsuya Atsumi, Yoshiaki Ando, Shinichi Matsuda, Shiho Tomizawa, Riwa Tanaka, Nobuhiro Takagi, Ayako Nakasone

  Modern Rheumatology 28 3 435 - 443 2018年05月04日 [査読有り][通常論文]
   

  Objective: To search for signs and symptoms before serious infection (SI) occurs in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients. Methods: Individual case safety reports, including structured (age, sex, adverse event [AE]) and unstructured (clinical narratives) data, were analyzed by automated text mining from a Japanese post-marketing AE-reporting database (16 April 2008–10 April 2015) assuming the following: treated in Japan TCZ RA treatment ≥1 SI unable to exclude causality between TCZ and SIs. Results: The database included 7653 RA patients 1221 reports met four criteria, encompassing 1591 SIs. Frequent SIs were pneumonia (15.9%), cellulitis (9.9%), and sepsis (5.0%). Reports for 782 patients included SI onset date 60.7% of patients had signs/symptoms ≤28 days before SI diagnosis, 32.7% had signs/symptoms with date unidentified, 1.7% were asymptomatic, and 4.9% had unknown signs/symptoms. The most frequent signs/symptoms were for skin (swelling and pain) and respiratory (cough and pyrexia) infections. Among 68 patients who had normal laboratory results for C-reactive protein, body temperature, and white blood cell count, 94.1% had signs or symptoms of infection. Conclusion: This study identified prodromal signs and symptoms of SIs in RA patients receiving TCZ. Data mining clinical narratives from post-marketing AE databases may be beneficial in characterizing SIs.
• Antiphospholipid syndrome, “the best prophet of the future”

  Olga Amengual, Tatsuya Atsumi

  Modern Rheumatology 28 3 409 - 416 2018年05月04日 [査読有り][通常論文]
   

  The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of venous and arterial thromboses, often multiple, and obstetric-related adverse events in the presence of antiphospholipid antibodies (aPL). APS, first described in 1983, as thrombosis, abortion and cerebral disease, is nowadays recognised as a systemic disease with a wide constellation of clinical manifestations related to acute and chronic vascular lesions. The presence of aPL is the serological hallmark of APS representing a heterogeneous population of autoantibodies with many antigenic specificities directed to phospholipid-binding proteins, either alone or in combination with phospholipids. Many assays have been developed for aPL detection. Particularly, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies and lupus anticoagulant are essential tools for APS diagnosis. The cumulative evidence indicates that aPL are pathogenic autoantibodies binding to target cells and promoting thrombosis and pregnancy complications through a wide range of pathological mechanisms not yet fully understood. Finally, the recognition of the important role of aPL to assess the individual risk of thrombosis or pregnancy complications has expanded the concept of aPL, and currently aPL profile is regarded as a major risk factor for clinical thrombotic events.
• Improvement in the proinsulin/C-peptide ratio during treatment with ipragliflozin in Japanese patients with type 2 diabetes mellitus

  Takahiro Takase, Akinobu Nakamura, Chiho Yamamoto, Tatsuya Atsumi, Hideaki Miyoshi

  Expert Opinion on Pharmacotherapy 19 7 631 - 632 2018年05月03日 [査読有り][通常論文]
  
• Effect of the sodium-glucose cotransporter 2 inhibitor luseogliflozin on pancreatic beta cell mass in db/db mice of different ages.

  Kiyohiko Takahashi, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Naoyuki Kitao, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi

  Scientific reports 8 1 6864 - 6864 2018年05月01日 [査読有り][通常論文]
   

  To examine the effects of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, on pancreatic beta cell mass in db/db mice of different ages. db/db mice aged 6, 10, 14 and 24 weeks old were fed either standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group). After 4 weeks, immunohistochemistry and gene expression tests were conducted. In 6-week-old db/db mice, immunohistochemistry revealed a significant increase in beta cell mass in the luseo group compared with the control group after 4 weeks of treatment. Gene expression profiling of isolated islets showed upregulation Mafa, Pdx1, Ki67 and Ccnd2 in the luseo group. Beta cell mass decreased with age in db/db mice in the control group. Beta cell mass in the luseo group significantly increased compared with the control group regardless of age, although beta cell mass in the 28-week-old luseo group (4 weeks of treatment in 24-week-old db/db mice) was significantly lower than in the 10-week-old luseo group (4 weeks of treatment in 6-week-old db/db mice). Luseogliflozin preserved beta cell mass in db/db mice. The protective effect was more evident in the earlier phase of diabetes.
• Tocilizumab reduced production of systemic sclerosis-related autoantibodies and anti-cyclic citrullinated protein antibodies in two patients with overlapping systemic sclerosis and rheumatoid arthritis.

  Kono M, Yasuda S, Kono M, Atsumi T

  Scandinavian journal of rheumatology 47 3 248 - 250 2018年05月 [査読有り][通常論文]
  
• Effect of combined treatment with bisphosphonate and vitamin D on atherosclerosis in patients with systemic lupus erythematosus: a propensity score-based analysis.

  Kazumasa Ohmura, Masaru Kato, Toshiyuki Watanabe, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Yoichi M Ito, Norihiro Sato, Tatsuya Atsumi

  Arthritis research & therapy 20 1 72 - 72 2018年04月17日 [査読有り][通常論文]
   

  BACKGROUND: Premature atherosclerosis is one of the major complications of systemic lupus erythematosus (SLE). Recently, the biological linkage between atherosclerosis and osteoporosis has garnered much attention. The aim of this study is to explore correlation between the development of atherosclerosis and anti-osteoporotic treatment. METHODS: Consecutive patients with SLE (n = 117) who underwent carotid ultrasonography were retrospectively analyzed using propensity scoring. RESULTS: Of the 117 patients, 42 (36%), 27 (23%), and 30 (26%) were receiving bisphosphonates and vitamin D (BP + VD), bisphosphonates alone, or vitamin D alone, respectively. Low bone mineral density was more frequent, and carotid plaque was less prevalent in the BP + VD group compared with other treatment groups. Age (OR = 1.57) and BP + VD treatment (OR = 0.24) were shown by multivariate analysis to be associated with the presence of carotid plaque. In all strata divided using the propensity score, carotid plaque was statistically significantly less prevalent (p = 0.015, Mantel-Haenszel test) in the BP + VD group relative to the other treatment groups. CONCLUSION: Combined treatment with bisphosphonate and vitamin D may have a role in preventing atherosclerosis in patients with SLE.
• The role of genetics and epigenetics in rheumatic diseases: are they really a target to be aimed at?

  Masaru Kato, Shinsuke Yasuda, Tatsuya Atsumi

  Rheumatology International 38 8 1 - 6 2018年04月05日 [査読有り][通常論文]
   

  To date, numerous genetic and epigenetic studies have been performed and provided a crucial step forward in our understanding of the pathogenesis of rheumatic diseases. However, most of the recent advances in the treatment of rheumatic diseases including biological therapies are not based on or even discrepant from these genetic and epigenetic findings. For example, tumor necrosis factor inhibitors are quite successful in the treatment of rheumatoid arthritis (RA), Behçet’s disease (BD), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) but not in that of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögren’s syndrome (SS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV), conversely, RA shares genetic backgrounds more with SLE, SSc, SS and AAV than BD, AS and PsA. In this review, we briefly highlight the findings from recent genetic and epigenetic studies and discuss what needs to be studied to provide a novel, more efficacious management of rheumatic diseases.
• Alternative pathway activation due to low level of complement factor H in primary antiphospholipid syndrome.

  Hiroyuki Nakamura, Kenji Oku, Yusuke Ogata, Kazumasa Ohmura, Yoko Yoshida, Etsuko Kitano, Yuichiro Fujieda, Masaru Kato, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Yoshihiro Fujimura, Tsukasa Seya, Tatsuya Atsumi

  Thrombosis research 164 63 - 68 2018年04月 [査読有り][通常論文]
   

  INTRODUCTION: Although complement activation has been proposed as a possible thrombophilic mechanism in antiphospholipid syndrome (APS), the origin of complement activation in APS remains unclear. Here, we focused on complement regulatory factors (CRF), which control the complement system to prevent damage to host tissue. We evaluated the function of two major CRF, membrane cofactor protein (MCP) and factor H (FH), in APS patients. MATERIALS AND METHODS: In this study, we analyzed preserved serum samples from 27 patients with primary APS (PAPS), 20 with APS complicated with SLE (APS + SLE), 24 with SLE (SLE), and 25 with other connective tissue diseases (Other CTD). Serum MCP and FH levels were tested by ELISA. Autoantibodies against FH were determined by both ELISA and western-blotting. RESULTS: Serum complement levels of PAPS were lower than those of other CTD (median C3: 82 vs 112 mg/dL, p < 0.01, C4: 15 vs 22 mg/dL, p < 0.05). Serum MCP levels did not significantly differ among the groups. Serum FH levels were significantly lower in PAPS patients compared with SLE or other CTD (median 204, 1275, and 1220 μg/mL, respectively, p < 0.01). In PAPS patients, serum FH levels were positively correlated with serum C3 levels (p < 0.01, R = 0.55), but no correlation was found with serum C4 levels (p = 0.22, R = 0.33). Autoantibodies against FH were not detected in any of our patients. CONCLUSIONS: Activation of the alternative complement pathway due to low level of FH is one of the possible thrombophilic mechanisms in PAPS.
• Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: Final report of a 52-week, multicenter postmarketing surveillance study.

  Mimori T, Harigai M, Atsumi T, Fujii T, Kuwana M, Matsuno H, Momohara S, Takei S, Tamura N, Takasaki Y, Yamamoto K, Ikeuchi S, Kushimoto S, Koike T

  Modern rheumatology 29 2 1 - 10 2018年04月 [査読有り][通常論文]
   

  OBJECTIVES: We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA). METHODS: This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52. RESULTS: Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52. CONCLUSION: Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA.
• The Impact of Systemic Lupus Erythematosus on the Clinical Phenotype of Antiphospholipid Antibody Positive Patients: Results from AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Reposi

  Unlu O, Erkan D, Barbhaiya M, Andrade D, Nascimento I, Rosa R, Banzato A, Pengo V, Ugarte A, Gerosa M, Ji L, Efthymiou M, Branch DW, de Jesus GR, Tincani A, Belmont HM, Fortin PR, Petri M, Rodriguez E, Pons-Estel GJ, Knight JS, Atsumi T, Willis R, Zuily S, Tektonidou MG, TheBehalf of APS ACTION

  Arthritis care & research 2018年04月 [査読有り][通常論文]
  
• 血管炎モデルに対する好中球細胞外トラップ(NETs)制御を介した遺伝子組換えトロンボモジュリン(rTM)の効果

  渡邉 加奈子, 中沢 大悟, 西尾 妙織, 渥美 達也

  日本腎臓学会誌 60 3 349 - 349 (一社)日本腎臓学会 2018年04月
• イプラグリフロジンを開始する際にSU薬は中止すべきか少量残すべきか?

  高橋 清彦, 三好 秀明, 宮 愛香, 三次 有奈, 山本 知穂, 野本 博司, 曹 圭龍, 中村 昭伸, 丹羽 祐勝, 高橋 清仁, 萬田 直紀, 栗原 義夫, 青木 伸, 渥美 達也

  糖尿病 61 Suppl.1 S - 232 (一社)日本糖尿病学会 2018年04月
• 高齢者2型糖尿病患者におけるSU薬からレパグリニド切り替えはグリコアルブミン(GA)/HbA1c比を改善する

  大森 一乃, 高瀬 崇宏, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 61 Suppl.1 S - 237 (一社)日本糖尿病学会 2018年04月
• GLP-1受容体作動薬連日投与製剤からデュラグルチド切り替えによる患者満足度の改善効果

  高瀬 崇宏, 三好 秀明, 檀浦 みどり, 山本 知穂, 宮 愛香, 野本 博司, 曹 圭龍, 中村 昭伸, 栗原 義夫, 青木 伸, 渥美 達也

  糖尿病 61 Suppl.1 S - 351 (一社)日本糖尿病学会 2018年04月
• First-Line, Non-Criterial Antiphospholipid Antibody Testing for the Diagnosis of Antiphospholipid Syndrome in Clinical Practice: A Combination of Anti-β2 -Glycoprotein I Domain I and Anti-Phosphatidylserine/Prothrombin Complex Antibodies Tests.

  Hiroyuki Nakamura, Kenji Oku, Olga Amengual, Kazumasa Ohmura, Yuichiro Fujieda, Masaru Kato, Toshiyuki Bohgaki, Shinsuke Yasuda, Tatsuya Atsumi

  Arthritis care & research 70 4 627 - 634 2018年04月 [査読有り][通常論文]
   

  OBJECTIVE: To assess the value of a combination of anti-β2 -glycoprotein I (anti-β2 GPI) domain I antibody and anti-phosphatidylserine/prothrombin complex (anti-PS/PT) antibody tests for the diagnosis of antiphospholipid syndrome (APS). METHODS: This cross-sectional study involved a cohort of the patients who visited our clinic from April 2005 to March 2013. Tests for anti-β2 GPI domain I antibodies, IgG anti-PS/PT antibodies, and IgM anti-PS/PT antibodies, together with tests for criteria-defined antiphospholipid antibodies (aPL), were performed in all patients. The total antiphospholipid score (aPL-S) was calculated for each patient according to titers of and positivity for aPL. RESULTS: The study enrolled 157 patients (51 patients with APS and 106 with non-APS autoimmune diseases). All 21 patients positive for both anti-β2 GPI domain I antibodies and IgG and/or IgM (IgG/IgM) anti-PS/PT antibodies had APS with a high total aPL-S (median 46, range 26-76), as did all of the 10 patients who were positive for anti-β2 GPI domain I antibodies but negative for IgG/IgM anti-PS/PT antibodies (median 22, range 4-39). Of the 14 patients who were positive for IgG/IgM anti-PS/PT antibodies but negative for anti-β2 GPI domain I antibodies, 11 (79%) had APS; these individuals also had high total aPL-S values (median 23, range 11-60). In contrast, only 9 of the 112 patients (8%) with none of these antibodies had APS. CONCLUSION: The combination of the IgG anti-β2 GPI domain I antibody and IgG/IgM anti-PS/PT antibody tests shows a high positive predictive value for the diagnosis of APS and a strong correlation with the aPL-S. This combination as the first-line test for aPL may contribute to the simple and definite identification of APS with a high risk of thrombosis in clinical practice.
• Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis.

  Yuta Kochi, Yoichiro Kamatani, Yuya Kondo, Akari Suzuki, Eiryo Kawakami, Ryosuke Hiwa, Yukihide Momozawa, Manabu Fujimoto, Masatoshi Jinnin, Yoshiya Tanaka, Takashi Kanda, Robert G Cooper, Hector Chinoy, Simon Rothwell, Janine A Lamb, Jiří Vencovský, Heřman Mann, Koichiro Ohmura, Keiko Myouzen, Kazuyoshi Ishigaki, Ran Nakashima, Yuji Hosono, Hiroto Tsuboi, Hidenaga Kawasumi, Yukiko Iwasaki, Hiroshi Kajiyama, Tetsuya Horita, Mariko Ogawa-Momohara, Akito Takamura, Shinichiro Tsunoda, Jun Shimizu, Keishi Fujio, Hirofumi Amano, Akio Mimori, Atsushi Kawakami, Hisanori Umehara, Tsutomu Takeuchi, Hajime Sano, Yoshinao Muro, Tatsuya Atsumi, Toshihide Mimura, Yasushi Kawaguchi, Tsuneyo Mimori, Atsushi Takahashi, Michiaki Kubo, Hitoshi Kohsaka, Takayuki Sumida, Kazuhiko Yamamoto

  Annals of the rheumatic diseases 77 4 602 - 611 2018年04月 [査読有り][通常論文]
   

  OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. METHODS: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. RESULTS: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10-8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. CONCLUSIONS: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.
• Impact of glucose loading on variations in CD4+ and CD8+ T cells in Japanese participants with or without type 2 diabetes

  Aika Miya, Akinobu Nakamura, Hideaki Miyoshi, Yoshinari Takano, Kana Sunagoya, Koji Hayasaka, Chikara Shimizu, Yasuo Terauchi, Tatsuya Atsumi

  Frontiers in Endocrinology 9 81  2018年03月20日 [査読有り][通常論文]
   

  Objective: The aim of this study was to examine the fluctuations in CD4+ T cells, CD8+ T cells, and natural CD4+CD25+FoxP3+T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM). Methods: 19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4+, CD8+, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min. Results: Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4+, CD8+, and Treg were observed between the DM group and the non-DM group. The proportion of CD8+ was significantly reduced, whereas the proportion of CD4+ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC0-120 min of CD8+ and the change in the free fatty acid level following the OGTT (ρ = 0.39, P < 0.05), but not that of glucose or insulin. Conclusion: The proportion of CD4+ T cells was increased and that of CD8+ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance.
• 超音波とMRIの複合的評価は生物学的疾患修飾性抗リウマチ薬(bDMARDs)を投与中の関節リウマチにおけるX線上の関節破壊の予測能を改善する(Composite Assessment of Ultrasonography and MRI Improves the Prognostic Power of Joint Destruction on Radiograph in Rheumatoid Arthritis on Biological Disease-modifying Antirheumatic Drugs(bDMARDs))

  Fujimori Motoshi, Kamishima Tamotsu, Seno Yumika, Sugimori Hiroyuki, Nishida Mutsumi, Atsumi Tatsuya

  日本放射線技術学会総会学術大会予稿集 74回 231 - 232 2018年03月
• SLE・抗リン脂質抗体症候群1 全身性エリテマトーデス患者の診療の質指標の開発

  矢嶋 宣幸, 佐田 憲映, 高橋 良, 浅野 善英, 東 光久, 亀田 秀人, 桑名 正隆, 上阪 等, 鈴木 勝也, 竹内 勤, 田中 良哉, 田村 直人, 松井 利浩, 三森 経世, 渥美 達也

  日本リウマチ学会総会・学術集会プログラム・抄録集 62回 445 - 445 (一社)日本リウマチ学会 2018年03月
• リウマチ性疾患の画像2:関節エコーその他 超高周波プローブを用いたSuperb Micro-vascular Imagingによる超音波検査でのラット足関節の早期関節炎診断

  西田 睦, 谷村 瞬, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 62回 485 - 485 (一社)日本リウマチ学会 2018年03月
• スタチンの関節炎抑制効果とその機序の解明

  谷村 瞬, 西田 睦, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 62回 778 - 778 (一社)日本リウマチ学会 2018年03月
• GLP-1受容体作動薬連日投与製剤からデュラグルチド切り替えによる患者満足度の検討

  高瀬 崇宏, 三好 秀明, 檀浦 みどり, 山本 知穂, 宮 愛香, 野本 博司, 中村 昭伸, 栗原 義夫, 青木 伸, 渥美 達也

  糖尿病 61 3 142 - 142 (一社)日本糖尿病学会 2018年03月
• Successful treatment of tocilizumab-resistant large vessel pulmonary arteritis with infliximab.

  Tanimura S, Kato M, Abe N, Ohira H, Tsujino I, Atsumi T

  Immunological medicine 41 1 39 - 42 2018年03月 [査読有り][通常論文]
  
• Satisfaction and efficacy of switching from daily dipeptidyl peptidase-4 inhibitors to weekly trelagliptin in patients with type 2 diabetes-Randomized controlled study.

  Mayuko Oita, Hideaki Miyoshi, Kota Ono, Akinobu Nakamura, Kyu Yong Cho, Hiroshi Nomoto, Kohei Yamamoto, Kazuno Omori, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi

  Endocrine journal 65 2 141 - 150 2018年02月26日 [査読有り][通常論文]
   

  We compared treatment satisfaction between daily dipeptidyl peptidase-4 (DPP-4) inhibitors and a weekly DPP-4 inhibitor in patients with type 2 diabetes. The study was a 12-week, open-label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes who had received daily DPP-4 inhibitors for more than 3 months. Patients were randomly assigned to a treatment cohort: (1) a group that continued taking daily DPP-4 inhibitors (daily group); or (2) a group that switched from daily DPP-4 inhibitors to a weekly DPP-4 inhibitor, trelagliptin (weekly group). The primary outcome was the change in treatment satisfaction levels from baseline to 12 weeks between the two groups, according to Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Diabetes Therapy-Related Quality of Life (DTR-QOL) questionnaire scores. The changes in glycemic control and body weight were also assessed. Of 49 patients initially enrolled in the study, 47 completed the study. The change in DTSQ scores in the weekly group was not significantly different from that in the daily group. However, the improvements in total score and subscale domains 1 and 2 in the DTR-QOL analysis, which relate to burden on social/daily activities and anxiety/dissatisfaction with treatment, were significantly greater in the weekly group than the daily group (p = 0.048, 0.013 and 0.045, respectively). Mean changes in glycated hemoglobin levels and body weight were comparable between the groups. Switching from daily DPP-4 inhibitors to a weekly DPP-4 inhibitor, trelagliptin, could partially improve treatment satisfaction levels in patients with type 2 diabetes without affecting glycemic control.
• Effects of statins on thrombosis development in patients with systemic lupus erythematosus and antiphospholipid antibodies.

  Watanabe T, Oku K, Amengual O, Hisada R, Ohmura K, Nakagawa I, Shida H, Bohgaki T, Horita T, Yasuda S, Atsumi T

  Lupus 27 2 225 - 234 2018年02月 [査読有り][通常論文]
  
• Understanding the Antibody Repertoire in Neuropsychiatric Systemic Lupus Erythematosus and Neuromyelitis Optica Spectrum Disorder: Do They Share Common Targets?

  Simone Mader, Venkatesh Jeganathan, Yoshiyuki Arinuma, Yuichiro Fujieda, Irena Dujmovic, Jelena Drulovic, Yuka Shimizu, Yuko Sakuma, Joel N. H. Stern, Cynthia Aranow, Meggan Mackay, Shinsuke Yasuda, Tatsuya Atsumi, Shunsei Hirohata, Betty Diamond

  Arthritis and Rheumatology 70 2 277 - 286 2018年02月01日 [査読有り][通常論文]
   

  Objective: IgG anti-DWEYS antibodies cross-reactive with DNA and the N-methyl-d-aspartate receptor subunits GluN2A and GluN2B are known to be associated with neuropsychiatric systemic lupus erythematosus (NPSLE). IgG anti-DWEYS have not been investigated in demyelinating NPSLE or in another demyelinating disorder, neuromyelitis optica spectrum disorder (NMOSD), which is a disease also found mainly in young women and associated with aquaporin 4 (AQP-4) or myelin oligodendrocyte glycoprotein (MOG) antibodies. This study was undertaken to investigate the frequency of all of these brain-reactive antibodies in patients with NPSLE, those with demyelinating NPSLE, and those with NMOSD. Methods: Serum samples from patients with NPSLE (n = 108), patients with SLE without neuropsychiatric manifestations (n = 38), patients with NMOSD (n = 33), and healthy controls (n = 106) were assessed for the frequency of IgG anti-brain antibodies as well as IgG antibodies to AQP-4, MOG, GluN2A/GluN2B, and double-stranded DNA (dsDNA). Results: Sera were positive for IgG anti–AQP-4 antibodies in 27 (82%) of 33 patients with NMOSD and 3 (27%) of 11 patients with demyelinating NPSLE, whereas all sera from patients with non-demyelinating NPSLE, patients with SLE, and healthy controls were negative for IgG anti–AQP-4. IgG anti-MOG were detected at high titers in 3 (50%) of 6 patients with NMOSD who were negative for IgG anti–AQP-4, and at low titers in 2 (18%) of 11 patients with demyelinating NPSLE and 1 (1%) of 97 patients with non-demyelinating NPSLE. IgG antibodies to dsDNA were present in 11 (33%) of 33 patients with NMOSD. Only 4 (12%) of 33 patients with NMOSD were positive for IgG anti-DWEYS, compared to 11 (29%) of 38 patients with SLE and 59 (55%) of 108 patients with NPSLE. IgG anti-DWEYS antibodies were present in 56 (58%) of 97 patients with non-demyelinating NPSLE and 3 (27%) of 11 patients with demyelinating NPSLE. Serum IgG brain-reactive antibodies were present at a similar frequency in patients with non-demyelinating NPSLE (72 [75%] of 96), those with demyelinating NPSLE (9 [82%] of 11), and those with SLE (32 [84%] of 38), but were less frequent in patients with NMOSD (20 [61%] of 33). Conclusion: Patients with demyelinating NPSLE should be tested for IgG antibodies to AQP-4, MOG, and DWEYS. IgG anti–AQP-4 can be considered diagnostic for NMOSD, whereas none of these antibodies appear to be diagnostic for demyelinating NPSLE. Moreover, IgG anti-dsDNA are present in patients with NMOSD but are not cross-reactive with IgG anti-DWEYS, indicating that the antigenic stimulus and mechanisms of tissue damage are potentially different between demyelinating NPSLE and NMOSD.
• Pulmonary arterial hypertension associated with connective tissue diseases: A review focusing on distinctive clinical aspects

  Masaru Kato, Tatsuya Atsumi

  European Journal of Clinical Investigation 48 2 2018年02月01日 [査読有り][通常論文]
   

  Recent studies have clarified that pulmonary arterial hypertension associated with connective tissue diseases (CTD-PAH) has some distinctive clinical aspects from other PAH, such as high prevalence, venous and cardiac involvement, less favourable outcome, helpfulness of detection algorithm, response to immunosuppression, pre-PAH conditions in borderline pulmonary arterial pressure and coexistence of interstitial lung disease. In this review, by focusing on these distinctive aspects, we discuss how to provide an efficacious and safe management of CTD-PAH and garner attention to areas where further evidence is desired.
• Overexpression of perilipin1 protects against atheroma progression in apolipoprotein E knockout mice.

  Kohei Yamamoto, Hideaki Miyoshi, Kyu Yong Cho, Akinobu Nakamura, Andrew S Greenberg, Tatsuya Atsumi

  Atherosclerosis 269 192 - 196 2018年02月 [査読有り][通常論文]
   

  BACKGROUND AND AIMS: Perilipin1 (PLIN1), a lipid droplet-associated protein, plays an important role in the regulation of lipolysis and lipid storage in adipocytes. PLIN1 has recently been reported to be expressed in macrophages within atheroma plaques, suggesting PLIN1 may play a role in the accumulation of lipids at the arterial wall and in the development of atherosclerosis. To clarify the role of PLIN1 in the pathophysiology of atherosclerosis, we assessed the progression of atherosclerosis in PLIN1 transgenic mice (Plin1Tg). METHODS: Plin1Tg were crossed with apolipoprotein E knockout mice (ApoeKO). C57BL/6J mice, ApoeKO and Plin1Tg/ApoeKO received a normal chow diet for 20 weeks. Body weight, gonadal fat mass and plasma lipid concentrations were measured. Aortas were collected for quantification of atheroma lesions and histological analysis by Oil Red O staining. RESULTS: Body weight, gonadal adipose mass and plasma triglyceride concentrations were not significantly different among the three groups. In contrast, the atherosclerotic lesion area was significantly increased in ApoeKO (14.2 ± 3.2%; p < .01) compared with C57BL/6J mice (3.3 ± 1.2%) and Plin1Tg/ApoeKO (5.6 ± 1.9%). CONCLUSIONS: Overexpressed PLIN1 in macrophages had a protected role against atheroma progression in ApoeKO in the absence of changes in gonadal fat mass or plasma lipid levels, presumably due to modification of the stability and/or inflammatory profile of macrophages.
• Composite assessment of power Doppler ultrasonography and MRI in rheumatoid arthritis: A pilot study of predictive value in radiographic progression after one year

  Motoshi Fujimori, Tamotsu Kamishima, Masaru Kato, Yumika Seno, Kenneth Sutherland, Hiroyuki Sugimori, Mutsumi Nishida, Tatsuya Atsumi

  British Journal of Radiology 91 1086 20170748  2018年 [査読有り][通常論文]
   

  © 2018 The Authors. Published by the British Institute of Radiology. Objective: Power Doppler ultrasonography (PDUS) and MRI are independently useful to predict structural damage in patients with rheumatoid arthritis (RA). We hypothesize that there is a complementary relationship between these modalities. The aim of this study is, therefore, to investigate the usefulness of the predictive value of composite assessment of PDUS and contrast-enhanced MRI in radiographic outcomes in patients with RA. Methods: 20 patients (17 females and 3 males) with RA on disease-modifying antirheumatic drugs underwent PDUS and MRI of both hands at baseline. Radiography of the bilateral hands was performed at baseline and at 1 year. Articular synovitis on PDUS was evaluated according to quantitative measurement. Synovitis, bone marrow edema and bone erosion were scored according to the RA MRI scoring method. The changes of joint space narrowing and bone erosion on radiograph were assessed by the Sharp/van der Heijde method. We applied t-statistics to combine the assessment of quantitative PDUS with semiquantitative MRI. Results: Structural damage progression for radiography was not correlated with any evaluations for MRI, while it showed significant correlation with synovitis on PDUS (rs = 0.597, p = 0.005). The composite assessment of both modalities (synovitis for PDUS and bone marrow edema for MRI) was correlated with structural damage progression on radiograph (rs = 0.792, p < 0.0001). Conclusion: Composite assessment of PDUS and MRI may have a stronger predictive value in radiographic progression than PDUS or MRI alone in RA. Advances in knowledge: Composite assessment of PDUS and MRI may be an effective predictor of structural damage in RA.
• 多施設共同疫学研究による体軸性脊椎関節炎の実態調査2018

  吉川 卓宏, 多田 久里守, 井上 久, 小林 茂人, 浦野 房三, 近藤 正一, 大西 直樹, 渥美 達也, 佐々木 貴紀, 竹内 勤, 公文 義雄, 梅田 雅孝, 川上 純, 田村 直人, 松井 聖

  日本脊椎関節炎学会誌 Suppl. 52 - 52 日本脊椎関節炎学会 2018年
• Satisfaction of switching to combination therapy with lixisenatide and basal insulin in patients with type 2 diabetes receiving multiple daily insulin injection therapy: A randomized controlled trial.

  Aika Miya, Akinobu Nakamura, Hideaki Miyoshi, Kyu Yong Cho, So Nagai, Yoshio Kurihara, Shin Aoki, Masataka Taguri, Yasuo Terauchi, Tatsuya Atsumi

  Journal of diabetes investigation 9 1 119 - 126 2018年01月 [査読有り][通常論文]
   

  AIMS/INTRODUCTION: We compared the satisfaction levels of patients with type 2 diabetes undergoing combination therapy with lixisenatide (LIX) and basal insulin with that of patients undergoing multiple daily insulin injection (MDI) therapy. MATERIALS AND METHODS: The study was a 12-week open-label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes receiving MDI for >3 months. Patients were randomly assigned to each treatment cohort: (i) a group that continued MDI (MDI group); and (ii) a group that switched from MDI to combination therapy with LIX and basal insulin (LIX group). The primary outcome was change in Diabetes Treatment Satisfaction Questionnaire scores from baseline to 12 weeks between these two groups. Key secondary outcomes were glycated hemoglobin and body weight changes. RESULTS: A total of 31 patients were initially enrolled in the study, and 26 of them completed the study. The change in Diabetes Treatment Satisfaction Questionnaire scores in the LIX group was significantly greater compared with that in the MDI group. Mean changes in glycated hemoglobin levels were -0.05 ± 0.37% in the MDI group and 0.04 ± 0.38% in the LIX group (P = 0.36). Mean changes in body weight were +0.6 ± 1.8 kg in the MDI group and -2.5 ± 1.8 kg in the LIX group (P < 0.01). CONCLUSIONS: Switching from MDI to combination therapy with LIX and basal insulin improved satisfaction levels while maintaining glycemic control in Japanese patients with type 2 diabetes.
• Potential importance of a histopathological analysis in thyroidal diseases with high serum IgG4 levels

  Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, So Nagai, Chikara Shimizu, Tatsuya Atsumi

  Internal Medicine 57 3 453  2018年 [査読有り][通常論文]
  
• Autologous haematopoietic stem cell transplantation for Japanese patients with systemic sclerosis: Long-term follow-up on a phase II trial and treatment-related fatal cardiomyopathy.

  Nakamura H, Odani T, Yasuda S, Noguchi A, Fujieda Y, Kato M, Oku K, Bohgaki T, Sugita J, Endo T, Teshima T, Atsumi T

  Modern rheumatology 28 5 1 - 6 2018年01月 [査読有り][通常論文]
   

  OBJECTIVES: The objective of this study is to elucidate the efficacy and safety of autologous haematopoietic stem cell transplantation (HSCT) for Japanese patients with systemic sclerosis (SSc). METHODS: A phase II clinical trial included SSc patients diagnosed within the last three years having at least one of the following clinical features: diffuse skin sclerosis with modified Rodman total thickness skin score (mRSS) ≥ 15, refractory digital ulcer or interstitial lung disease (ILD). HSCT were performed after conditioning using cyclophosphamide. RESULTS: Fourteen patients were enrolled and underwent HSCT. Median follow-up period was 137 months. Overall survival or event-free survival rate was 93% or 40% at 10 years, respectively. Eight patients (57%) achieved more than a 50% decrease in mRSS from baseline within six months after HSCT. Six patients (43%) required additional immunosuppressive treatments due to progression of diffuse skin sclerosis and/or ILD during follow-up period. Adverse events related to HSCT occurred in six patients (43%). Severe cardiomyopathy occurred in two patients, and one of them had a fatal course. CONCLUSION: HSCT is a feasible treatment bringing favourable results to more than half of our patients with SSc. Careful selection of the patients is essential for whom benefited from HSCT, considering the risk-benefit balance of the treatment.
• Efficient detection of pulmonary arterial hypertension using serum haptoglobin level and cardiac MRI in patients with connective tissue diseases: A pilot study

  H. Nakamura, Masaru Kato, A. Noguchi, H. Ohira, I. Tsujino, T. Atsumi

  Clinical and Experimental Rheumatology 36 2 345 - 346 2018年 [査読有り][通常論文]
  
• 後天性血友病A診療ガイドライン 2017年改訂版

  酒井 道生, 天野 景裕, 小川 孔幸, 高見 昭良, 徳川 多津子, 野上 恵嗣, 羽藤 高明, 藤井 輝久, 松本 功, 松本 剛史, 家子 正裕, 武山 雅博, 関 義信, 日笠 聡, 備後 真登, 岡 敏明, 小倉 妙美, 白幡 聡, 鈴木 隆史, 嶋 緑倫, 瀧 正志, 竹谷 英之, 西田 恭治, 長江 千愛, 福武 勝幸, 堀越 泰雄, 松下 正, 窓岩 清治, 森下 英理子, 渥美 達也, 冨山 佳昭, 和田 英夫, 後天性血友病A診療ガイドライン作成委員会

  日本血栓止血学会誌 28 6 715 - 747 (一社)日本血栓止血学会 2017年12月 

  診断 1.本症の診断ならびに治療は本疾患に精通している医師(以下、熟練医)の指導のもとで行われることが望ましい(Grade C、Level IV)。即ち、突然の出血症状とともに、スクリーニング検査でAPTTのみが延長(血小板数正常、PT正常)しさらに第VIII因子活性(FVIII:C)の低下を認めた場合は、本症を疑い熟練医へコンサルトすることが勧められる。ただし出血症状が重篤であり、すぐにFVIII:Cや第VIII因子インヒビター(以下、インヒビター)の結果が得られない場合は、APTTのみ延長が判明した段階で熟練医へコンサルトもしくは本疾患の診療が可能な診療施設へ搬送することが望ましい。2.APTT延長、FVIII:Cの低下に加え、インヒビターが陽性であれば、本症の疑いが極めて強い。ただし確定診断のためには、フォンヴイレブランド因子(von Willebrand factor:VWF)の低下やループスアンチコアグラント(lupusanticoaglant:LA)の存在を否定する必要がある。3.インヒビターが検出された時点で明らかな基礎疾患がなくてもその後に基礎疾患が判明する場合があるので、絶えず自己免疫疾患や悪性腫蕩の存在に留意すべきである(Grade C、Level IV)。4.先天性血友病Aと異なり、本症ではFVIII:Cと臨床的重症度は一致しない。そのため、FVIII:Cが検出された場合でも重篤な出血を起こす可能性があることに留意すべきである(Grade C、Level IV)。5.インヒビターのFVIII:C抑制作用は時間および温度依存性であるためAPTTクロスミキシング試験を行う場合は、混合血棄を作成直後と37℃で2時間鮮置後の両方の測定が必須である(Grade C、Level IV)。6.インヒビター力価を測定する際には、予め被検血紫を56℃で30分間孵置し血漿中に存在する第VIII因子を不活化することが勧められる(Grade C、Level IV)。7.本症のインヒビターはしばしばタイプIIといわれる反応動態を示す。タイプHインヒビターの力価測定法はいまだ標準化されておらずインヒビター力価を臨床的重症度の絶対的な指標としない(Grade C、Level IV)。むしろ、免疫抑制療法の効果判定のための検査として評価した方がよい。止血治療 8.生命予後に直結する臓器出血もしくは貧血の進行をともなう軟部組織への出血に対してはすみやかに止血治療を開始すべきである(Grade C、Level IV)。9.止血治療として、遺伝子組換え活性型第VII因子製剤(recombinantactivated factor VII:rFVIIa)(Grade B、Level III)、活性型プロトロンピン複合体製剤(activatedprothrombin complex concentrate:APCC)(Grade B、Level III)、もしくは乾燥濃縮人血液凝固第X因子加活性化第VII因子製剤(FX/FVIIa)(Grade C、Level IV)のいずれかを選択する。一般に、3製剤のうちいずれの製剤がより有効かを予め予測することは困難で投与後の臨床症状の改善度によってその効果を判定する必要がある。なおFX/FVIIaは2014年11月からわが国でのみ使用可能となったが、実臨床における使用成績に関する報告はまだ少ない。10.インヒビター力価が低くかっFVIII:Cが検出される場合にはDDAVPもしくは第VIII因子製剤の使用も考慮される(Grade C、Level IV)。ただしその効果判定にはFVIII:Cを注意深くモニタリングする必要がある。免疫抑制療法 11.本症では、多くの場合はインヒビターが消失するまで常に出血リスクを伴い、死因の約半数を出血が占めるとされているため、免疫抑制療法は本症の診断後直ちに開始すべきである(Grade B、Level IIb)。12.本症に対する免疫抑制療法の第一選択は、prednisolone(PSL)単独投与もしくはPSLとcyclophosphamide(CPA)の併用療法とする(Grade B、Level IIb)。13.PSLの初期投与量は1mg/kg/日を基本とする(Grade C、Level IV)。治療開始時あるいは治療中にPSLの代替としてmethylprednisolone(m-PSL)によるステロイドパルス療法を選択することも可能であるが、PSLよりも有効で、あることを示すエビデンスはない。14.CPAは1〜2mg/kg/日の経口投与を基本とする(Grade C、Level IV)。治療開始時にCPAを併用するかは、症例毎にベネフィットとリスクを検討した上で判断する。また、高齢者などで感染症などの副作用のリスクが高いと判断される場合にはCPAパルス療法も考慮する。15.妊娠中あるいは妊娠する可能性のある女性に対しては、できるだけCPAや他のアルキル化剤の使用を避ける(Grade B、Level III)。16.免疫抑制療法の効果判定は、第VIII因子活性(FVIII:C)、インヒビター力価およびAPTTの測定で行う。中でもインヒビター力価を最も重視しインヒビター力価の低下〜消失が認められた場合は適時用量の減量および中止を、一方で、治療開始3〜5週間後でも効果が認められない場合は、薬剤の変更や追加を考慮する(Grade C、Level IV)。17.PSLとCPA以外の免疫抑制剤は、抗CD20抗体:rituximab(RTX)、cyclosporin A(CyA)などの中から選択する(Grade C、Level IV)。とくにRTXについては、PSL単独投与もしくはPSL+CPA併用療法への治療抵抗例、およびPSLとCPAの投与禁忌例において、RTX単独投与もしくはPSLやCPAとの併用療法が第二選択として推奨される(Grade B、Level III)。ただし現時点ではこれらの薬剤に、"後天性血友病A"や"凝固因子の障害による出血性素因"に対する保険適用は認められていない。なお、高用量γグロブリン製剤の単独投与、あるいは併用療法は推奨されない(Grade B、Level IIb)。18.基礎疾患を有する場合や薬剤関連発症例では、原疾患の治療や被偽薬の中止が可能であれば、免疫抑制療法と並行して考慮すべきである(Grade C、Level IV)。19.本症の死因の約半数は感染症に起因するとの報告があり免疫抑制療法中は免疫機能を十分に評価しながら、感染症の予防ならびに早期発見に努めるべきである(Grade C、Level IV)。20.治療終了後に再燃をきたす症例が報告されており寛解後も長期にわたる慎重なフォローアップが勧められる(Grade C、Level IV)。(著者抄録)
• MRIで下垂体腫瘍を認めないクッシング病の1例

  桑原 咲, 川田 晋一朗, 馬場 菜月, 続木 惇, 半田 喬久, 枝川 幸子, 高瀬 崇宏, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 93 3 658 - 658 (一社)日本内分泌学会 2017年12月
• スタチン製剤の関節炎抑制効果と機序の検討

  谷村 瞬, 渥美 達也, 西田 睦, 堀江 達則, 神島 保, 齋藤 克己, 西端 友香, 益田 紗季子, 石津 明洋, 外丸 詩野

  北海道医学雑誌 92 2 105 - 105 北海道医学会 2017年11月
• Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head

  Sakamoto Y, Yamamoto T, Sugano N, Takahashi D, Watanabe T, Atsumi T, Nakamura J, Hasegawa Y, Akashi K, Narita I, Miyamoto T, Takeuchi T, Ikari K, Amano K, Fujie A, Kubo T, Tada Y, Kaneuji A, Nakamura H, Miyamura T, Kabata T, Yamaji K, Okawa T, Sudo A, Ohzono K, Tanaka Y, Yasunaga Y, Matsuda S, Imai Y, Japanese Research Committee on, Idiopathic Osteonecrosis of the, Femoral Head, Akiyama M, Kubo M, Kamatani Y, Iwamoto Y, Ikegawa S

  Scientific reports 7 15035  2017年11月 [査読有り][通常論文]
   

  Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using similar to 60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.
• Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analyses of four multinational phase 3 randomized trials.

  Tanaka Y, Atsumi T, Amano K, Harigai M, Ishii T, Kawaguchi O, Rooney TP, Akashi N, Takeuchi T

  Modern rheumatology 28 4 1 - 9 2017年11月 [査読有り][通常論文]
  
• 血管・動脈硬化 ペリリピン1過剰発現マウスにおける動脈硬化進展抑制効果についての検討

  山本 浩平, 三好 秀明, 野本 博司, Cho Kyu Yong, 中村 昭伸, 渥美 達也

  糖尿病合併症 31 Suppl.1 239 - 239 (一社)日本糖尿病合併症学会 2017年10月
• 膵島・インスリン分泌 血清高分子アディポネクチン値とインスリン分泌との関連 DOSANCO Health studyによる検討

  中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 寺内 康夫, 玉腰 暁子, 渥美 達也

  糖尿病合併症 31 Suppl.1 297 - 297 (一社)日本糖尿病合併症学会 2017年10月
• 【補体と腎疾患】補体と腎疾患 SLE/APS

  大村 一将, 渥美 達也

  腎と透析 83 4 605 - 609 (株)東京医学社 2017年10月 [査読有り][通常論文]
  
• Power Doppler signal calibration in the finger joint between two models of ultrasound machine: a pilot study using a phantom and joints in patients with rheumatoid arthritis

  Ryosuke Sakano, Katsumi Saito, Tamotsu Kamishima, Mutsumi Nishida, Tatsunori Horie, Atsushi Noguchi, Michihito Kono, Kenneth Sutherland, Tatsuya Atsumi

  ACTA RADIOLOGICA 58 10 1238 - 1244 2017年10月 [査読有り][通常論文]
   

  Background: Despite the advantages of ultrasound (US) in the management of rheumatoid arthritis (RA) patients, power Doppler (PD) US may be highly dependent on the type of US machine used. Purpose: To present a method to calibrate the PD signal of two models of US machines by use of a flow phantom and finger joints of patients with RA. Material and Methods: For the phantom study, the PD signal count was measured in the flow phantom perfusing blood mimicking fluid at various injection rates and pulse repetition frequencies (PRFs). The quantitative PD index was calculated with ImageJ. For the clinical study, the second and third metacarpophalangeal joints of five consecutive patients with RA were examined. The quantitative PD index was measured at various PRFs by use of two models of machine (the same models as the phantom study). Results: For the phantom and clinical studies, negative correlations were found between the PRF and the quantitative PD index when the flow velocity was constant and positive correlations between flow velocity and the quantitative PD index at constant PRF. There was a significant difference in the depiction performance of synovial blood flow between the two models, which can be calibrated by adjusting the PRF values derived from the phantom study in each model. Conclusion: Signal calibration of pannus vascularity between US machines may be possible by adjusting the PRF value according to flow phantom data. Different US machines can thus provide equivalent examination results concerning the pannus vascularity.
• Myeloperoxidase/HLA Class II Complexes Recognized by Autoantibodies in Microscopic Polyangiitis.

  Ryosuke Hiwa, Koichiro Ohmura, Noriko Arase, Hui Jin, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Fumiji Saito, Chikashi Terao, Tatsuya Atsumi, Hirotsugu Iwatani, Tsuneyo Mimori, Hisashi Arase

  Arthritis & rheumatology (Hoboken, N.J.) 69 10 2069 - 2080 2017年10月 [査読有り][通常論文]
   

  OBJECTIVE: Autoantibodies against myeloperoxidase (MPO) that are expressed in neutrophils play an important role in the pathogenesis of microscopic polyangiitis (MPA). We recently observed that misfolded cellular proteins are transported to the cell surface by HLA class II molecules and are targeted by autoantibodies in patients with rheumatoid arthritis or antiphospholipid syndrome, suggesting that HLA class II molecules play an important role in autoantibody recognition. The aim of this study was to address the role of HLA class II molecules in the cell surface expression of MPO in patients with MPA. METHODS: The association of MPO with HLA-DR was analyzed using MPO and HLA-DR transfectants as well as neutrophils from healthy donors and patients with MPA. Autoantibody binding to the MPO/HLA-DR complex was analyzed by flow cytometry. The association of MPO with HLA-DR was assessed using the immunoprecipitation technique. The function of MPO-antineutrophil cytoplasmic antibody (ANCA) was assessed using a neutrophil-like cell line expressing HLA-DR and MPO. RESULTS: MPO protein was detected on the cell surface in the presence of HLA-DR, and the MPO/HLA-DR complex was recognized by MPO-ANCA. A competitive inhibition assay suggested that MPO associated with HLA-DR expresses cryptic autoantibody epitopes for MPO-ANCA. Autoantibody binding to the MPO/HLA-DR complex was correlated with disease susceptibility conferred by each HLA-DR allele, suggesting that the MPO/HLA-DR complex is involved in the pathogenicity of MPA. Indeed, MPO-HLA class II complexes were detected in neutrophils from a patient with MPA as well as in cytokine-stimulated neutrophils from healthy donors. Moreover, MPO-ANCA stimulated MPO/HLA-DR complex-expressing HL-60 cells. CONCLUSION: Our findings suggest that MPO complexed with HLA class II molecules is involved in the pathogenesis of MPA as a target for MPO-ANCA.
• The effects of vildagliptin compared with metformin on vascular endothelial function and metabolic parameters: a randomized, controlled trial (Sapporo Athero-Incretin Study 3)

  Naoyuki Kitao, Hideaki Miyoshi, Tomoo Furumoto, Kota Ono, Hiroshi Nomoto, Aika Miya, Chiho Yamamoto, Atsushi Inoue, Kenichi Tsuchida, Naoki Manda, Yoshio Kurihara, Shin Aoki, Akinobu Nakamura, Tatsuya Atsumi

  CARDIOVASCULAR DIABETOLOGY 16 1 125  2017年10月 [査読有り][通常論文]
   

  Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects in the early stage of atherosclerosis in patients with type 2 diabetes, although similar effects in advanced atherosclerosis were not shown in recent randomized placebo-controlled studies. Therefore, we investigated the efficacy of DPP-4 inhibitor on endothelial function and glycemic metabolism compared with high-dose metformin. Methods: In this multicenter, open-labeled, prospective, randomized, parallel-group comparison study, patients with type 2 diabetes treated with low-dose metformin (500-750 mg/day) were enrolled and randomly assigned to a vildagliptin, a DPP-4 inhibitor, add-on group (Vilda) or a double dose of metformin group (high Met) for 12 weeks. Flow-mediated dilation (FMD) and serum metabolic markers were assessed before and after treatment. In addition, glycemic control and metabolic parameters were also assessed. Results: Ninety-seven subjects (aged 58.7 +/- 11.0 years; body mass index, 25.9 +/- 4.4 kg/m(2); HbA1c, 7.3 +/- 0.5%; FMD, 5.8 +/- 2.6%) were enrolled. Eight subjects dropped out by the end of the study. There were no significant differences between the two groups in baseline characteristics. After 12 weeks, HbA1c was significantly improved in the Vilda group compared with the high Met group (-0.80 +/- 0.38% vs. -0.40 +/- 0.47%, respectively; p < 0.01). However, there were no significant differences in FMD (-0.51 [-1.08-0.06]% vs. -0.58 [-1.20-0.04]%). Although the apolipoprotein B/apolipoprotein A1 ratio was significantly reduced in the Vilda group compared with baseline (0.66-0.62; p < 0.01), the change did not differ significantly between the two groups (-0.04 vs. 0.00; p = 0.27). Adiponectin levels were significantly increased in the Vilda group compared with the high Met group (0.75 mu g/mL vs. 0.01 mu g/mL; p < 0.01). Conclusions: Regardless of glycemic improvement, combination therapy of vildagliptin and metformin did not affect endothelial function but may exert favorable effects on adipokine levels and lipid profile in patients with type 2 diabetes without advanced atherosclerosis.
• Clinical feature and anti-phospholipid antibody profiles of pregnancy failure in young women with antiphospholipid antibody syndrome treated with conventional therapy.

  Kaneko K, Mishima S, Goto M, Mitsui M, Tanigaki S, Oku K, Ozawa N, Inoue E, Atsumi T, Sago H, Murashima A

  Modern rheumatology 28 4 1 - 6 2017年10月 [査読有り][通常論文]
   

  OBJECTIVE: To elucidate clinical feature and anti-phospholipid antibody (aPL) profiles, including lupus anticoagulant (LA), anti-cardiolipin (CL) antibodies and anti-phosphatidylserine/prothrombin (PS/PT) antibodies, of pregnancy failure in patients with antiphospholipid antibody syndrome (APS) already treated with conventional therapy. MATERIALS AND METHODS: Thirty-four women with a history of pregnancy who were diagnosed with APS between 2008 and 2016 were included in the study. We defined the successful pregnancy group as women who gave birth to a healthy baby over 1500 g after 34 weeks of pregnancy under conventional treatment (heparin and/or low-dose aspirin). The unsuccessful pregnancy group was defined as women whose pregnancy outcomes did not meet the aforementioned criteria despite the conventional therapy. The clinical features and aPL profiles were compared between the two groups. RESULTS: Fifteen women were classified into the unsuccessful pregnancy group; seven women were in the successful pregnancy group. Having history of both thrombosis and pregnancy morbidity and LA positivity were significantly more prevalent in the unsuccessful pregnancy group than in the successful pregnancy group (p <.05, respectively). In contrast, single positivity of anti-CL antibody was negatively associated with APS-associated pregnancy morbidity under the conventional treatment (p <.01). The proportion of anti-PS/PT IgG-positive patients was significantly higher in the unsuccessful pregnancy group (p = .02, OR 18.7, 95% CI 1.50, 232.29) with high concordance rate with LA (97% consistence). CONCLUSION: History of both thrombosis and pregnancy morbidity and the positivity of LA and/or anti-PS/PT-IgG, not but anti-CL-antibodies were correlated with APS-associated pregnancy morbidity refractory to conventional treatment. Clinical feature and aPL profiles might help us to make risk assessment for adverse pregnancy outcomes in patients with APS.
• Decreased haptoglobin levels inversely correlated with pulmonary artery pressure in patients with pulmonary arterial hypertension: A cross-sectional study

  Hiroyuki Nakamura, Masaru Kato, Toshitaka Nakaya, Michihiro Kono, Shun Tanimura, Takahiro Sato, Yuichiro Fujieda, Kenji Oku, Hiroshi Ohira, Toshiyuki Bohgaki, Shinsuke Yasuda, Ichizo Tsujino, Masaharu Nishimura, Tatsuya Atsumi

  MEDICINE 96 43 e8349  2017年10月 [査読有り][通常論文]
   

  We investigated the serum haptoglobin levels in patients with pulmonary arterial hypertension (PAH) based on the hypothesis that haptoglobin levels would reflect subclinical hemolysis due to microangiopathy in pulmonary arterioles.This cross-sectional study included 3 groups of patients attending Hokkaido University Hospital: PAH, chronic thromboembolic pulmonary hypertension (CTEPH), and connective tissue diseases (CTD) without PAH (CTD-non-PAH) group. Serum haptoglobin levels were measured by standardized turbidimetric immunoassay in all patients. Demographic data, laboratory results, right heart catheter, and echocardiographic findings were extracted from the medical records. Decreased haptoglobin levels were defined as below 19mg/dL based on the 95th percentile of healthy controls.Thirty-five patients in PAH group including 11 with idiopathic PAH (IPAH) and 24 with CTD-associated PAH (CTD-PAH), 27 in CTEPH group, and 32 in CTD-non-PAH group were analyzed. Serum haptoglobin levels in PAH group (median 66mg/dL) were significantly lower than those in CTEPH group (median 94mg/dL, P=.03) and CTD-non-PAH group (median 79mg/dL, P=.03). The prevalence of decreased haptoglobin levels was 26% in PAH group, 15% in CTEPH group, and 6% in CTD-non-PAH group. Serum haptoglobin levels had a significant negative correlation (r=-0.66, P<.001) with mean pulmonary artery pressure in PAH group, particularly in CTD-PAH subgroup (r=-0.74, P<.001), but no correlation in IPAH subgroup (r=-0.52, P=.13) and in CTEPH group (r=-0.17, P=.41). Follow-up cases of CTD-PAH showed lowering pulmonary artery pressure led to normalizing serum haptoglobin levels.Serum haptoglobin levels decreased in PAH patients and inversely correlated with pulmonary artery pressure in CTD-PAH patients, suggesting their potential as a surrogate marker for CTD-PAH.
• インスリン使用中の2型糖尿病患者におけるDPP-4阻害薬からダパグリフロジンへの切替え効果

  續木 惇, 野本 博司, 土田 和久, 半田 喬久, 川田 晋一朗, 馬場 菜月, 柳谷 慎吾, 枝川 幸子, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 檀浦 みどり, 北尾 直之, 山本 浩平, 曹 圭毅, 中村 昭伸, 三好 秀明, 渥美 達也

  肥満研究 23 Suppl. 207 - 207 (一社)日本肥満学会 2017年09月
• Thrombotic risk stratification by platelet count in patients with antiphospholipid antibodies: a longitudinal study

  R. Hisada, M. Kato, E. Sugawara, Y. Fujieda, K. Oku, T. Bohgaki, O. Amengual, S. Yasuda, T. Atsumi

  JOURNAL OF THROMBOSIS AND HAEMOSTASIS 15 9 1782 - 1787 2017年09月 [査読有り][通常論文]
   

  Background Thrombocytopenia is a non-criteria clinical manifestation of antiphospholipid syndrome. However, it remains to be elucidated whether thrombocytopenia increases thrombotic risk in antiphospholipid antibody (aPL) carriers. Objectives To investigate the impact of platelet count in terms of predicting thrombotic events in aPL carriers, and to stratify the thrombotic risk by combining platelet count and antiphospholipid score (aPL-S), which represents a quantification of aPL varieties and titers. Patients/methods A single-center, retrospective, longitudinal study comprising 953 consecutive patients who were suspected of having autoimmune disease between January 2002 and December 2006 was performed. Low platelet count was defined as a count of < 150 x 10(3) L-1 at the time of aPL testing. Results A negative correlation was observed between aPL-S and platelet count (r = - 0.2477). Among aPL-positive patients, those with a low platelet count developed thrombosis more frequently than those without (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.11-7.88). Among aPL-negative patients, no difference was found in the predictive value of thrombosis regardless of platelet count. Patients with aPLs were further divided into two subgroups according to aPL-S. Among low-aPL-S patients, those with low platelet counts developed thrombosis more frequently than those without (HR 3.44, 95% CI 1.05-11.2). In contrast, high-aPL-S patients developed thrombosis frequently regardless of platelet count. Conclusions aPL carriers with low platelet counts are at high risk of developing thrombosis. In particular, low-aPL-S carriers' may be stratified by platelet count in terms of predicting future thrombotic events.
• The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome

  Mayumi Sugiura-Ogasawara, Yosuke Omae, Minae Kawashima, Licht Toyo-Oka, Seik-Soon Khor, Hiromi Sawai, Tetsuya Horita, Tatsuya Atsumi, Atsuko Murashima, Daisuke Fujita, Tomio Fujita, Shinji Morimoto, Eriko Morishita, Shinji Katsuragi, Tamao Kitaori, Kinue Katano, Yasuhiko Ozaki, Katsushi Tokunaga

  JOURNAL OF HUMAN GENETICS 62 9 831 - 838 2017年09月 [査読有り][通常論文]
   

  Antiphospholipid syndrome (APS) is the most important treatable cause of recurrent pregnancy loss. The live birth rate is limited to only 70-80% in patients with APS undergoing established anticoagulant therapy. Lupus anticoagulant (LA), but not anticardiolipin antibody (aCL), was found to predict adverse pregnancy outcome. Recent genome-wide association studies (GWAS) of APS focusing on aCL have shown that several molecules may be involved. This is the first GWAS for obstetric APS focusing on LA. A GWAS was performed to compare 115 Japanese patients with obstetric APS, diagnosed according to criteria of the International Congress on APS, and 419 healthy individuals. Allele or genotype frequencies were compared in a total of 426 344 single-nucleotide polymorphisms (SNPs). Imputation analyses were also performed for the candidate regions detected by the GWAS. One SNP (rs2288493) located on the 3'-UTR of TSHR showed an experiment-wide significant APS association (P=7.85E-08, OR=6.18) under a recessive model after Bonferroni correction considering the number of analyzed SNPs. Another SNP (rs79154414) located around the C1D showed a genome-wide significant APS association (P=4.84E-08, OR=6.20) under an allelic model after applying the SNP imputation. Our findings demonstrate that a specific genotype of TSHR and C1D genes can be a risk factor for obstetric APS.
• A case of osteomalacia due to deranged mineral balance caused by saccharated ferric oxide and short-bowel syndrome A case report

  Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, So Nagai, Naoyuki Kitao, Chikara Shimizu, Tatsuya Atsumi

  MEDICINE 96 39 e8147  2017年09月 [査読有り][通常論文]
   

  Rationale: Saccharated ferric oxide has been shown to lead to elevation of fibroblast growth factor 23, hypophosphatemia, and, consequently, osteomalacia. Moreover, mineral imbalance is often observed in patients with short-bowel syndrome to some degree. Patient concerns: A 62-year-old woman with short-bowel syndrome related with multiple resections of small intestines due to Crohn disease received regular intravenous administration of saccharated ferric oxide. Over the course of treatment, she was diagnosed with tetany, which was attributed to hypocalcemia. Additional assessments of the patient revealed not only hypocalcemia, but also hypophosphatemia, hypomagnesemia, osteomalacia, and a high concentration of fibroblast growth factor 23 (314 pg/mL). Diagnoses: We diagnosed her with mineral imbalance-induced osteomalacia due to saccharated ferric oxide and short-bowel syndrome. Interventions: Magnesium replacement therapy and discontinuation of saccharated ferric oxide alone. Outcomes: These treatments were able to normalize her serum mineral levels and increase her bone mineral density. Lessons: This case suggests that adequate evaluation of serum minerals, including phosphate and magnesium, during saccharated ferric oxide administration may be necessary, especially in patients with short-bowel syndrome.
• ゲノムワイド関連解析を用いた産科抗リン脂質抗体症候群の新たな関連遺伝子の探索

  吉原 紘行, 大前 陽輔, 杉浦 真弓, 川嶋 実苗, 豊岡 理人, Khor Seik-Soon, 澤井 浩美, 堀田 哲也, 渥美 達也, 村島 温子, 藤田 太輔, 藤田 富雄, 森本 真司, 森下 英理子, 北折 珠央, 片野 衣江, 尾崎 康彦, 徳永 勝士

  日本臨床免疫学会会誌 40 4 318 - 318 日本臨床免疫学会 2017年08月
• Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial

  Tatsuya Atsumi, Yoshiya Tanaka, Kazuhiko Yamamoto, Tsutomu Takeuchi, Hisashi Yamanaka, Naoki Ishiguro, Katsumi Eguchi, Akira Watanabe, Hideki Origasa, Shinsuke Yasuda, Yuji Yamanishi, Yasuhiko Kita, Tsukasa Matsubara, Masahiro Iwamoto, Toshiharu Shoji, Osamu Togo, Toshiyuki Okada, Desiree van der Heijde, Nobuyuki Miyasaka, Takao Koike

  ANNALS OF THE RHEUMATIC DISEASES 76 8 1348 - 1356 2017年08月 [査読有り][通常論文]
   

  Objectives To investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone. Methods MTX-naive patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTX -> MTX; n=108, PBO+MTX -> MTX; n=71). Patients who flared could receive rescue treatment with open-label CZP. Results 34 CZP+MTX -> MTX patients and 14 PBO+MTX -> MTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (p<0.001)). Remission rates decreased after CZP discontinuation; however, higher rates were maintained through week 104 in CZP+MTX -> MTX versus PBO+MTX -> MTX (41.5% vs 29.3% (p=0.026), 34.6% vs 24.2% (p=0.049) and 41.5% vs 33.1% (p=0.132) at week 104 in SDAI, Boolean and DAS28(erythrocyte sedimentation rate) remission. CZP retreated patients due to flare (n=28) showed rapid clinical improvement. The incidence of overall adverse events was similar between groups. Conclusions In MTX-naive patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years, even after stopping CZP.
• Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease

  Junya Yamamoto, Saori Nishio, Fumihiko Hattanda, Daigo Nakazawa, Toru Kimura, Michio Sata, Minoru Makita, Yasunobu Ishikawa, Tatsuya Atsumi

  KIDNEY INTERNATIONAL 92 2 377 - 387 2017年08月 [査読有り][通常論文]
   

  Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1(flox/flox): Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogenactivated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD.
• Measurement of NET formation in vitro and in vivo by flow cytometry

  Sakiko Masuda, Sakika Shimizu, Junji Matsuo, Yuka Nishibata, Yoshihiro Kusunoki, Fumihiko Hattanda, Haruki Shida, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  CYTOMETRY PART A 91A 8 822 - 829 2017年08月 [査読有り][通常論文]
   

  Neutrophil extracellular traps (NETs) are extracellular chromatin fibers adorned with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils. NETosis is the metamorphosis of neutrophils with NET formation that follows decondensation of DNA and rupture of the plasma membrane. Although NETs play important roles in innate immunity, excessive formation of NETs can be harmful to the hosts. Until now, various methods for evaluation of NETs have been reported. Although each has a virtue, the gold standard has not been established. Here we demonstrate a simple, objective, and quantitative method to detect NETs using flow cytometry. This method uses a plasma membrane-impermeable DNA-binding dye, SYTOX Green. SYTOX Green-positive cells were detected in human peripheral polymorphonuclear cells exposed to a NET inducer, phorbol 12-myristate 13-acetate (PMA). The number of SYTOX Green-positive cells was increased depending on the exposure duration and concentrations of PMA. Furthermore, co-localization of MPO and plasma membrane-appendant DNA of SYTOX Green-positive cells was demonstrated. Moreover, a NET inhibitor, diphenylene iodonium, could significantly reduce the number of SYTOX Green-positive cells induced by PMA. The collective evidence suggests that SYTOX Green-positive cells include neutrophils that formed NETs. The established method could detect neutrophils that underwent NETosis but not early apoptosis with equivalence in quantification to another well-used image analysis, which is based on fluorescent staining. Additionally, NETs that were formed in vivo were also detectable by this method. It is conceivable that the established method will bring us better understanding of the relation between NETosis and human diseases. (c) 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.
• How to Identify High-Risk APS Patients: Clinical Utility and Predictive Values of Validated Scores

  Kenji Oku, Olga Amengual, Shinsuke Yasuda, Tatsuya Atsumi

  CURRENT RHEUMATOLOGY REPORTS 19 8 51  2017年08月 [査読有り][通常論文]
   

  Purpose of Review Antiphospholipid syndrome (APS) is a clinical disorder characterised by thrombosis and/or pregnancy morbidity in the persistence of antiphospholipid (aPL) antibodies that are pathogenic and have procoagulant activities. Thrombosis in APS tends to recur and require prophylaxis; however, the stereotypical treatment for APS patients is inadequate and stratification of the thrombotic risks is important as aPL are prevalently observed in various diseases or elderly population. Recent Findings It is previously known that the multiple positive aPL or high titre aPL correlate to thrombotic events. To progress the stratification of thrombotic risks in APS patients and to quantitatively analyse those risks, antiphospholipid score (aPL-S) and the Global Antiphospholipid Syndrome Score (GAPSS) were defined. These scores were raised from the large patient cohort data and either aPL profile classified in detail (aPL-S) or simplified aPL profile with classical thrombotic risk factors (GAPSS) was put into a scoring system. Both the aPL-S and GAPSS have shown a degree of accuracy in identifying high-risk APS patients, especially those at a high risk of thrombosis. However, there are several areas requiring improvement, or at least that clinicians should be aware of, before these instruments are applied in clinical practice. One such issue is standardisation of the aPL tests, including general testing of phosphatidylserinedependent antiprothrombin antibodies (aPS/PT). Summary Additionally, clinicians may need to be aware of the patient's medical history, particularly with respect to the incidence of SLE, which influences the cutoff value for identifying high-risk patients.
• A randomized controlled trial comparing the effects of dapagliflozin and DPP-4 inhibitors on glucose variability and metabolic parameters in patients with type 2 diabetes mellitus on insulin

  Hiroshi Nomoto, Hideaki Miyoshi, Hajime Sugawara, Kota Ono, Shingo Yanagiya, Mayuko Oita, Akinobu Nakamura, Tatsuya Atsumi

  DIABETOLOGY & METABOLIC SYNDROME 9 54  2017年07月 [査読有り][通常論文]
   

  Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors improve hyperglycemia, and the usefulness of co-administration of DPP-4 inhibitors and insulin therapy has been well established. However, it has been still uncertain whether combination therapy of SGLT2 inhibitors and insulin is superior to that of DPP-4 inhibitors and the latter. Therefore, we investigated the superiority of dapagliflozin on glucose fluctuation compared with DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) on insulin using a continuous glucose monitoring (CGM) system. Methods: In this prospective, randomized, open-label controlled trial, 36 patients with T2DM and treated with DPP-4 inhibitors and insulin therapy, were enrolled and allocated into two groups. The patients either switched their DPP-4 inhibitors to dapagliflozin 5 mg for 12 weeks, or continued their DPP-4 inhibitors for the same period. CGM analyses and metabolic markers were assessed before and after treatment periods. Results: In total, data from 29 patients were analyzed. There were no significant differences in the mean amplitude of glycemic excursions and other CGM profiles in either group after treatment. Within the dapagliflozin treatment group, significant reductions of body mass index and albuminuria, and increases of HbA1c, hemoglobin and hematocrit were observed, but improvement of albuminuria was not significant if compared with the DPP-4 continuation group. Conclusions: Combination therapy of dapagliflozin and insulin was not superior in glucose fluctuation to DPP-4 inhibitors on insulin. However, dapagliflozin may in part provide favorable effects on metabolism in patients with T2DM treated with insulin therapy.
• ペリリピン1過剰発現マウスにおける動脈硬化進展抑制効果についての検討

  山本 浩平, 三好 秀明, 野本 博司, 曹 圭龍, 中村 昭伸, 渥美 達也

  日本動脈硬化学会総会プログラム・抄録集 49回 198 - 198 (一社)日本動脈硬化学会 2017年06月
• Acute aortic thrombosis related to antiphospholipid antibodies

  H. Nakamura, O. Amengual, T. Horita, M. Kato, K. Oku, T. Bohgaki, S. Yasuda, T. Atsumi

  LUPUS 26 7 783 - 784 2017年06月 [査読有り][通常論文]
  
• Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.

  Chikashi Terao, Takahisa Kawaguchi, Philippe Dieude, John Varga, Masataka Kuwana, Marie Hudson, Yasushi Kawaguchi, Marco Matucci-Cerinic, Koichiro Ohmura, Gabriela Riemekasten, Aya Kawasaki, Paolo Airo, Tetsuya Horita, Akira Oka, Eric Hachulla, Hajime Yoshifuji, Paola Caramaschi, Nicolas Hunzelmann, Murray Baron, Tatsuya Atsumi, Paul Hassoun, Takeshi Torii, Meiko Takahashi, Yasuharu Tabara, Masakazu Shimizu, Akiko Tochimoto, Naho Ayuzawa, Hidetoshi Yanagida, Hiroshi Furukawa, Shigeto Tohma, Minoru Hasegawa, Manabu Fujimoto, Osamu Ishikawa, Toshiyuki Yamamoto, Daisuke Goto, Yoshihide Asano, Masatoshi Jinnin, Hirahito Endo, Hiroki Takahashi, Kazuhiko Takehara, Shinichi Sato, Hironobu Ihn, Soumya Raychaudhuri, Katherine Liao, Peter Gregersen, Naoyuki Tsuchiya, Valeria Riccieri, Inga Melchers, Gabriele Valentini, Anne Cauvet, Maria Martinez, Tsuneyo Mimori, Fumihiko Matsuda, Yannick Allanore

  Annals of the rheumatic diseases 76 6 1150 - 1158 2017年06月 [査読有り][通常論文]
   

  OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.
• Insulin-Induced Distant Site Lipoatrophy

  Aki Kondo, Akinobu Nakamura, Jun Takeuchi, Hideaki Miyoshi, Tatsuya Atsumi

  DIABETES CARE 40 6 E67 - E68 2017年06月 [査読有り][通常論文]
  
• 常染色体優性多発嚢胞腎(ADPKD)モデルマウスにおける出生時低体重による嚢胞形成抑制機序の解析

  八反田 文彦, 牧田 実, 武田 紗夜, 渡邉 加奈子, 近藤 桂一, 川島 圭介, 石川 洋三, 楠 由宏, 石川 康暢, 西尾 妙織, 渥美 達也

  日本腎臓学会誌 59 3 261 - 261 (一社)日本腎臓学会 2017年04月
• 腎移植前耐糖能異常症例では移植前OGTT60分値が耐糖能改善の予測因子である

  大森 一乃, 中村 昭伸, 岩見 大基, 三好 秀明, 寺内 康夫, 篠原 信雄, 渥美 達也

  糖尿病 60 Suppl.1 S - 265 (一社)日本糖尿病学会 2017年04月
• 短期高脂肪食負荷誘導性膵β細胞増殖機序の検討

  北尾 直之, 中村 昭伸, 高橋 清彦, 山本 浩平, 野本 博司, チョウ 圭龍, 三好 秀明, 寺内 康夫, 渥美 達也

  日本内分泌学会雑誌 93 1 289 - 289 (一社)日本内分泌学会 2017年04月
• 123I-MIBGシンチグラフィで偽陽性を呈し、褐色細胞腫との鑑別が困難であった腎癌副腎転移の一例

  高瀬 崇宏, 野本 博司, 鬼頭 健一, 土田 和久, 平田 恵里奈, 柳谷 真悟, 枝川 幸子, 老田 真佑子, 大森 一乃, 近藤 亜樹, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 93 1 337 - 337 (一社)日本内分泌学会 2017年04月
• 甲状腺ホルモンの尿L-FABP測定への影響

  檀浦 みどり, 竹内 淳, 大森 一乃, 高橋 清彦, 北尾 直之, 山本 浩平, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 93 1 356 - 356 (一社)日本内分泌学会 2017年04月
• インスリン使用中の2型糖尿病患者におけるDPP-4阻害薬からダパグリフロジンへの切替え効果(第二報)

  土田 和久, 野本 博司, 枝川 幸子, 鬼頭 健一, 平田 恵里奈, 柳谷 慎吾, 老田 真佑子, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 60 Suppl.1 S - 146 (一社)日本糖尿病学会 2017年04月
• テルミサルタン合剤を用いた糖尿病腎症合併2型糖尿病患者におけるARBの次に追加すべき降圧薬の検討

  山本 浩平, 野本 博司, 宮 愛香, 近藤 琢磨, 栗原 義夫, 青木 伸, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 60 Suppl.1 S - 238 (一社)日本糖尿病学会 2017年04月
• 持続血糖モニタリング下で術前オクトレオチド投与を行い低血糖の消失を確認できたインスリノーマの一例

  老田 真佑子, 柳谷 真悟, 土田 和久, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 野本 博司, 曹 圭龍, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 60 Suppl.1 S - 252 (一社)日本糖尿病学会 2017年04月
• SGLT2阻害薬Luseogliflozinの膵β細胞保護作用

  高橋 清彦, 中村 昭伸, 大森 一乃, 北尾 直之, 野本 博司, 三好 秀明, 寺内 康夫, 渥美 達也

  糖尿病 60 Suppl.1 S - 395 (一社)日本糖尿病学会 2017年04月
• 短期高脂肪食負荷誘導性膵β細胞増殖メカニズムの検討

  北尾 直之, 中村 昭伸, 山本 浩平, 野本 博司, 曹 圭龍, 三好 秀明, 寺内 康夫, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 54回 75 - 75 日本臨床分子医学会 2017年04月
• 抗リン脂質抗体測定法の標準化

  北折 珠央, 尾崎 康彦, 片野 衣江, 奥 健志, 渥美 達也, 杉浦 真弓

  日本生殖医学会雑誌 62 1-2 97 - 98 (一社)日本生殖医学会 2017年04月
• 巨大多発性肝嚢胞に対する球状塞栓物質を用いた肝動脈塞栓術治療の安全性および有効性の検討

  西尾 妙織, 八反田 文彦, 石川 洋三, 阿保 大介, 曽山 武士, 作原 祐介, 渥美 達也

  日本腎臓学会誌 59 3 243 - 243 (一社)日本腎臓学会 2017年04月
• 日本人の耐糖能障害における加齢の影響 DOSANCO Health studyによる検討

  中村 昭伸, 三好 秀明, 鵜川 重和, 中村 幸志, 中川 貴史, 玉腰 暁子, 渥美 達也

  糖尿病 60 Suppl.1 S - 149 (一社)日本糖尿病学会 2017年04月
• Impact of renal transplantation on glucose tolerance in Japanese recipients with impaired glucose tolerance

  A. Nakamura, D. Iwami, H. Miyoshi, K. Morita, M. Taguri, Y. Terauchi, N. Shinohara, T. Atsumi

  Diabetic Medicine 34 4 569 - 576 2017年04月01日 [査読有り][通常論文]
   

  Aims: To investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. Methods: We conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index-2 (ISSI-2). Results: Of the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. Conclusions: More than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients.
• 新規ヒトモノクローナル抗カルジオリピンIgG抗体が示す新たな抗カルジオリピン抗体サブセット

  奥 健志, 金塚 雄作, 中村 浩之, 大村 一将, 藤枝 雄一郎, 加藤 将, アメングアル・オルガ, 保田 晋助, 渥美 達也

  日本血栓止血学会誌 28 2 229 - 229 (一社)日本血栓止血学会 2017年04月 [査読有り][通常論文]
  
• 高陽性的中率検査の組み合わせによる効率的な抗リン脂質抗体症候群のスクリーニングについて

  中村 浩之, 奥 健志, 大西 直樹, 久田 諒, 大村 一将, 藤枝 雄一郎, 加藤 将, 坊垣 暁之, アメングアル・オルガ, 保田 晋助, 渥美 達也

  日本血栓止血学会誌 28 2 230 - 230 (一社)日本血栓止血学会 2017年04月 [査読有り][通常論文]
  
• H因子の低下による補体代替経路活性化が抗リン脂質抗体症候群の向血栓性に関与する

  中村 浩之, 奥 健志, 大西 直樹, 久田 諒, 大村 一将, 藤枝 雄一郎, 加藤 将, 坊垣 暁之, アメングアル・オルガ, 保田 晋助, 渥美 達也

  日本血栓止血学会誌 28 2 243 - 243 (一社)日本血栓止血学会 2017年04月 [査読有り][通常論文]
  
• 抗C1q自己抗体は習慣性流産の原因となる新たな病原性自己抗体である

  大村 一将, 奥 健志, 北折 珠央, 藤枝 雄一郎, 加藤 将, 坊垣 暁之, Amengual Olga, 保田 晋助, 杉浦 真弓, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 54回 65 - 65 日本臨床分子医学会 2017年04月 [査読有り][通常論文]
  
• 抗リン脂質抗体症候群における末梢血リンパ球サブセットおよび一塩基多型(SNP)の解析

  久田 諒, 加藤 将, 菅原 恵理, 中村 浩之, 大村 一将, 中川 久子, 藤枝 雄一郎, 奥 健志, 坊垣 暁之, アメングアル・オルガ, 堀田 哲也, 保田 晋助, 渥美 達也

  日本血栓止血学会誌 28 2 229 - 229 (一社)日本血栓止血学会 2017年04月 [査読有り][通常論文]
  
• Factors associated with an inadequate hypoglycemia in the insulin tolerance test in Japanese patients with suspected or proven hypopituitarism

  Kiyohiko Takahashi, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Chikara Shimizu, Masataka Taguri, Yasuo Terauchi, Tatsuya Atsumi

  ENDOCRINE JOURNAL 64 4 387 - 392 2017年04月 [査読有り][通常論文]
   

  We attempted to identify the predictors of an inadequate hypoglycemia in insulin tolerance test (ITT), defined as a blood glucose level higher than 2.8 mmol/L after insulin injection, in Japanese patients with suspected or proven hypopituitarism. A total of 78 patients who had undergone ITT were divided into adequate and inadequate hypoglycemia groups. The relationships between the subjects' clinical parameters and inadequate hypoglycemia in ITT were analyzed. Stepwise logistic regression analysis identified high systolic blood pressure (SBP) and high homeostasis model assessment of insulin resistance (HOMA-IR) as being independent factors associated with inadequate hypoglycemia in ITT. Receiver operating characteristic (ROC) curve analysis revealed the cutoff value for inadequate hypoglycemia was 109 mmHg for SBP and 1.4 for HOMA-IR. The areas under ROC curve for SBP and HOMA-IR were 0.72 and 0.86, respectively. We confirmed that high values of SBP and HOMA-IR were associated with inadequate hypoglycemia in ITT, regardless of the degree of reduction of pituitary hormone levels. Furthermore, the strongest predictor of inadequate hypoglycemia was obtained by using the cutoff value of HOMA-IR. Our results suggest that HOMA-IR is a useful pre-screening tool for ITT in these populations.
• Effects of 50 mg vildagliptin twice daily vs. 50 mg sitagliptin once daily on blood glucose fluctuations evaluated by long-term self-monitoring of blood glucose

  Hiroshi Nomoto, Kimihiko Kimachi, Hideaki Miyoshi, Hiraku Kameda, Kyu Yong Cho, Akinobu Nakamura, So Nagai, Takuma Kondo, Tatsuya Atsumi

  ENDOCRINE JOURNAL 64 4 417 - 424 2017年04月 [査読有り][通常論文]
   

  To date, several clinical trials have compared differences in glucose fluctuation observed with dipeptidyl peptidase-4 inhibitor treatment in patients with type 2 diabetes mellitus. However, most patients were assessed for limited periods or during hospitalization. The aim of the present study was to evaluate the effects of switching from sitagliptin to vildagliptin, or vice versa, on 12-week glucose fluctuations using self-monitoring of blood glucose in the standard care setting. We conducted a multicenter, prospective, open-label controlled trial in Japanese patients with type 2 diabetes. Thirty-two patients were treated with vildagliptin (50 mg) twice daily or sitagliptin (50 mg) once daily and were allocated to one of two groups: vildagliptin treatment for 12 weeks before switching to sitagliptin for 12 weeks, or vice versa. Daily profiles of blood glucose were assessed several times during each treatment period, and the mean amplitude of glycemic excursions and M-value were calculated. Metabolic biomarkers such as hemoglobin Alc (HbAlc), glycated albumin, and 1,5-anhydroglucitol were also assessed. With vildagliptin treatment, mean amplitude of glycemic excursions was significantly improved compared with sitagliptin treatment (57.9 +/- 22.2 vs. 68.9 +/- 33.0 mg/dL; p=0.0045). M-value (p=0.019) and mean blood glucose (p=0.0021) were also lower with vildagliptin, as were HbAlc, glycated albumin, and 1,5-anhydroglucitol. There were no significant differences in other metabolic parameters evaluated. Reduction of daily blood glucose profile fluctuations by vildagliptin was superior to that of sitagliptin in Japanese patients with type 2 diabetes.
• [Programs for Continuing Medical Education 2016: A Session: 8. Recent Strategy to Treat Patients with Rheumatoid Arthritis].

  Atsumi T

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 106 3 499 - 504 2017年03月 [査読有り][通常論文]
  
• 関節リウマチにおける手の滑膜炎定量のためのダイナミック造影強調MRIを用いた簡易的なアプローチ 完全自動化した全画素の分析(Simplified Approach to Quantification for Hand Synovitis in Rheumatoid Arthritis Using Dynamic Contrast Enhanced MRI: Full-Automatic Pixel-By-Pixel Analysis)

  Kobayashi Yuto, Kamishima Tamotsu, Ichikawa Shota, Sugimori Hiroyuki, Noguchi Atsushi, Kono Michihito, Atsumi Tatsuya

  日本放射線技術学会総会学術大会予稿集 73回 178 - 179 2017年03月
• 血管炎 ANCA関連血管炎(AAV)における抗NETs抗体の存在と病的意義

  八反田 文彦, 楠 由宏, 志田 玄貴, 中沢 大悟, 西尾 妙織, 益田 紗季子, 外丸 詩野, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 61回 431 - 431 (一社)日本リウマチ学会 2017年03月
• SLE・抗リン脂質抗体症候群 活動性ループス腎炎に対する中等量ステロイド併用ミコフェノール酸モフェチルによる寛解導入療法の有効性

  河野 通大, 保田 晋助, 阿部 早和子, 大西 直樹, 土井 基嗣, 谷村 瞬, 久田 諒, 菅原 恵理, 中村 浩之, 大村 一将, 嶋村 抄苗, 清水 裕香, 藤枝 雄一郎, 加藤 将, 奥 健志, 坊垣 暁之, アメングアル・オルガ, 渥美 達也

  日本リウマチ学会総会・学術集会プログラム・抄録集 61回 460 - 460 (一社)日本リウマチ学会 2017年03月 [査読有り][通常論文]
  
• 関節リウマチの治療 用法・用量・スイッチ・無効・減量・中止 アバタセプト減量による関節リウマチ維持療法 北海道・東北地域での多施設前向き介入試験

  保田 晋助, 大村 一将, 金澤 洋, 栗田 崇史, 近 祐次郎, 石井 智徳, 藤枝 雄一郎, 浄土 智, 谷村 一秀, 三浪 三千男, 泉山 朋政, 松本 巧, 天崎 吉晴, 鈴木 陽子, 笠原 英樹, 山内 尚文, 加藤 将, 神島 保, 堤 明人, 竹森 弘光, 小池 隆夫, 渥美 達也

  日本リウマチ学会総会・学術集会プログラム・抄録集 61回 565 - 565 (一社)日本リウマチ学会 2017年03月 [査読有り][通常論文]
  
• Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study

  O. Amengual, R. Forastiero, M. Sugiura-Ogasawara, K. Otomo, K. Oku, C. Favas, J. Delgado Alves, P. Zigon, A. Ambrozic, M. Tomsic, I. Ruiz-Arruza, G. Ruiz-Irastorza, M. L. Bertolaccini, G. L. Norman, Z. Shums, J. Arai, A. Murashima, A. E. Tebo, M. Gerosa, P. L. Meroni, I. Rodriguez-Pinto, R. Cervera, J. Swadzba, J. Musial, T. Atsumi

  LUPUS 26 3 266 - 276 2017年03月 [査読有り][通常論文]
   

  Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study (n=247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed (k=0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0-29.3), p<0.0001. Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study (n=214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed (k=0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6-16), p<0.0001. Sensitivity, specificity, LR+and LR- for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.
• Effectiveness and safety of tocilizumab in achieving clinical and functional remission, and sustaining efficacy in biologics-naive patients with rheumatoid arthritis: The FIRST Bio study

  Naoki Ishiguro, Tatsuya Atsumi, Masayoshi Harigai, Tsuneyo Mimori, Norihiro Nishimoto, Takayuki Sumida, Tsutomu Takeuchi, Yoshiya Tanaka, Ayako Nakasone, Nobuhiro Takagi, Hisashi Yamanaka

  MODERN RHEUMATOLOGY 27 2 217 - 226 2017年03月 [査読有り][通常論文]
   

  Objective: To evaluate effectiveness and safety of tocilizumab (TCZ) in biologic-naive Japanese patients with rheumatoid arthritis (RA) in real-world settings, and to analyze the relationship between disease duration and clinical outcomes.Methods: The FIRST Bio study was a postmarketing surveillance study of intravenous TCZ in biologics-naive patients who had a prior inadequate response or were intolerant to 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD). Effectiveness, safety, and concomitant csDMARD administration were assessed.Results: Of the 839 patients analyzed, 72.3% completed 52 weeks of treatment. The Clinical Disease Activity Index (CDAI) remission rate at week 52 was 36.8%. Contributing factors for CDAI remission were younger age, early disease stage, and no comorbidities. Health Assessment Questionnaire Disability Index 0.5 was achieved in 65.1% of patients, and was significantly associated with disease duration. Discontinuation of concomitant methotrexate (MTX) and glucocorticoids (GCs) was possible in 19.3% and 34.1% of patients, respectively, without decreasing remission rate. The incidence (events/100 patient-years) of serious adverse events was 18.09, the most common being infection.Conclusion: These data validate the importance of TCZ treatment in the early stages of RA in biologic-naive patients to achieve increased effectiveness. The safety profile of TCZ was reconfirmed. Furthermore, TCZ therapy may allow discontinuation of concomitant MTX and GCs without affecting remission.
• Brain MRI abnormalities defined as risks for poor prognosis in lupus patients with acute confusional state: Are they antibody mediated?

  Shinsuke Yasuda, Yuka Shimizu, Tatsuya Atsumi

  MODERN RHEUMATOLOGY 27 2 191 - 192 2017年03月 [査読有り][通常論文]
  
• Active synovitis in the presence of osteitis predicts residual synovitis in patients with rheumatoid arthritis with a clinical response to treatment.

  Fukae J, Tanimura K, Isobe M, Kitano A, Henmi M, Nakai M, Aoki Y, Sakamoto F, Narita A, Ito T, Mitsuzaki A, Matsuhashi M, Shimizu M, Kamishima T, Atsumi T, Koike T

  International journal of rheumatic diseases 21 10 1809 - 1814 2017年02月 [査読有り][通常論文]
   

  AIM: To clarify the relationship between active synovitis/osteitis and subsequent residual synovitis (R-synovitis) in patients with rheumatoid arthritis (RA). METHODS: Three hundred and twenty finger joints of 16 patients with active RA at baseline (Disease Activity Score with 28 joints - erythrocyte sedimentation rate > 3.2) who subsequently achieved clinical low disease activity or remission afterwards were analyzed. Synovial vascularity (SV) was assessed according to a semi-quantitative ultrasound score (grades 0-3). Active synovitis was defined by SV positivity at baseline. R-synovitis was defined by the presence of grade > 2 SV at the 24th week. Osteitis was detected by magnetic resonance imaging (MRI) at baseline as trabecular bone lesions with water content and indistinct margins. RESULTS: Ultrasonography detected active synovitis in 116 joints at baseline. Forty-seven joints had R-synovitis at the 24th week. MRI detected osteitis in 12 joints at baseline. The presence of active synovitis with osteitis at baseline was significantly correlated with R-synovitis at the 24th week. CONCLUSIONS: Active synovitis in the presence of osteitis predicted R-synovitis regardless of whether there was a clinical improvement in RA.
• Impact of incretin-related agents on endothelial cell function

  Hiroshi Nomoto, Hideaki Miyoshi, Akinobu Nakamura, Tatsuya Atsumi, Naoki Manda, Yoshio Kurihara, Shin Aoki, on behalf of SAIS Study Group

  Clinical Trials in Degenerative Diseases 2 1 2017年
• Safety and effectiveness of 24-week treatment with iguratimod, a new oral disease-modifying antirheumatic drug, for patients with rheumatoid arthritis: interim analysis of a post-marketing surveillance study of 2679 patients in Japan

  Tsuneyo Mimori, Masayoshi Harigai, Tatsuya Atsumi, Takao Fujii, Masataka Kuwana, Hiroaki Matsuno, Shigeki Momohara, Syuji Takei, Naoto Tamura, Yoshinari Takasaki, Satoshi Ikeuchi, Satoru Kushimoto, Takao Koike

  MODERN RHEUMATOLOGY 27 5 755 - 765 2017年 [査読有り][通常論文]
   

  Objective: To determine the real-world safety and effectiveness of iguratimod (IGU) for rheumatoid arthritis (RA), a 52-week, Japanese, post-marketing surveillance study was conducted. An interim analysis at week 24 was performed. Methods: This study included all RA patients who received IGU following its introduction to the market. All adverse events (AEs) and adverse drug reactions (ADRs) were collected. Effectiveness was evaluated by the change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) from baseline to week 24. Results: Safety was analyzed in 2679 patients. The overall incidences of AEs, ADRs, and serious ADRs were 38.41, 31.65, and 3.21%, respectively; the most commonly reported serious ADRs were pneumonia/bacterial pneumonia, interstitial lung disease, and Pneumocystis jiroveci pneumonia. Concomitant glucocorticoid use and comorbid conditions associated with respiratory disease were identified as risk factors for serious infections. Pulmonary alveolar hemorrhage and increased international normalized ratio of prothrombin time were observed with concomitant use of IGU and warfarin. The DAS28-CRP decreased from baseline to week 24. Conclusion: Although a safety concern was identified with concomitant use of IGU and warfarin, this real-world study showed no other new safety concerns and similar effectiveness to clinical trials. IGU is a new therapeutic option for RA patients.
• Effectiveness of a Medical English Course on Communication Abilities of Graduate Medical Students

  アメングアル オルガ

  Medical Science Educator Journal 2017年 [査読有り][通常論文]
  
• Risk factors for development of systemic lupus erythematosus among Japanese females: medical history and reproductive factors

  Masakazu Washio, Hiroki Takahashi, Gen Kobashi, Chikako Kiyohara, Yoshifumi Tada, Toyoko Asami, Yuichiro Ide, Tatsuya Atsumi, Takahiko Horiuchi

  INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES 20 1 76 - 83 2017年01月 [査読有り][通常論文]
   

  Aim:The aim of the present study was to examine the influence of medical history and reproductive factors on the development of systemic lupus erythematosus (SLE) among Japanese females. Methods: One hundred and sixty female SLE patients and 660 female volunteers were studied in a case-control study. Unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CIs). Results: The present study demonstrated that medical histories of operations without blood transfusion (OR = 1.64, 95% CI = 1.10-2.44) and operations with blood transfusion (OR = 4.44, 95% CI = 1.93-10.23) increased the risk of SLE with adjustment for age, region, smoking and alcohol drinking. Among 91 SLE patients and 284 control subjects who had the experience of married life, nulliparity (OR = 2.29, 95% CI = 1.05-5.17), increased the risk of SLE, while the risk decreased according to the number of children (one to two vs. none, OR = 0.27, 95% CI = 0.10-0.73; three or more vs. none, OR = 0.14, 95% CI = 0.04-0.51; P for trend < 0.01). Conclusions: Several factors are suggested to be associated with the development of SLE among Japanese females.
• Pixel-by-Pixel Arterial Spin Labeling Blood Flow Pattern Variation Analysis for Discrimination of Rheumatoid Synovitis: A Pilot Study

  Taro Sakashita, Tamotsu Kamishima, Hiroyuki Sugimori, Minghui Tang, Atsushi Noguchi, Michihito Kono, Kenneth Sutherland, Tatsuya Atsumi

  MAGNETIC RESONANCE IN MEDICAL SCIENCES 16 1 78 - 83 2017年 [査読有り][通常論文]
   

  We examined the capability of a gray-scale arterial spin labeling blood flow pattern variation (BFPV) map with two different post labeling delay (PLD) times to discriminate pannus in patients with rheumatoid arthritis (RA) at 3T. There was a statistically significant difference in the BFPV values between artery, pannus, and surrounding tissue. Furthermore, the color-coded BFPV map was able to accurately distinguish pannus from other tissues. These results suggest this approach may be capable of identifying pannus noninvasively.
• Bi-ventricular interplay in patients with systemic sclerosis-associated pulmonary arterial hypertension: Detection by cardiac magnetic resonance

  Atsushi Noguchi, Masaru Kato, Michihito Kono, Kazumasa Ohmura, Hiroshi Ohira, Ichizo Tsujino, Noriko Oyama-Manabe, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Masaharu Nishimura, Tatsuya Atsumi

  MODERN RHEUMATOLOGY 27 3 481 - 488 2017年 [査読有り][通常論文]
   

  Objectives: Pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) has a poor prognosis compared to PAH associated with other connective tissue diseases (CTD). The objective of this study was to examine the difference in hemodynamic state between SSc-PAH and other CTD-PAH by performing cardiac magnetic resonance (CMR) imaging.Methods: A single center retrospective analysis was conducted comprising 40 consecutive CTD patients who underwent right heart catheterization and CMR at the same period from January 2010 to October 2015.Results: Thirty-two patients had pre-capillary pulmonary hypertension. Of these, 15 had SSc and 17 had other CTD. CMR measurements, particularly the ratio of right to left end-diastolic volume (RVEDV/LVEDV), correlated well with mean pulmonary arterial pressure (mPAP). Conversely, RVEDV/LVEDV and mPAP correlated differently in SSc and non-SSc patients. In SSc patients, the ratio of RVEDV/LVEDV to mPAP was significantly higher compared to non-SSc patients. In the follow-up study, 2 SSc patients exhibited increased RVEDV/LVEDV in spite of decreased mPAP following treatment. Kaplan-Meier analysis revealed poor prognosis of patients with increased RVEDV/LVEDV following treatment.Conclusions: Our data indicated that altered bi-ventricular interplay detected at CMR may represent SSc-related cardiac involvement and reflect poor prognosis of SSc-PAH.
• Safety and effectiveness of 24-week treatment with iguratimod, a new oral disease-modifying antirheumatic drug, for patients with rheumatoid arthritis: interim analysis of a post-marketing surveillance study of 2679 patients in Japan (vol 27, pg 755, 2017)

  T. Mimori, M. Harigai, T. Atsumi, T. Fujii, M. Kuwana, H. Matsuno

  MODERN RHEUMATOLOGY 27 5 V - V 2017年 [査読有り][通常論文]
  
• Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects

  Takahiro Takase, Akinobu Nakamura, Hideaki Miyoshi, Chiho Yamamoto, Tatsuya Atsumi

  ENDOCRINE JOURNAL 64 3 363 - 367 2017年 [査読有り][通常論文]
   

  In this study, we investigated the ameliorating effects of ipragliflozin on fatty liver in patients with type 2 diabetes. The factors that influenced the amelioration of fatty liver were also examined. Analysis included data of 21 Japanese patients with type 2 diabetes obtained from our prospective observational study. After obtaining patients' informed consent, once-daily ipragliflozin (50 mg/day) was given for 16 weeks. In addition to several clinical parameters, body composition was also compared before and after 16 weeks of treatment. The extent of fatty liver was estimated using a fatty liver index (FLI). After 16 weeks, FLI significantly decreased, from 70.1 +/- 19.4 to 60.3 +/- 25.5 (p = 0.0009) as well as levels of fasting plasma glucose (FPG), HbA1c, body weight, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and fat mass. To reveal the factors influencing the FLI changes observed on ipragliflozin treatment, correlations between changes in FLI and several other measured parameters were examined. Changes in FPG (correlation coefficient = 0.4683, p = 0.0323) and HbA1c (correlation coefficient = 0.4383, p = 0.0469) showed significant positive correlations with changes in FLI. On the other hand, no correlations of changes in FLI were observed with body weight, VAT, SAT nor fat mass. In conclusion, ipragliflozin ameliorated FLI in Japanese patients with type 2 diabetes. Improvement in FLI was associated with that of glucose intolerance.
• Takayasu Arteritis with Varied-size Vessel Involvement

  Michihiro Kono, Shinsuke Yasuda, Tatsuya Atsumi

  JOURNAL OF RHEUMATOLOGY 44 1 125 - 126 2017年01月 [査読有り][通常論文]
  
• Hyponatremia can be a powerful predictor of the development of isolated ACTH deficiency associated with nivolumab treatment

  Kyu Yong Cho, Hideaki Miyoshi, Akinobu Nakamura, Takashi Kurita, Tatsuya Atsumi

  ENDOCRINE JOURNAL 64 2 235 - 236 2017年 [査読有り][通常論文]
  
• Subcutaneous panniculitis-like T-cell lymphoma with haemophagocytic syndrome during tocilizumab therapy for juvenile idiopathic arthritis

  H. Nakamura, T. Sugai, M. Kato, K. C. Hatanaka, T. Atsumi

  CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 35 1 174 - 174 2017年01月 [査読有り][通常論文]
  
• Effectiveness of whole-body magnetic resonance imaging for the efficacy of biologic anti-rheumatic drugs in patients with rheumatoid arthritis: A retrospective pilot study

  Michihito Kono, Tamotsu Kamishima, Shinsuke Yasuda, Keita Sakamoto, Sawako Abe, Atsushi Noguchi, Toshiyuki Watanabe, Yuka Shimizu, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Tatsuya Atsumi

  MODERN RHEUMATOLOGY 27 6 953 - 960 2017年 [査読有り][通常論文]
   

  Objectives: To evaluate the scoring of whole-body magnetic resonance imaging (WBMRI) for efficacy assessment in rheumatoid arthritis (RA) patients receiving biological disease-modifying anti-rheumatic drugs (bDMARDs).Methods: Thirty consecutive RA patients receiving bDMARDs were included in this retrospective study. Contrast WBMRI was performed before and 1 year after bDMARDs initiation.Results: At baseline, mean age was 57.1 years and mean disease duration was 3.0 years. Median disease activity score in 28 joints improved from 5.1 to 2.1. Treatment with bDMARDs improved mean whole-body synovitis score from 31.2 to 23.2 and median whole-body bone-edema score from 11 to 3. Whole-body bone-erosion score improved in seven patients and deteriorated in 17 patients. Logistic regression analysis identified whole-body synovitis score as a poor prognostic factor for whole-body bone-erosion progression. Bone-edema score in individual bones was identified as a poor prognostic factor for the progression of bone-erosion. Changes in hand synovitis score correlated with those of other joints, but neither changes in bone-edema nor erosion score of hands correlated with those of other joints in WBMRI.Conclusions: WBMRI scoring may be a novel useful tool to evaluate the efficacy of anti-rheumatic drugs, as well as a potential predictor of joint prognosis, in patients with RA.
• Maintenance treatment using abatacept with dose reduction after achievement of low disease activity in patients with rheumatoid arthritis (MATADOR) - A prospective, multicenter, single arm pilot clinical trial

  Shinsuke Yasuda, Kazumasa Ohmura, Hiroshi Kanazawa, Takashi Kurita, Yujiro Kon, Tomonori Ishii, Yuichiro Fujieda, Satoshi Jodo, Kazuhide Tanimura, Michio Minami, Tomomasa Izumiyama, Takumi Matsumoto, Yoshiharu Amasaki, Yoko Suzuki, Hideki Kasahara, Naofumi Yamauchi, Masaru Kato, Tamotsu Kamishima, Akito Tsutsumi, Hiromitsu Takemori, Takao Koike, Tatsuya Atsumi

  MODERN RHEUMATOLOGY 27 6 930 - 937 2017年 [査読有り][通常論文]
   

  Objectives: To preliminarily evaluate the feasibility of maintenance therapy with reduced dose of intravenous abatacept (ABT) to 250mg/body/month after achieving remission or low disease activity (LDA).Patients and methods: RA patients treated with ABT at 13 sites were enrolled in this prospective interventional pilot study during the period between March 2013 and March 2015. Inclusion criteria were (1) age at 20 years or older, (2) under treatment with monthly intravenous ABT at approved doses, (3) DAS28-CRP lower than 2.7 at least for 6 months, (4) agreed to join this trial with written informed consent and (5) body weight under 125kg. Enrolled patients were maintained with intravenous monthly ABT at a reduced dose of 250mg/body (MATADOR protocol). The primary end point was the proportion of the patients continued with MATADOR protocol at week 48. MATADOR protocol was discontinued upon disease flare or other reasons such as patients' request or severe adverse event (AE). Disease activities and structural changes were also evaluated.Results: Fifty-three patients fulfilled the entry criteria and were followed for 1-year. MATADOR protocol was continued for 1-year in 43 (81%) of the evaluated patients. Three patients experienced severe AEs. Mean DAS28-CRP and remission rate were 1.56 and 88% when ABT reduced and 1.80 and 81% at 1-year, respectively. Structural remission was achieved in 34 out of 42 evaluated patients.Conclusions: Reduced dose of intravenous ABT was proposed as a feasible choice for maintenance therapy for RA after achievement of remission/LDA, although further randomized trials would be awaited.
• Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide

  Eri Sugawara, Masaru Kato, Ryo Hisada, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi

  INTERNAL MEDICINE 56 4 445 - 448 2017年 [査読有り][通常論文]
   

  Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH.
• 特定機能病院における糖尿病療養支援の方向性に関する一考察 外来初診患者の臨床的特徴から

  佐藤 三穂, 佐藤 仁美, 鷲見 尚己, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病ケア 13 12 1146 - 1150 (株)メディカ出版 2016年12月 

  特定機能病院における糖尿病療養支援の方向性について、看護師の視点から明らかにすることを目的に、2012年1月〜12月に特定機能病院である当院の糖尿病専門外来を初診で受診した糖代謝異常患者399名(男性209名、女性190名、平均年齢58±16歳)の診療録を後ろ向きに調査した。その結果、初診患者の27.1%が周術期管理目的で、初診時から1年以上継続して当外来を受診している患者は31.1%、1年間に外来看護師による看護介入があったのは11.5%であった。これらの結果に、複数の診療科を有し専門的治療の役割を担う特定機能病院の特徴を勘案し、特定機能病院における糖尿病療養支援の方向性として、周術期、または糖尿病以外の疾患を抱える糖尿病患者への支援、病診連携による医療スタッフ間の効果的な情報共有や連携方法の検討、さらに療養支援が必要な患者を拾い上げて効果的なタイミングで介入するための、看護師と医師の情報共有やスクリーニングの方法について、今後検討していく必要があると考えられた。
• 原発性肺癌に対する抗PD-1抗体ニボルマブ投与中にACTH単独欠損症を発症した1例

  鬼頭 健一, 曹 圭龍, 土田 和久, 平田 恵里奈, 柳谷 真悟, 老田 真佑子, 大森 一乃, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 92 S.Branc 12 - 12 (一社)日本内分泌学会 2016年12月
• Differentiating biosimilarity and comparability in biotherapeutics

  Valderilio Azevedo, Brian Hassett, Joao Eurico Fonseca, Tatsuya Atsumi, Javier Coindreau, Ira Jacobs, Ehab Mahgoub, Julie O'Brien, Ena Singh, Steven Vicik, Brian Fitzpatrick

  CLINICAL RHEUMATOLOGY 35 12 2877 - 2886 2016年12月 [査読有り][通常論文]
   

  The manufacture of biologics is a complex process involving numerous steps. Over time, differences may arise as a result of planned changes to the manufacturing processes of a biologic from the same manufacturer. Comparability is the regulatory process that outlines the scope of an assessment required of an already licensed biologic after a manufacturing process change made by the same manufacturer. The aim of a comparability assessment is to demonstrate that any pre-manufacturing and post-manufacturing changes have no adverse impact on quality, safety, and efficacy of the biologic. A comparability assessment is distinct from a biosimilarity assessment, which involves extensive assessment of a biologic that is highly similar to the originator (reference product) in terms of quality, safety, and efficacy. The US Food and Drug Administration, European Medicines Agency, and World Health Organization have applied the fundamental comparability concepts into their respective biosimilarity guidance documents. In this review, we examine the rationale behind the distinct, highly regulated approval processes governing changes that may occur over time to an originator biologic due to planned manufacturing changes (as described by a comparability exercise) and those that outline the approval of a proposed biosimilar drug, based on its relationship with the reference product (biosimilarity evaluations).
• The Presence of Anti-Lactoferrin Antibodies in a Subgroup of Eosinophilic Granulomatosis with Polyangiitis Patients and Their Possible Contribution to Enhancement of Neutrophil Extracellular Trap Formation

  Haruki Shida, Daigo Nakazawa, Yu Tateyama, Arina Miyoshi, Yoshihiro Kusunoki, Fumihiko Hattanda, Sakiko Masuda, Utano Tomaru, Tamihiro Kawakami, Tatsuya Atsumi, Akihiro Ishizu

  FRONTIERS IN IMMUNOLOGY 7 636  2016年12月 [査読有り][通常論文]
   

  Lactoferrin (Lf) is one of the antigens of antineutrophil cytoplasmic antibodies (ANCA) and functions as an endogenous suppressor of neutrophil extracellular trap (NET) formation. However, the prevalence and pathogenicity of anti-lactoferrin antibodies (aLf) in ANCA-associated vasculitis (AAV) remain unrevealed. This study aimed to examine the significance of aLf in AAV, initially. Sixty-five sera from AAV patients, including 41 microscopic polyangiitis, 5 granulomatosis with polyangiitis, and 19 eosinophilic granulomatosis with polyangiitis (EGPA) patients, were subjected to aLf detection using enzyme-linked immunosorbent assay. Clinical characteristics were compared between aLf-positive and aLf-negative patients. Neutrophils from healthy donors were exposed to suboptimal dose (10 nM) of phorbol myristate acetate (PMA) with aLf followed by evaluation of NET formation. Results demonstrated that 4 out of 65 AAV sera (6.2%) were positive for aLf. All of them were EGPA sera (4/19, 21.1%). In EGPA, the frequency of renal involvement, serum CRP levels, and Birmingham Vasculitis Activity Score (BVAS) in the aLf-positive patients was significantly higher than those in the aLf-negative patients, and the aLf titer correlated positively with the serum CRP level and BVAS. The NET formation was particularly enhanced by combined stimulation of 10 nM PMA and 1 mu g/mL aLf. IgG isolated from sera of the aLf-positive EGPA patients (250 mu g/mL) enhanced NET formation induced by 10 nM of PMA, and the effect was abolished completely by absorption of the aLf. This pilot study suggests that aLf enhance NET formation induced by PMA and are associated with disease activity of EGPA.
• 抗リン脂質抗体の新たな展開 抗リン脂質抗体症候群と補体活性化

  奥 健志, 大村 一将, 渥美 達也

  Reproductive Immunology and Biology 31 1-2 88 - 88 日本生殖免疫学会 2016年11月 [査読有り][通常論文]
  
• Clinical significance of lupus anticoagulant and genome-wide association study in obstetric antiphospholipid syndrome

  Sugiura Mayumi, Kitaori Tamao, Ozaki Yasuhiko, Katano Kinue, Oku Kenji, Horita Tetsuya, Atsumi Tatsuya, Murashima Atsuko, Omae Yosuke, Tokunaga Katsushi

  JOURNAL OF REPRODUCTIVE IMMUNOLOGY 118 145  2016年11月 [査読有り][通常論文]
  
• Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study)

  Yuko Kaneko, Tatsuya Atsumi, Yoshiya Tanaka, Masayuki Inoo, Hitomi Kobayashi-Haraoka, Koichi Amano, Masayuki Miyata, Yohko Murakawa, Hidekata Yasuoka, Shintaro Hirata, Hayato Nagasawa, Eiichi Tanaka, Nobuyuki Miyasaka, Hisashi Yamanaka, Kazuhiko Yamamoto, Tsutomu Takeuchi

  ANNALS OF THE RHEUMATIC DISEASES 75 11 1917 - 1923 2016年11月 [査読有り][通常論文]
   

  Objective To compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active rheumatoid arthritis (RA). Methods This is a 2-year randomised, controlled study. RA patients with moderate or high disease activity despite methotrexate were randomly assigned either to tocilizumab added to methotrexate (add-on) or tocilizumab switched from methotrexate (switch). The primary endpoint was the DAS28 remission rate at week 24. Secondary objectives included other clinical efficacy indices, radiological outcomes assessed with the van der Heijde-modified total Sharp scoring system (mTSS), and safety. Results Of 223 randomised patients, 83% completed 52 weeks. DAS28 remission rates at week 24 were 70% for add-on and 55% for switch (p=0.02), but they became comparable at week 52 (72% vs 70%, p=0.86). Structural remission rates (mTSS=0.5) at week 52 were not different (66% vs 64%, p=0.92). However, clinically relevant radiographic progression rates (CRRP; mTSS=3) tended to be higher with the switch than with the add-on (15% vs 7%, p=0.07). Radiographic progression in the CRRP patients was larger with the switch than with the add-on (9.0/year vs 5.0/year, p=0.04). The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24 weeks (1.56 vs 0.49, p=0.001) but not for the following 28 weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group. Conclusions In RA patients with inadequate response to methotrexate, tocilizumab added to methotrexate more rapidly suppressed inflammation than tocilizumab switched from methotrexate, leading to superior clinical efficacy and prevention of joint destruction.
• Analysis of bone metabolism during early stage and clinical benefits of early intervention with alendronate in patients with systemic rheumatic diseases treated with high-dose glucocorticoid: Early DIagnosis and Treatment of OsteopoRosis in Japan (EDITOR-J) study

  Yoshiya Tanaka, Hiroko Mori, Takatoshi Aoki, Tatsuya Atsumi, Yutaka Kawahito, Hisanori Nakayama, Shigeto Tohma, Yuji Yamanishi, Hitoshi Hasegawa, Kazuhide Tanimura, Nobuo Negoro, Yukitaka Ueki, Atsushi Kawakami, Katsumi Eguchi, Kazuyoshi Saito, Yosuke Okada

  JOURNAL OF BONE AND MINERAL METABOLISM 34 6 646 - 654 2016年11月 [査読有り][通常論文]
   

  We conducted a prospective multicenter study to assess early changes in the dynamics of bone metabolism in patients with systemic connective tissue diseases following commencement of high-dose glucocorticoid therapy and the benefits of early treatment with bisphosphonate and vitamin D analogue. The subjects of this randomized controlled trial were 106 female patients with systemic connective tissue diseases treated for the first time with glucocorticoids at doses equivalent to prednisolone aeyen20 mg/day (age aeyen 18 years). One week after initiation of glucocorticoid therapy, patients were randomly assigned to treatment with alfacalcidol at 1 mu g/day (n = 33), alendronate 35 mg/week (n = 37), and alfacalcidol plus alendronate (n = 36). The primary endpoints were changes in lumbar spine bone density at 6 months of treatment and the frequency of bone fracture at 12 months. Commencement of glucocorticoid therapy was associated with a rapid and marked bone resorption within 1 week. The combination of alfacalcidol and alendronate administered after the first week of glucocorticoid therapy halted the pathological processes affecting bone metabolism, increased bone density, and reduced the incidence of bone fracture over a period of 12 months. Taken together, the use of the combination of alfacalcidol and alendronate improved bone metabolism, increased bone density, and significantly reduced the incidence of bone fracture during 1-year high-dose glucocorticoid therapy.
• 局在診断に苦慮した異所性ACTH産生膵神経内分泌腫瘍の一例

  老田 真佑子, 中村 昭伸, 枝川 幸子, 大森 一乃, 高瀬 崇宏, 近藤 亜樹, 菅原 基, 一山 芽衣, 山本 浩平, 山本 知穂, 亀田 友香, 野本 博司, 曹 圭龍, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 92 2 481 - 481 (一社)日本内分泌学会 2016年10月
• オクトレオチドの効果をCGMで確認し得た高齢インスリノーマの1例

  大森 一乃, 老田 真佑子, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 山本 知穂, 亀田 友香, 野本 博司, ちょう 圭龍, 中村 昭伸, 永井 聡, 清水 力, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 92 2 489 - 489 (一社)日本内分泌学会 2016年10月
• 抗PD-1抗体ニボルマブ投与によりACTH単独欠損症を呈した一例

  高橋 由華, 曹 圭龍, 大森 一乃, 老田 真佑子, 高瀬 崇宏, 高橋 清彦, 北尾 直之, 山本 浩平, 亀田 友香, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 92 2 495 - 495 (一社)日本内分泌学会 2016年10月
• Role of apolipoprotein B100 and oxidized low-density lipoprotein in the monocyte tissue factor induction mediated by anti-β2 glycoprotein i antibodies

  K. Otomo, O. Amengual, Y. Fujieda, H. Nakagawa, M. Kato, K. Oku, T. Horita, S. Yasuda, M. Matsumoto, K. I. Nakayama, S. Hatakeyama, T. Koike, Tatsuya Atsumi

  Lupus 25 1288 - 1298 2016年10月01日 [査読無し][通常論文]
   

  © The Author(s), 2016. Objective The objective of this paper is to elucidate the not yet known plasma molecule candidates involved in the induction of tissue factor (TF) expression mediated by β2GPI-dependent anticardiolipin antibody (aCL/β2GPI) on monocytes. Methods Human serum incubated with FLAG-β2GPI was applied for affinity chromatography with anti- FLAG antibody. Immunopurified proteins were analyzed by a liquid chromatography coupled with mass spectrometry (LC-MS). TF mRNA induced by the identified molecules on monocytes was also analyzed. Results Apolipoprotein B100 (APOB) was the only identified serum molecule in the MS search. Oxidized LDL, containing APOB as well as ox-Lig1 (a known ligand of β2GPI), was revealed as a β2GPI-binding molecule in the immunoprecipitation assay. TF mRNA was markedly induced by oxidized LDL/β2GPI complexes with either WBCAL-1 (monoclonal aCL/β2GPI) or purified IgG from APS patients. The activities of lipoprotein-associated phospholipase A2, one of the component molecules of oxidized LDL, were significantly higher in serum from APS patients than in those from controls. Conclusion APOB (or oxidized LDL) was detected as a major β2GPI binding serum molecule by LC-MS search. Oxidized LDL/aCL/β2GPI complexes significantly induced TF expressions on monocytes. These data suggest that complexes of oxidized LDL and aCL/β2GPI may have a crucial role in the pathophysiology of APS.
• Complement and thrombosis in the antiphospholipid syndrome

  Kenji Oku, Hiroyuki Nakamura, Michihiro Kono, Kazumasa Ohmura, Masaru Kato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Olga Amengual, Tatsuya Atsumi

  AUTOIMMUNITY REVIEWS 15 10 1001 - 1004 2016年10月 [査読有り][通常論文]
   

  The involvement of complement activation in the pathophysiology of antiphospholipid syndrome (APS) was first reported in murine models of antiphospholipid antibody (aPL)-related pregnancy morbidities. We previously reported that complement activation is prevalent and may function as a source of procoagulant cell activation in the sera of APS patients. Recently, autoantibodies against C1q, a component of complement 1, were reported to be correlated with complement activation in systemic lupus erythematosus. These antibodies target neoepitopes of deformed C1q bound to various molecules (i.e., anionic phospholipids) and induce accelerated complement activation. We found that anti-C1q antibodies are more frequently detected in primary APS patients than in control patients and in refractory APS patients with repeated thrombotic events. The titer of anti-C1q antibodies was significantly higher in refractory APS patients than in APS patients without flare. The binding of C1q to anionic phospholipids may be associated with the surge in complement activation in patients with anti-C1q antibodies when triggered by 'second-hit' biological stressors such as infection. Such stressors will induce overexpression of anionic phospholipids, with subsequent increases in deformed C1q that is targeted by anti-C1q antibodies. (C) 2016 Published by Elsevier B.V.
• Significance of fully automated tests for the diagnosis of antiphospholipid syndrome

  Kenji Oku, Olga Amengual, Masaru Kato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Naoya Sakamoto, Masahiro Ieko, Gary L. Norman, Tatsuya Atsumi

  THROMBOSIS RESEARCH 146 1 - 6 2016年10月 [査読有り][通常論文]
   

  Antiphospholipid antibodies (aPLs) can vary both immunologically and funcLionally, thus i is important to effectively and correctly identify their presence when diagnosing antiphospholipid syndrome. Furthermore, since many immunologicallfunclional tests are necessary Lo measure aPLs, complete examinations are often no performed in many cases due o significath burden on the testing departments. To address this issue, we measured aPLs defined accordingio the classification criteria (anlicardiolipin araibody: aCL) IgG/IgM and anti-132 glycoprotein I antibody (a beta(2)GPI) (IgG/IgM) as well as non-criteria antibodies (aCL IgA, a beta(2)GPI IgA and a beta(2)GPI domain I), in a cohort 01 211 patients (61 APS, 140 disease controls and 10 healthy individuals). APLs were measured using a fully automated chemiluminescent immunoassay instrument (BIO-FLASH (R)/ACL AcuStara (R)) and with conventional ELISA tests. We demonstrated that both sensitivity and accuracy of diagnosis of aCL IgG and beta(2)GPI IgG were high, in agreement with the past reports. When multiple aPLs were examined, the accuracy of diagnosis increased. The proportion of APS patients that were positive for 2 Of more types of aPLs (47/61, 77%) was higher than that of patients with systemic lupus erythematosus (SLE)( 3/37, 9%), those with non-SLE connective tissues diseases (1/53,2%), those with other diseases or healthy volunteers. Based on these findings, it was concluded that the fully automated chemiluminescent immunoassay instrument, which allows the simultaneous evaluation of many types of aPLs, offers clear advantages for a more complete, more rapid and less labor-intensive alternative to running multiple ELISA and could help in better diagnosis for suspected APS patients. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (thip://creativecommons.orglicenscs,thy-nc-nd/4.0,/).
• AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts

  Masaru Kato, Caroline Ospelt, Christoph Kolling, Tomohiro Shimizu, Michihito Kono, Shinsuke Yasuda, Beat A. Michel, Renate E. Gay, Steffen Gay, Kerstin Klein, Tatsuya Atsumi

  ONCOTARGET 7 39 64221 - 64232 2016年09月 [査読有り][通常論文]
   

  Valosin containing protein (p97) is a chaperone implicated in a large number of biological processes including endoplasmic reticulum (ER)-associated protein degradation and autophagy. Silencing of p97 in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) increased the amount of polyubiquitinated proteins, whereas silencing of its interaction partner histone deacetylase 6 (HDAC6) had no effect. Furthermore, silencing of p97 in RASFs increased not only rates of apoptotic cell death induced by TRAIL but also induced an autophagy-associated cell death during ER stress that was accompanied by the formation of polyubiquitinated protein aggregates and large vacuoles. Finally, we demonstrated an anti-arthritic effect of siRNAs targeting p97 in collagen-induced arthritis in rats. Our data indicate that p97 may be a new potential target in the treatment of RA.
• ステロイド依存性ネフローゼ症候群に対してリツキシマブを投与した成人9症例の検討

  渡邉 加奈子, 西尾 妙織, 川島 圭介, 近藤 桂一, 八反田 文彦, 石川 洋三, 楠 由宏, 牧田 実, 石川 康暢, 渥美 達也

  日本腎臓学会誌 58 6 804 - 804 (一社)日本腎臓学会 2016年08月
• Rheumatology Q&A 画像が明かす診断と治療のポイント(第12回) 全身性エリテマトーデスに対する免疫抑制治療中に多発肺粒状影および下肢蜂窩織炎が出現した女性、原因は?

  河野 通大, 渥美 達也

  Rheumatology Clinical Research 5 2 140 - 143 (株)先端医学社 2016年08月 [査読有り][通常論文]
  
• Post-steroid neuropsychiatric manifestations are significantly more frequent in SLE compared with other systemic autoimmune diseases and predict better prognosis compared with de novo neuropsychiatric SLE

  Yuka Shimizu, Shinsuke Yasuda, Yuki Kako, Shin Nakagawa, Masatoshi Kanda, Ryo Hisada, Kazumasa Ohmura, Sanae Shimamura, Haruki Shida, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Ichiro Kusumi, Tatsuya Atsumi

  AUTOIMMUNITY REVIEWS 15 8 786 - 794 2016年08月 [査読有り][通常論文]
   

  In patients with systemic lupus erythematosus (SLE), neuropsychiatric (NP) symptoms sometimes occur after administration of corticosteroids, making differential diagnosis between NPSLE and steroid-induced psychosis challenging for clinicians. The aim of this study was to clarify the characteristics of post-steroid NP disease (PSNP) in patients with SLE. Clinical courses of 146 patients with SLE and 162 with other systemic autoimmune diseases, all in the absence of NP manifestations on admission, were retrospectively analyzed. Forty-three NPSLE patients on admission (de novo NPSLE) were also investigated. All patients were consecutively recruited and treated with 40 mg/day or more of prednisolone in Hokkaido University Hospital between April 2002 and March 2015. The prevalence of PSNP was strikingly higher in SLE patients than other systemic autoimmune diseases (24.7% vs. 7.4%, OR 4.09, 95% CI 2.04-8.22). As independent risk factors to develop PSNP in SLE patients, past history of mental disorder and the presence of antiphospholipid syndrome were identified using multiple logistic regression analysis. In patients with PSNP-SLE, mood disorder was significantly more frequent than in de novo NPSLE (47.2% vs. 20.9%, OR 3.38, 95% CI 126-9.04). Of PSNP-SLE patients, two-thirds were with one or more abnormal findings in cerebrospinal fluid, electroencephalogram, MRI or SPECT. Majority of our PSNP-SLE patients received intensified immunosuppressive treatments and experienced improvement in most cases. PSNP-SLE had better relapse-free survival than de novo NPSLE (p < 0.05, log rank test). In conclusion, PSNP frequently occurred in patients with SLE and treated successfully with immunosuppressive therapy, indicating that NPSLE is likely to harbor patients with PSNP-SLE. (C) 2016 Elsevier B.V. All rights reserved.
• Autoantibodies against a complement component 1 q subcomponent contribute to complement activation and recurrent thrombosis/pregnancy morbidity in anti-phospholipid syndrome

  Kenji Oku, Olga Amengual, Ryo Hisada, Kazumasa Ohmura, Ikuma Nakagawa, Toshiyuki Watanabe, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi

  RHEUMATOLOGY 55 8 1403 - 1411 2016年08月 [査読有り][通常論文]
   

  Objective. To investigate the prevalence and significance of the autoantibodies against complement component 1 q subcomponent (C1q) in patients with APS. Methods. In all, 40 consecutive primary APS patients, 42 patients with non-SLE CTDs and 20 SLE patients negative for aPL were enrolled in this retrospective analysis. Refractory APS was defined as a clinical status of recurring thrombosis or pregnancy morbidity during adequate secondary prophylaxis. An ELISA was used to measure serum levels of anti-C1q antibodies and anaphylatoxins (C3a, C4a). Results. Anti-C1q antibodies were found in 36% (15/42) and 2.5% (1/40) of primary APS patients and controls, respectively. Among primary APS patients, anti-C1q antibody titres were significantly correlated with serum C4a levels (P = 0.013). Neither the prevalence nor the titre of anti-C1q antibodies was associated with any specific clinical manifestations of APS, nor titres of aPL. Refractory APS patients (n = 10) had a higher prevalence of anti-C1q antibodies (9/10 vs 6/32, P = 0.01) than APS patients without recurrence (n = 32). Conclusion. Anti-C1q antibodies are associated with complement activation in APS and may contribute to the pathogenesis, particularly in refractory cases.
• Comparative effects of vildagliptin and sitagliptin determined by continuous glucose monitoring in patients with type 2 diabetes mellitus

  Naohide Koyanagawa, Hideaki Miyoshi, Kota Ono, Akinobu Nakamura, Kyu Yong Cho, Kohei Yamamoto, Yoshinari Takano, Midori Dan-noura, Tatsuya Atsumi

  ENDOCRINE JOURNAL 63 8 747 - 753 2016年08月 [査読有り][通常論文]
   

  The dipeptidyl peptidase-4 inhibitors vildagliptin and sitagliptin are effective in treating patients with type 2 diabetes mellitus. Patients receiving standard doses of sitagliptin plus insulin may require increased doses of sitagliptin or switching to vildagliptin to improve blood glucose control. This study compared the effects of increasing sitagliptin and switching to vildagliptin in type 2 diabetes patients receiving standard doses of sitagliptin plus insulin. This prospective, randomized, parallel-group comparison trial enrolled 33 type 2 diabetes patients receiving 50 mg sitagliptin once daily plus insulin. Seventeen patientg were randomized to 50 mg vildagliptin twice daily, and 16 to 100 mg sitagliptin once daily, and evaluated by continuous glucose monitoring at baseline and after 8 weeks. The primary end-point was the change in mean amplitude of glycemic excursions (MAGE). MAGE decreased from baseline in both the vildagliptin (-13.4 +/- 35.7 mg/dL) and sitagliptin (-8.4 +/- 24.3 mg/dL) groups, but neither within-nor between-group changes were statistically significant. Similarly, the areas under the curve for blood glucose levels >= 180 mg/dL and <70 mg/dL tended to improve in both groups, but these differences were not statistically significant. In contrast, HbAlc was significantly reduced only in the vildagliptin group, from 7.1 +/- 0.6% at baseline to 6.8 +/- 0.6% at 8 weeks (p=0.006). Increasing sitagliptin dose and switching to vildagliptin had limited effects in improving MAGE in type 2 diabetic patients treated with standard doses of sitagliptin.
• 短期的な血糖コントロールによる神経機能の改善効果：簡易神経伝導測定機器（DPNチェックHDN-1000）を用いた検討

  高瀬 崇宏, 三好 秀明, 亀田 玲奈, 枝川 幸子, 老田 真佑子, 大森 一乃, 近藤 亜樹, 菅原 基, 宮 愛香, 山本 知穂, 亀田 友香, 中村 昭伸, 渥美 達也

  Diabetes Frontier Online 3 e1 004 - 004 2016年06月21日 [査読有り]
  
• Ribophorin II is involved in the tissue factor expression mediated by phosphatidylserine-dependent antiprothrombin antibody on monocytes

  Yuichiro Fujieda, Olga Amengual, Masaki Matsumoto, Kimiko Kuroki, Hidehisa Takahashi, Michihito Kono, Takashi Kurita, Kotaro Otomo, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Katsumi Maenaka, Shigetsugu Hatakeyama, Keiichi I. Nakayama, Tatsuya Atsumi

  RHEUMATOLOGY 55 6 1117 - 1126 2016年06月 [査読有り][通常論文]
   

  Objective. Phosphatidylserine-dependent, also called aPS-PT, recognizes the phosphati dylserine-prothrombin complex, which is associated with APS. We have previously reported that aPS-PT induces tissue factor (TF) expression on monocytes through the p38 mitogen-activated protein kinase pathway. However, the cell surface interaction between prothrombin and aPS-PT, which is involved in the activation of cell-signalling pathways, has remained unknown. The objective of this study was to identify membrane proteins involved in the binding of prothrombin and aPS-PT to monocyte surfaces as well as the induction of TF expression. Methods. RAW264.7 cells with FLAG-tagged prothrombin were incubated and separated using affinity chromatography with anti-FLAG antibody-conjugated Sepharose beads. Immunopurified proteins were then analysed by an online nano-liquid chromatography-tandem mass spectrometry. The binding between prothrombin and the identified protein, ribophorin II (RPN2), was analysed by ELISA and surface plasmon resonance. To elucidate the role of RPN2 in TF expression, the TF mRNA level in RAW264.7 cells treated with RPN2 small interfering RNA was determined by quantitative real-time PCR (qPCR). Results. RPN2 was identified as a candidate molecule involved in the binding of prothrombin to the cell surface. The binding between prothrombin and RPN2 was confirmed by ELISA and surface plasmon resonance. RAW264.7 cells treated with RPN2 small interfering RNA showed significant reduction of the TF expression mediated by prothrombin and a mouse monoclonal aPS-PT. Conclusion. We identified that RPN2 is one of the prothrombin-binding proteins on monocyte surfaces, suggesting that RPN2 is involved in the pathophysiology of thrombosis in patients with APS.
• Ipragliflozin effectively reduced visceral fat in Japanese patients with type 2 diabetes under adequate diet therapy

  Chiho Yamamoto, Hideaki Miyoshi, Kota Ono, Hajime Sugawara, Reina Kameda, Mei Ichiyama, Kohei Yamamoto, Hiroshi Nomoto, Akinobu Nakamura, Tatsuya Atsumi

  ENDOCRINE JOURNAL 63 6 589 - 596 2016年06月 [査読有り][通常論文]
   

  To investigate if ipraglifiozin, a novel sodium-glucose co-transporter 2 inhibitor, alters body composition and to identify variables associated with reductions in visceral adipose tissue in Japanese patients with type 2 diabetes mellitus. This prospective observational study enrolled Japanese participants with type 2 diabetes mellitus. Subjects were administered ipraglifiozin (50 mg/day) once daily for 16 weeks. Body composition, visceral adipose tissue volume and plasma variables were measured at 0, 8, and 16-weeks. The subjects' lifestyle habits including diet and exercise were evaluated at baseline and 16 weeks. The primary endpoint was defined as the decrease of visceral adipose tissue mass. Twenty-four of 26 enrolled participants completed the study. The visceral adipose tissue decreased significantly (110 +/- 33 to 101 +/- 36 cm(2), p = 0.005) as well as other parameters for metabolic insufficiency including hemoglobin A1c. Seventy-one % of the total body weight reduction (-2.49 kg) was estimated by a decrease in fat mass (-1.77 kg), and the remaining reduction (22%) by water volume (-0.55 kg). A minor but significant reduction in the skeletal muscle index was also observed. Correlation analyses were performed to identify variables associated with changes in visceral adipose tissue and the only significant variable identified was diet therapy (Spearman's r = -0.416, p = 0.043). Ipragliflozin significantly decreased visceral adipose tissue, and improved parametres for metabolic dysfunction. Adequate diet therapy would be necessary to induce and enhance the therapeutic merit.
• Treatment Patterns, Direct Cost of Biologics, and Direct Medical Costs for Rheumatoid Arthritis Patients: A Real-world Analysis of Nationwide Japanese Claims Data

  Naonobu Sugiyama, Yutaka Kawahito, Takao Fujii, Tatsuya Atsumi, Tatsunori Murata, Yosuke Morishima, Yuri Fukuma

  CLINICAL THERAPEUTICS 38 6 1359 - 1375 2016年06月 [査読有り][通常論文]
   

  Purpose: The aims of this article were to characterize the patterns of treating rheumatoid arthritis with biologics and to evaluate costs using claims data from the Japan Medical Data Center Co, Ltd. Methods: Patients aged 16 to <75 years who were diagnosed with rheumatoid arthritis and prescribed adalimumab (ADA), etanercept (ETN), infliximab (IFX), tocilizumab (TCZ), abatacept, certolizumab, or golimumab between January 2005 and August 2014 were included. For the cross-sectional analysis, the annual costs of ETN, IFX, ADA, and TCZ from 2009 to 2013 were assessed. For the longitudinal analysis, patients prescribed these biologics as the first line of biologics, from January 2005 to August 2014, were included. The cost of biologic treatment over 1, 2, and 3 years (including prescription of subsequent biologics) and direct medical costs (including treatment of comorbidities) were compared between groups. Discontinuation and switching rates in each group were estimated, and multivariate analyses were conducted to estimate an adjusted hazard ratio of discontinuation and switching rates among each group. The dose of each first-line biologic treatment until discontinuation was analyzed to calculate relative dose intensity. Findings: The cross-sectional annual biologic costs of ETN, IFX, ADA, and TCZ were similar to$8000 (2009 and 2013), $13,000 (2009) and $15,000 (2013), $10,000 (2009) and $11,000 (2013), and $9000 (2009) and $8000 (2013), respectively. In longitudinal analyses (n = 764), 276 (36%) initiated ETN; 242 (32%), IFX; 147 (19%), ADA; and 99 (13%), TCZ. The 1-year cumulative annual biologic costs per patient from the initial prescription of ETN, IFX, ADA, and TCZ as the first-line biologic treatment were similar to$11,000, $19,000, $16,000, and $12,000. The corresponding direct medical costs over 1 year from the initial prescription were similar to$17,000, $26,000, $22,000, and $22,000. Costs remained greatest in the IFX-initiation group at year 3. The discontinuation rates at 36 months with ETN, IFX, ADA, and TCZ were 37.7%, 52.3%, 55.8%, and 39.5%; the switching rates were 12.5%, 27.1%, 31.0%, and 16.7%. The mean (95% CI) relative dose intensities until discontinuation of ETN 25 mg, ETN 50 mg, IFX, ADA, and TCZ were 1.02 (0.95-1.10), 0.82 (0.79-0.85), 1.16 (1.12-1.20), 0.95 (0.90-0.99), and 0.96 (0.93-1.00). Implications: Considered costs and discontinuation and switching event rates were lowest with ETN versus IFX, ADA, or TCZ used as the first-line biologic. Despite limitations, these findings imply clinical cost-reductive benefits of ETN as the first line biologic treatment option for rheumatoid arthritis in Japan. (C) 2016 Elsevier HS Journals, Inc. All rights reserved.
• Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cells.

  Kanda M, Yamanaka H, Kojo S, Usui Y, Honda H, Sotomaru Y, Harada M, Taniguchi M, Suzuki N, Atsumi T, Wada H, Baghdadi M, Seino K

  Proceedings of the National Academy of Sciences of the United States of America 113 24 E3394 - E3402 2016年06月 [査読有り][通常論文]
   

  Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-gamma upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-gamma production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-gamma production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-gamma production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-gamma production in iNKT cells.
• Peptidylarginine Deiminase Inhibitor Suppresses Neutrophil Extracellular Trap Formation and MPO-ANCA Production

  Yoshihiro Kusunoki, Daigo Nakazawa, Haruki Shida, Fumihiko Hattanda, Arina Miyoshi, Sakiko Masuda, Saori Nishio, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  FRONTIERS IN IMMUNOLOGY 7 1 - 7 2016年06月 [査読有り][通常論文]
   

  Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis is a systemic small-vessel vasculitis, wherein. MPO-ANCA plays a critical role in the pathogenesis. Neutrophil extracellular traps (NETs) released from activated neutrophils are composed of extracellular web-like DNA and antimicrobial proteins, including MPO. Diverse stimuli, such as phorbol myristate acetate (PMA) and ligands of toll-like receptors (TLR), induce NETs. Although TLR-mediated NET formation can occur with preservation of living neutrophilic functions (called vital NETosis). PMA-stimulated neutrophils undergo cell death with NET formation (called suicidal NETosis). In the process of suicidal NETosis, histones are citrullinated by peptidylarginine deiminase 4 (PAD4). Since this step is necessary for decondensation of DNA. PAD4 plays a pivotal role in suicidal NETosis. Although NETs are essential for elimination of microorganisms, excessive formation of NETs has been suggested to be implicated in MPO-ANCA production. This study aimed to determine if pan-PAD inhibitors could suppress MPO-ANCA production in vivo. At first, NETs were induced in peripheral blood neutrophils derived from healthy donors (1 x 10(6)/ml) by stimulation with 20 nM PMA with or without 20 mu M propylthiouracil (PTU), an anti-thyroid drug. We then determined that the in vitro NET formation was inhibited completely by 200 mu M Cl-amidine, a pan PAD inhibitor. Next, we established mouse models with MPO-ANCA production. BALB/c mice were given intraperitoneal (i.p.) injection of PMA (50 ng at days 0 and 7) and oral PTU (2.5 mg/day) for 2 weeks. These mice were divided into two groups; the first group was given daily i.p. injection of PBS (200 mu l/day) = 13) and the other group with daily i.p. injection of Cl-amidine (0.3 mg/200 mu l PBS/day) (n = 7). Two weeks later, citrullination as an indicator of NET formation in the peritoneum and serum MPO-ANCA titer was compared between the two groups. Results demonstrated that citrullination in the peritoneum was significantly reduced in the Cl-amidine-treated mice compared with the vehicle-injected control mice (38% reduction). Additionally, the serum MPO-ANCA titer of the Cl-amidine-treated mice (32.3 +/- 31.0 ng/ml) was significantly lower than that in the vehicle-injected mice (132.1 +/- 41.6 ng/ml). The collective findings indicate that excessive formation of NETs may be implicated in MPO-ANCA production in vivo.
• Reactivation of occult hepatitis B virus infection in patients with rheumatic diseases: pathogenesis, risk assessment and prevention

  Masaru Kato, Tatsuya Atsumi

  RHEUMATOLOGY INTERNATIONAL 36 5 635 - 641 2016年05月 [査読有り][通常論文]
   

  Over the past decade, reactivation of occult hepatitis B virus (HBV) infection has garnered much attention from rheumatologists owing to a number of reports which have indicated the potential risk of biologics in causing this previously ignored infectious complication. Hepatitis due to reactivation of occult HBV infection occurs only occasionally but with high mortality upon occurrence, placing us in a clinical dilemma "to address or not to address?" In this review, we discuss how biological and other immunosuppressive therapies increase the risk of developing reactivation of occult HBV infection and attempt to solve this clinical quandary.
• 耐糖能異常症例における腎移植後の糖代謝改善

  中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 田栗 正隆, 寺内 康夫, 篠原 信雄, 渥美 達也

  日本内分泌学会雑誌 92 1 213 - 213 (一社)日本内分泌学会 2016年04月
• 日本人腎移植症例における移植2年後の耐糖能の推移

  大森 一乃, 中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 篠原 信雄, 渥美 達也

  糖尿病 59 Suppl.1 S - 295 (一社)日本糖尿病学会 2016年04月
• シタグリプチンとグリメピリドの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study 1

  野本 博司, 三好 秀明, 古本 智夫, 井上 篤, 曹 圭龍, 中村 昭伸, 渥美 達也, 萬田 直紀, 栗原 義夫, 青木 伸

  糖尿病 59 Suppl.1 S - 290 (一社)日本糖尿病学会 2016年04月
• 【今、知っておきたい「リウマチ」のすべて】(Part3)薬物治療の新しい話題 薬物治療 バイオ製剤の新しい知見<バイオオリジナル製剤>TNF阻害剤 Fc領域を持たないTNF阻害剤セルトリズマブ

  大村 一将, 渥美 達也

  Bone Joint Nerve 6 2 371 - 377 (株)アークメディア 2016年04月 [査読有り][通常論文]
  
• 血管炎 抗ラクトフェリン抗体は好酸球性多発血管炎性肉芽腫症において好中球細胞外トラップの形成を促進し、疾患活動性に関与する

  志田 玄貴, 中沢 大悟, 八反田 文彦, 楠 由宏, 益田 紗季子, 外丸 詩野, 川上 民裕, 渥美 達也, 石津 明洋

  日本リウマチ学会総会・学術集会プログラム・抄録集 60回 479 - 479 (一社)日本リウマチ学会 2016年03月
• リウマチ性疾患患者の挙児希望と妊娠 難治性抗リン脂質抗体症候群合併妊娠の臨床像と、それらに対する大量免疫グロブリン療法の有効性についての検討

  金子 佳代子, 橋本 就子, 後藤 美賀子, 奥 健志, 渥美 達也, 村島 温子

  日本リウマチ学会総会・学術集会プログラム・抄録集 60回 399 - 399 (一社)日本リウマチ学会 2016年03月
• The Fifth Domain of Beta 2 Glycoprotein I Protects from Natural IgM Mediated Cardiac Ischaemia Reperfusion Injury

  Peng Zhang, James C. Weaver, Gang Chen, Julia Beretov, Tatsuya Atsumi, Miao Qi, Ravinay Bhindi, Jian C. Qi, Michele C. Madigan, Bill Giannakopoulos, Steven A. Krilis

  PLOS ONE 11 3 e0152681  2016年03月 [査読有り][通常論文]
   

  Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (beta 2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of beta 2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of beta 2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1(-/-) and beta 2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous beta 2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and beta 2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1-/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance. Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.
• 腎移植後に耐糖能異常は改善される

  中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 寺内 康夫, 篠原 信雄, 渥美 達也

  日本内科学会雑誌 105 Suppl. 253 - 253 (一社)日本内科学会 2016年02月
• 【自己抗原の構造と修飾】抗リン脂質抗体症候群の対応抗原の構造と機能

  河野 通大, 加藤 将, 渥美 達也

  炎症と免疫 24 2 89 - 94 (株)先端医学社 2016年02月 [査読有り][通常論文]
   

  抗リン脂質抗体症候群(APS)は抗リン脂質抗体(aPL)が持続的に検出され、血栓症や妊娠合併症を呈する自己免疫疾患である。aPLのおもな対応抗原はβ2-グリコプロテインI(β2GP I)とプロトロンビンであり、その生理機能は多彩である。APSの病態形成において、対応抗原存在下に、aPLによる向血栓細胞のp38 mitogen-activated protein kinaseのリン酸化を介した組織因子の誘導が重要であり、また向血栓細胞活性化の経路において、細胞表面受容体であるCD36や、酸化low density lipoprotein(LDL)とβ2GP Iとの複合体の存在が重要であることが明らかとなった。さらに近年、APSにおけるhuman leukocyte antigen(HLA)class IIとβ2GP Iとの関連が新たに報告され、今後抗リン脂質抗体症候群の更なる病態の解明と、より病態機序に則した治療薬の開発が望まれる。(著者抄録)
• The responses of macrophages in interaction with neutrophils that undergo NETosis

  Daigo Nakazawa, Haruki Shida, Yoshihiro Kusunoki, Arina Miyoshi, Saori Nishio, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  JOURNAL OF AUTOIMMUNITY 67 19 - 28 2016年02月 [査読有り][通常論文]
   

  Neutrophil extracellular traps (NETs) are net-like chromatin fibers decorated with antimicrobial proteins, which are released from dying neutrophils. The death of neutrophils with NET formation is called NETosis. Although NETs play important roles in the innate immunity, especially in the elimination of microbes, the extracellular release of DNA and intra-cytoplasmic/nuclear proteins can, on the other hand, result in diverse adversities to the hosts. Therefore, NETosis is adequately regulated in vivo. Currently, two mechanisms, namely DNase I-dependent digestion and phagocytosis by macrophages, have been shown as such regulatory mechanisms. In this study, we focused on the interaction of macrophages and neutrophils that underwent NETosis. Results demonstrated that macrophages displayed a phenotype dependent response after degradation of NETs. Several hours after the interaction, M2 macrophages induced a pro-inflammatory response, while M1 macrophages underwent cell death with nuclear decondensation. This nuclear decondensation of M1 macrophages occurred in a peptidylarginine deiminase 4-dependent manner and resulted in a local release of extracellular DNA. Thereafter, M1 macrophages degraded DNA derived from themselves in a caspase-activated DNase-dependent manner resulting in the clearance of extracellular DNA within 24 h. This transient increase and subsequent clearance mechanism of extracellular DNA seems very reasonable in terms of the double-edged sword-like property of NETs. The collective findings demonstrate a novel phenotype- and time-dependent regulation of NETosis by macrophages. (C) 2015 The Authors. Published by Elsevier Ltd.
• Usefulness of the octreotide test in Japanese patients for predicting the presence/absence of somatostatin receptor 2 expression in insulinomas

  Akinobu Nakamura, Tomoko Mitsuhashi, Yoshinari Takano, Hideaki Miyoshi, Hiraku Kameda, Hiroshi Nomoto, So Nagai, Yutaka Hatanaka, Chikara Shimizu, Yasuo Terauchi, Tatsuya Atsumi

  ENDOCRINE JOURNAL 63 2 135 - 142 2016年02月 [査読有り][通常論文]
   

  We investigated the relationship between the results of the octreotide test and somatostatin receptor (SSTR) 2 expression in insulinoma patients, to evaluate the usefulness of this test for predicting SSTR2 expression in insulinomas in Japanese patients. Five females and one male were included in the study. All patients underwent the octreotide test before the surgery carried out to resect the tumor, and histopathological examination of the resected tumor was performed by a single experienced pathologist. SSTR2 expression was evaluated by the SSTR2 immunohistochemistry scoring system. Insulinoma was clinically diagnosed and surgically resected in all six patients. In the octreotide test, suppression of insulin secretion was sufficient after loading in patients 1-4 and 6. In patient 5, however, the suppression of insulin secretion was insufficient, which resulted in severe hypoglycemia with endogenous relative hyperinsulinemia after the octreotide loading. The histopathological findings revealed SSTR2 expression in the insulinomas of patients 1-4 and 6, but not in the insulinoma of patient 5. In conclusion, improvement of hyperinsulinemic hypoglycemia by octreotide in Japanese insulinoma patients was associated with SSTR2 expression in the tumor. Our results suggest that the octreotide test could be useful for predicting SSTR2 expression in the tumor.
• A&R

  渥美 達也

  臨床リウマチ 28 4 241 - 242 一般社団法人 日本臨床リウマチ学会 2016年
• P1-15 IgG phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome

  Olga Amengual, 奥 健志, 杉浦 真弓, 村島 温子, 渥美 達也

  日本臨床免疫学会会誌 39 4 382a - 382a 日本臨床免疫学会 2016年 

    Phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) are strongly correlated with lupus anticoagulant. We evaluated the value of IgG aPS/PT for diagnosing antiphospholipid syndrome (APS). Methods: We performed an initial cross-sectional multi-centre study involving 8 centres/7 countries. Clinical and laboratory data were retrospectively collected. Specimens were blinded,and IgG aPS/PT determinations performed at Inova Diagnostics (USA, Inova) using 2 ELISA kits: MBL (Japan) and Inova. A validation study was carried out (5 centres/5 countries). Results: In the initial study (n = 247), IgG aPS/PT titers were concordant between the two ELISA tests (r = 0.827, p < 0.001). In samples with concordant results (n = 204), IgG aPS/PT were more prevalent in APS patients (51%) than in patients without APS (9%) (OR: 10.8 [95%CI 4-29], p < 0.0001). In the validation study (n = 214), there was as well a good concordance between IgG aPS/PT titers obtained by both ELISAs (r = 0.803, p < 0.001) , and IgG aPS/PT were more frequently found in APS patients. Conclusions: Performance of IgG aPS/PT is reliable. IgG aPS/PT detection is an easily performed laboratory parameter that may help in APS diagnosis.

• 6学会合同シンポジウム4 β2-グリコプロテインI/HLA class II複合体は抗リン脂質抗体症候群の標的抗原である

  谷村 憲司, 出口 雅士, 蝦名 康彦, 渥美 達也, 山田 秀人, 荒瀬 尚

  日本臨床免疫学会会誌 39 4 306 - 306 日本臨床免疫学会 2016年 

    β2-glycoprotein I（β2GPI）は抗リン脂質抗体（aPL）の主要抗原であり，また，抗リン脂質抗体症候群（APS）の疾患感受性にHLA class II（HLA-II）遺伝子多型が関与する．しかし，HLA-II分子が疾患感受性を制御する機序については不明である．

    最近，MHC-IIがペプチドへの分解を免れたmisfolded蛋白を提示し，B細胞を直接活性化する機構が報告された．今回，この新規抗原提示機構とAPSの病因・病態との関連を解析した．

    初めに，β2GPIとHLA-IIを共発現させた293T細胞を用いた免疫沈降により，full-lengthのβ2GPIとHLA-IIが複合体を形成していることを確認した．さらに，ヒトaPLモノクローナル抗体とAPS患者血清中の自己抗体がβ2GPIとAPS疾患感受性アレルであるHLA-II（HLA-DR7, DR4）の複合体に対して高い結合親和性を有することが分かった．また，流産組織を用いた蛍光免疫染色により，APS患者の脱落膜血管内皮細胞にβ2GPIとHLA-DRが共発現していることを明らかにした．APS患者120名の血清中のβ2GPI/HLA-DR7複合体に対する自己抗体の抗体価をFlow cytometry法で測定したところ，APS患者の約80％で陽性で，さらに，抗カルジオリピン抗体や抗β2GPI抗体が陰性であるAPS患者の約半数で本自己抗体が陽性となった．また，ヒトaPLモノクローナル抗体はβ2GPI/HLA-DR7発現細胞に特異的に補体依存性細胞障害を誘導した．

    APS患者血清中に，misfolded β2GPI/HLA-II複合体に対する自己抗体が存在することを初めて明らかにした．この自己抗体によって血管内皮細胞が障害され，血栓症や流産を惹起さるというAPSの新しい病態が示された．

• Laboratory Markers With Clinical Significance in the Antiphospholipid Syndrome

  Olga Amengual, Maria L. Bertolaccini, Tatsuya Atsumi

  Handbook of Systemic Autoimmune Diseases 12 47 - 69 2016年 [査読有り][通常論文]
   

  Antiphospholipid syndrome (APS) is a clinical condition characterized by recurrent thrombosis and obstetric-related adverse events associated with the persistent presence of antiphospholipid antibodies (aPL). The aPL family is a heterogeneous group of autoantibodies with different antigenic specificities. The dominant antigenic targets for aPL in APS are phospholipid-binding plasma proteins such as β2glycoprotein I (β2GPI) and prothrombin. In the laboratory, aPLs can be detected by a diverse range of tests. There is not a unique or gold-standard test for the diagnosis of APS. The aPL tests can be broadly categorized into two groups: solid-phase assays such as anticardiolipin antibodies, anti-β2GPI antibodies, antiprothrombin antibodies, or phosphatidylserine-dependent antiprothrombin antibodies, and functional assays characterized by their ability to prolong phospholipid-dependent coagulation tests, known as lupus anticoagulant. In this chapter, we detail the currently available laboratory assays for aPL detection, and discuss the value of each aPL as laboratory marker for APS.
• The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression

  Tatsuya Atsumi, Kazuhiko Yamamoto, Tsutomu Takeuchi, Hisashi Yamanaka, Naoki Ishiguro, Yoshiya Tanaka, Katsumi Eguchi, Akira Watanabe, Hideki Origasa, Shinsuke Yasuda, Yuji Yamanishi, Yasuhiko Kita, Tsukasa Matsubara, Masahiro Iwamoto, Toshiharu Shoji, Toshiyuki Okada, Desiree van der Heijde, Nobuyuki Miyasaka, Takao Koike

  ANNALS OF THE RHEUMATIC DISEASES 75 1 75 - 83 2016年01月 [査読有り][通常論文]
   

  Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol (CZP) and methotrexate (MTX) as first-line treatment for MTX-naive, early rheumatoid arthritis (RA) with poor prognostic factors, compared with MTX alone. Methods MTX-naive, early RA patients with <= 12 months persistent disease, high anti-cyclic citrullinated peptide, and either rheumatoid factor positive and/or presence of bone erosions were enrolled in this multicentre, double-blind, randomised placebo (PBO)-controlled study. Patients were randomised 1: 1 to CZP+MTX or PBO+MTX for 52 weeks. Primary endpoint was inhibition of radiographic progression (change from baseline in modified Total Sharp Score (mTSS CFB)) at week 52. Secondary endpoints were mTSS CFB at week 24, and clinical remission rates at weeks 24 and 52. Results 316 patients randomised to CZP+MTX (n=159) or PBO+MTX (n=157) had comparable baseline characteristics reflecting features of early RA (mean disease duration: 4.0 vs 4.3 months; Disease Activity Score 28-joint assessment (DAS28)) (erythrocyte sedimentation rate (ESR)): 5.4 vs 5.5; mTSS: 5.2 vs 6.0). CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 (mTSS CFB=0.36 vs 1.58; p<0.001) and week 24 (mTSS CFB=0.26 vs 0.86; p=0.003). Clinical remission rates (Simple Disease Activity Index, Boolean and DAS28 (ESR)) of the CZP+MTX group were significantly higher compared with those of the PBO +MTX group, at weeks 24 and 52. Safety results in both groups were similar, with no new safety signals observed with addition of CZP to MTX. Conclusions In MTX-naive early RA patients with poor prognostic factors, CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms, demonstrating the efficacy of CZP in these patients.
• Degludec is superior to glargine in terms of daily glycemic variability in people with type 1 diabetes mellitus

  Chiho Yamamoto, Hideaki Miyoshi, Yutaka Fujiwara, Reina Kameda, Mei Ichiyama, Hiroshi Nomoto, Hiraku Kameda, Akinobu Nakamura, Tatsuya Atsumi

  ENDOCRINE JOURNAL 63 1 53 - 60 2016年01月 [査読有り][通常論文]
   

  To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes.
• Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study

  Ken-ei Sada, Masayoshi Harigai, Koichi Amano, Tatsuya Atsumi, Shouichi Fujimoto, Yukio Yuzawa, Yoshinari Takasaki, Shogo Banno, Takahiko Sugihara, Masaki Kobayashi, Joichi Usui, Kunihiro Yamagata, Sakae Homma, Hiroaki Dobashi, Naotake Tsuboi, Akihiro Ishizu, Hitoshi Sugiyama, Yasunori Okada, Yoshihiro Arimura, Seiichi Matsuo, Hirofumi Makino

  MODERN RHEUMATOLOGY 26 5 730 - 737 2016年 [査読有り][通常論文]
   

  Objective: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. Results: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had <= 1, 2, and >= 3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. Conclusions: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.
• Accurate quantitative assessment of synovitis in rheumatoid arthritis using pixel-by-pixel, time-intensity curve shape analysis

  Taro Sakashita, Tamotsu Kamishima, Yuto Kobayashi, Hiroyuki Sugimori, Minghui Tang, Kenneth Sutherland, Atsushi Noguchi, Michihito Kono, Tatsuya Atsumi

  BRITISH JOURNAL OF RADIOLOGY 89 1061 20151000  2016年 [査読有り][通常論文]
   

  Objective: To improve on the reproducibility and sensitivity of the assessment of patients with rheumatoid arthritis (RA), two semi-automated measurement methods of the area of enhancing pannus (AEP), based on thresholding (AEP_THRES) and pixel-by-pixel time-intensity curve analysis (AEP_TIC), were evaluated as an alternative for the gold-standard manual contouring method (AEP_MANUAL). Methods: 8 patients (7 females and 1 male) with RA of the wrist or finger joints participated in the study. A three-dimensional contrast-enhanced dynamic sequence was used at 3 T. After identifying the most relevant time-intensity curve (TIC) shape in terms of synovitis by comparing with the synovitis score using the RA-MRI scoring system, three different approaches for measuring the AEP were performed. Spearman's test of rank correlation was used to compare AEPs via two semi-automated methods (AEP_THRES and AEP_TIC) against manual segmentation (AEP_MANUAL) in the entire hand region as well as the wrist and the finger regions. Results: The TIC shape of "washout after fast initial enhancement" had excellent correlation with synovitis score (r = 0.809). The correlation coefficient between AEP_TIC and AEP_MANUAL was evaluated to be better than that of AEP_THRES and AEP_MANUAL in the wrist region (AEP_THRES: r = 0.716, AEP_TIC: r = 0.815), whereas these were of comparable accuracy for the entire hand and the finger regions. Conclusion: This study suggests that TIC analysis may be an alternative to manual contouring for pannus quantification and provides important clinical information of the extent of the disease in patients with RA. Advances in knowledge: TIC shape analysis can be applied for new quantitative assessment for RA synovitis in the wrist.
• Prognosis and progress in immunotherapies for organ involvements in systemic autoimmune diseases

  Shinsuke Yasuda, Michihito Kono, Sanae Shimamura, Takashi Kurita, Toshio Odani, Tatsuya Atsumi

  Japanese Journal of Clinical Immunology 39 1 8 - 17 2016年 [査読有り][通常論文]
   

  Treatment of organ involvements accompanied by systemic autoimmune diseases is still challenging for clinicians, reminding the existence of unmet needs. Among them, lupus nephritis (LN), neuropsychiatric lupus, interstitial lung diseases (ILD) complicated with polymyositis/dermatomyositis (PM/DM) or systemic sclerosis (SSc) are the most severe conditions with poor prognosis. Because of the rarity and severity of the disease status, and of variety in evaluation methods, randomized clinical trials tend to be difficult in recruiting patients, in designing protocols, and in meeting primary endpoints. In such tough conditions, superiority of IVCY over corticosteroids alone for LN has been established, which is now going to be replaced by mycophenolate mofetil (MMF). Moreover, non-inferiority of tacrolimus to MMF is reported and efficacy of biologics such as Rituximab and Abatacept for LN is under investigation. In contrast, PM/DM-ILD is not suitable for randomized controlled trial because of the severity/acute progression in some patients. Intensive immunosuppressive regimen is recommended for those with poor prognostic factor(s). Cyclophosphamide has limited efficacy in SSc-ILD. Hematopoietic stem cell transplantation elongated patient survival and improved ILD, but with high treatment-related mortality rate. Efficacy of rituximab and MMF has been reported in small-sized trials. In this review, previously established treatment as well as emerging immunotherapies for organ involvements will be discussed. Our experiences in autoimmune settings also will be introduced.
• Circulating Neutrophil Extracellular Trap Levels in Well-Controlled Type 2 Diabetes and Pathway Involved in Their Formation Induced by High-Dose Glucose

  Arina Miyoshi, Mai Yamada, Haruki Shida, Daigo Nakazawa, Yoshihiro Kusunoki, Akinobu Nakamura, Hideaki Miyoshi, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu

  PATHOBIOLOGY 83 5 243 - 251 2016年 [査読有り][通常論文]
   

  Objectives: Although intensive therapy for type 2 diabetes (T2D) prevents microvascular complications, 10% of well-controlled T2D patients develop microangiopathy. Therefore, the identification of risk markers for microvascular complications in well-controlled T2D patients is important. Recent studies have demonstrated that high-dose glucose induces neutrophil extracellular trap (NET) formation, which can be a risk for microvascular disorders. Thus, we attempted to determine the correlation of circulating NET levels with clinical/laboratory parameters in well-controlled T2D patients and to reveal the mechanism of NET formation induced by high-dose glucose. Methods: Circulating NET levels represented by myeloperoxidase (MPO)-DNA complexes in the serum of 11 well-controlled T2D patients and 13 healthy volunteers were determined by enzyme-linked immunosorbent assay. The pathway involved in the NET formation induced by high-dose glucose was determined using specific inhibitors. Results: Serum MPO-DNA complex levels were significantly higher in some well-controlled T2D patients in correlation with the clinical/laboratory parameters which have been regarded as risk markers for microvascular complications. The aldose reductase inhibitor, ranirestat, could inhibit the NET formation induced by high-dose glucose. Conclusions: Elevated levels of circulating NETs can be a risk marker for microvascular complications in well-controlled T2D patients. The polyol pathway is involved in the NET formation induced by high-dose glucose. (C) 2016 The Author(s) Published by S. Karger AG, Basel
• A Randomized Controlled Trial Comparing the Effects of Sitagliptin and Glimepiride on Endothelial Function and Metabolic Parameters: Sapporo Athero-Incretin Study 1 (SAIS1).

  Hiroshi Nomoto, Hideaki Miyoshi, Tomoo Furumoto, Koji Oba, Hiroyuki Tsutsui, Atsushi Inoue, Tatsuya Atsumi, Naoki Manda, Yoshio Kurihara, Shin Aoki

  PloS one 11 10 e0164255  2016年 [査読有り][通常論文]
   

  OBJECTIVES: The DPP-4 inhibitors are incretin-related drugs that improve hyperglycemia in a glucose-dependent manner and have been reported to exert favorable effects on atherosclerosis. However, it has not been fully elucidated whether DPP-4 inhibitors are able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of sitagliptin, a DPP-4 inhibitor, on endothelial function and glycemic metabolism compared with that of the sulfonylurea glimepiride. MATERIALS AND METHODS: In this multicenter, prospective, randomized parallel-group comparison study, 103 outpatients with type 2 diabetes (aged 59.9 ± 9.9 years with HbA1c levels of 7.5 ± 0.4%) with dietary cure only and/or current metformin treatment were enrolled and randomly assigned to receive sitagliptin or glimepiride therapy once daily for 26 weeks. Flow-mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force® Monitor), and serum metabolic markers were assessed before and after the treatment. RESULTS: During the study period, no statistically significant change in %FMD was seen in both groups (sitagliptin, 5.6 to 5.6%; glimepiride, 5.6 to 6.0%). Secretory units of islets in transplantation, TNF-α, adiponectin and biological antioxidant potential significantly improved in the sitagliptin group, and superoxide dismutase also tended to improve in the sitagliptin group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. CONCLUSIONS: Regardless of glycemic improvement, early sitagliptin therapy did not affect endothelial function but may provide favorable effects on beta-cell function and on inflammatory and oxidative stress in patients with type 2 diabetes without advanced atherosclerosis. TRIAL REGISTRATION: UMIN Clinical Trials Registry System UMIN 000004955.
• Glucose Tolerance is Improved Following Surgery for Silent Somatotroph Adenoma

  Miya A, Nakamura A, Miyoshi H, Kameda H, Nomoto H, Nagai S, Omori Y, Hatanaka CK, Kobayashi H, Shimizu C, Atsumi T

  International Journal of Diabetes and Clinical Research 2 6 2015年12月31日 [査読有り]
  
• 本邦における抗リン脂質抗体症候群関連妊娠合併症の診療の実際 内科医への質問表調査から

  奥 健志, 村島 温子, 大村 一将, オルガ・アメングアル, 坊垣 暁之, 堀田 哲也, 保田 晋助, 金子 佳代子, 中西 功, 野澤 和久, 杉浦 真弓, 渥美 達也

  日本臨床免疫学会会誌 38 6 457 - 465 日本臨床免疫学会 2015年12月 [査読有り][通常論文]
   

  背景:血栓症と妊娠合併症は抗リン脂質抗体症候群(APS)の二大病態である.APS血栓症の診療は膠原病内科医や血液内科医が行うことが多いが,APS関連妊娠合併症の診療も抗リン脂質抗体(aPL)の測定・解釈等内科医の助言が求められることが多い.目的:本邦における抗リン脂質抗体症候群関連妊娠合併症の診断・治療への内科医の関与について調査する.方法:厚生労働省科学研究費補助金分担研究班にて,全国550名の日本リウマチ学会評議員及び日本血栓止血学会評議員に質問表を送付し結果を解析した.結果:有効回答157/550通(28.5%)を得た.APS合併妊娠例は53/157施設(33.8%)で118.7例/年(2.24例/施設・年)が診断されていた.aPLの測定状況は,抗カルジオリピン抗体もしくはβ2GPI依存性抗カルジオリピン抗体のいずれか1種以上とループスアンチコアグラント1種以上を測定している施設が128/157施設(81.5%)であったが,分類基準で定義されるaPLを全て測定した施設は2/157施設(1.3%)で殆どの施設で検査施行が不十分であった.治療は,33.1‰42.3%の施設が方針を産科に委ねると回答した.治療法・期間に一定の見解を得なかった.結論:内科医が診療に関わるAPS関連妊娠合併症は比較的少数であった.未診断例が多いと考えられるが,その一因に不十分なaPL検査の施行が挙げられる.APS合併妊娠の治療方針は産科医に委ねるという回答が多く,内科系の医師も診療に参加しやすい指針の整備が望まれる.(著者抄録)
• [Biomarker of bone and cartilage destruction in rheumatoid arthritis].

  Tanimura S, Kato M, Atsumi T

  Clinical calcium 25 12 1769 - 1775 2015年12月 [査読有り][通常論文]
  
• 抗リン脂質抗体測定法に関する全国調査

  松本 洋介, 北折 珠央, 山田 秀人, 片野 衣江, 尾崎 康彦, 杉浦 真弓, 村島 温子, 渥美 達也

  Reproductive Immunology and Biology 30 1-2 111 - 111 日本生殖免疫学会 2015年11月
• Markers of thrombotic events in autoimmune diseases: Comparison of Antiphospholipid Score (aPL-S) and Global Anti-phospholipid Syndrome Score (GAPSS)

  Oku Kenji, Amengual Olga, Nakamura Hiroyuki, Hisada Ryo, Oomura Kazumasa, Mato Masaru, Bohgaki Toshiyuki, Horita Tetsuya, Yasuda Shinsuke, Atsumi Tatsuya

  JOURNAL OF REPRODUCTIVE IMMUNOLOGY 112 129 - 130 2015年11月 [査読有り][通常論文]
  
• Procoagulant Property of a Novel Patient-Derived Autoimmune IgG Type Monoclonal Anticardiolipin Antibody That Binds to Beta 2 Glycoprotein Domain I but Not to Total Beta 2 Glycoprotein I Molecule

  Oku Kenji, Kanetsuka Yusaku, Amengual Olga, Nakamura Hiroyuki, Oomura Kazumasa, Bohgaki Toshiyuki, Horita Tetsuya, Yasuda Shinsuke, Delaat Bas, Atsumi Tatsuya

  ARTHRITIS & RHEUMATOLOGY 67 2015年10月 [査読有り][通常論文]
  
• Reduction of HLA Class II Expression and Beta-2-Glycoprotein I Presentation By Fluvastatin in Vitro and in Vivo: Possible Mechanism of Statin-Induced-Deprocoagulation in the Antiphospholipid Syndrome

  Watanabe Toshiyuki, Oku Kenji, Amengual Olga, Hisada Ryo, Ohmura Kazumasa, Shida Haruki, Shimizu Yuka, Kato Masaru, Bohgaki Toshiyuki, Horita Tetsuya, Yasuda Shinsuke, Ishizu Akihiro, Arase Hisashi, Atsumi Tatsuya

  ARTHRITIS & RHEUMATOLOGY 67 2015年10月 [査読有り][通常論文]
  
• Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review.

  Amengual O, Fujita D, Ota E, Carmona L, Oku K, Sugiura-Ogasawara M, Murashima A, Atsumi T

  Lupus 24 11 1135 - 1142 2015年10月 [査読有り][通常論文]
  
• Inhibition of Small Maf Function in Pancreatic β-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion.

  Nomoto H, Kondo T, Miyoshi H, Nakamura A, Hida Y, Yamashita K, Sharma AJ, Atsumi T

  Endocrinology 156 10 3570 - 3580 2015年10月 [査読有り][通常論文]
   

  The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic beta-cell function and maturation. However, insights about the effects of small Maf factors on beta-cells are limited. Our goal was to elucidate the function of small-Maf factors on beta-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with beta-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of beta-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates beta-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve beta-cell function.
• Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

  Atsushi Ogata, Tatsuya Atsumi, Takaaki Fukuda, Yasuhiko Hirabayashi, Masaaki Inaba, Naoki Ishiguro, Motokazu Kai, Daisuke Kawabata, Daihei Kida, Hitoshi Kohsaka, Ryutaro Matsumura, Seiji Minota, Masaya Mukai, Takayuki Sumida, Kiyoshi Takasugi, Shigenori Tamaki, Tsutomu Takeuchi, Atsuhisa Ueda, Kazuhiko Yamamoto, Hisashi Yamanaka, Hajime Yoshifuji, Akira Nomura

  ARTHRITIS CARE & RESEARCH 67 10 1354 - 1362 2015年10月 [査読有り][通常論文]
   

  Objective. To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Methods. Patients who had completed 24 weeks of TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the double-blind period of the MUSASHI study were enrolled in an 84-week open-label extension period. All received TCZ-SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). Results. Overall, 319 patients received >= 1 dose of TCZ-SC during the open-label extension period; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing >= 70 kg, the percentage with a sufficient serum TCZ concentration (>= 1 mu g/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Conclusion. Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight.
• 1型糖尿病患者におけるインスリンデグルデクの血糖変動の検討

  瀧本 理子, 北尾 直之, 山本 知穂, 一山 芽衣, 宮 愛香, 山本 浩平, 三次 有奈, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 58 9 723 - 723 (一社)日本糖尿病学会 2015年09月
• 2型糖尿病患者におけるインスリンをベースとしたシタグリプチンとビルダグリプチンの血糖変動に及ぼす効果

  檀浦 みどり, 小梁川 直秀, 宮 愛香, 一山 芽衣, 山本 知穂, 山本 浩平, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 58 9 723 - 723 (一社)日本糖尿病学会 2015年09月
• 2型糖尿病に対するリキシセナチドと基礎インスリン製剤との併用療法の有用性

  重沢 郁美, 宮 愛香, 中村 昭伸, 橋本 玲奈, 北尾 直之, 一山 芽衣, 山本 知穂, 野本 博司, 三好 秀明, 渥美 達也

  糖尿病 58 9 732 - 732 (一社)日本糖尿病学会 2015年09月
• 自己血糖測定器(SMBG)を用いたシタグリプチンとビルダグリプチン投与下血糖変動の交差比較

  一山 芽衣, 耒海 公彦, 北尾 直之, 宮 愛香, 山本 知穂, 山本 浩平, 野本 博司, 亀田 啓, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 58 9 736 - 736 (一社)日本糖尿病学会 2015年09月
• 2型糖尿病患者におけるSGLT2阻害薬の有効性の検討

  山本 知穂, 橋本 玲奈, 北尾 直之, 一山 芽衣, 宮 愛香, 山本 浩平, 三次 有奈, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 58 9 738 - 738 (一社)日本糖尿病学会 2015年09月
• 膠原病 心臓MRIは強皮症性肺高血圧症の予後予測に有用である

  野口 淳史, 保田 晋助, 河野 通仁, 加藤 将, 真鍋 徳子, 佐藤 隆博, 辻野 一三, 西村 正治, 渥美 達也

  呼吸と循環 63 8 S34 - S34 (株)医学書院 2015年08月
• BRIEF REPORT Takayasu Arteritis and Ulcerative Colitis: High Rate of Co-Occurrence and Genetic Overlap

  Chikashi Terao, Takayoshi Matsumura, Hajime Yoshifuji, Yohei Kirino, Yasuhiro Maejima, Yoshikazu Nakaoka, Meiko Takahashi, Eisuke Amiya, Natsuko Tamura, Toshiki Nakajima, Tomoki Origuchi, Tetsuya Horita, Mitsuru Matsukura, Yuta Kochi, Akiyoshi Ogimoto, Motohisa Yamamoto, Hiroki Takahashi, Shingo Nakayamada, Kazuyoshi Saito, Yoko Wada, Ichiei Narita, Yasushi Kawaguchi, Hisashi Yamanaka, Koichiro Ohmura, Tatsuya Atsumi, Kazuo Tanemoto, Tetsuro Miyata, Masataka Kuwana, Issei Komuro, Yasuharu Tabara, Atsuhisa Ueda, Mitsuaki Isobe, Tsuneyo Mimori, Fumihiko Matsuda

  ARTHRITIS & RHEUMATOLOGY 67 8 2226 - 2232 2015年08月 [査読有り][通常論文]
   

  Objective. Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases. Methods. We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases. Results. Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3-9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P=0.0070) and showed significant enrichment of HLA-B*52:01 compared to TAK patients without UC (P=1.0 x 10(-5)) (odds ratio 12.14 [95% confidence interval 2.96-107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P=0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 x 10(-10)). Conclusion. UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA-B*52:01 may play a central role in their co-occurrence.
• Projectile haemorrhage of a brachial artery in a patient with clinically amyopathic dermatomyositis

  Michihito Kono, Shinsuke Yasuda, Toshiyuki Watanabe, Tatsuya Atsumi

  RHEUMATOLOGY 54 8 1530 - 1531 2015年08月 [査読有り][通常論文]
  
• The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis.

  Takashi Kurita, Shinsuke Yasuda, Koji Oba, Toshio Odani, Michihito Kono, Kotaro Otomo, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Tatsuya Atsumi

  Rheumatology (Oxford, England) 54 8 1536 - 1536 2015年08月 [査読有り][通常論文]
  
• リウマチ性疾患の難治性病態の治療(第2回) 抗リン脂質抗体症候群、劇症型APS、lupus anticoagulant-hypoprothrombinemia syndrome

  大村 一将, 奥 健志, 渥美 達也

  分子リウマチ治療 8 3 163 - 167 (株)先端医学社 2015年07月 [査読有り][通常論文]
   

  抗リン脂質抗体症候群は、病原性を有する抗リン脂質抗体の存在下で動静脈血栓症および妊娠合併症をきたす疾患であり、後天性血栓性疾患のなかで最も頻度の高い病態である。疾患特異的な治療は確立されておらず、血栓症の二次予防および妊娠合併症の管理が現在のところ治療の主体であるが、適切な治療管理によっても再発をくり返す難治例が存在し、その治療は臨床上の重要な課題である。また稀ではあるが、全身の血栓症から急激な経過で多臓器不全へと至る劇症型抗リン脂質抗体症候群、抗プロトロンビン抗体による後天性低プロトロンビン血症を背景とした出血症状をきたすLupus anticoagulant-hypoprothrombinemia syndromeといった特殊病態も存在し、難治性病態とあわせ概説する。(著者抄録)
• Long-term safety and efficacy of rituximab in 7 Japanese patients with ANCA-associated vasculitis.

  Nagafuchi Hiroko, Atsumi Tatsuya, Hatta Kazuhiro, Muso Eri, Takeno Mitsuhiro, Yamada Hidehiro, Ozaki Shoichi

  Modern rheumatology 25 4 603 - 8 2015年07月 [査読有り][通常論文]
   

  The safety and efficacy of rituximab were examined in a multicenter open-label pilot study in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan.Patients with refractory AAV were administered a rituximab infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients also received oral daily prednisolone. The primary outcome was complete remission, which was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 or 1.The mean age of the 7 patients was 57 (range, 34-71) years. The mean follow-up period after rituximab treatment was 62.9 (range, 4.8-81) months. The mean BVAS at entry was 16.7 (range, 2-34). Complete remission occurred in all cases, except in 1 case in which the patient died, with a significant decline in BVAS from baseline at 12 months after initiation of rituximab. Rituximab reduced granulomatous orbital involvement in a patient with granulomatosis with polyangiitis. Relapse occurred in five patients. Adverse events included de novo hepatitis B in one patient, cancer (hepatocellular carcinoma and prostate cancer) in two patients, and transient visual disturbance, atypical mycobacterial infection, urinary tract in
• Long-term safety and efficacy of rituximab in 7 Japanese patients with ANCA-associated vasculitis

  Hiroko Nagafuchi, Tatsuya Atsumi, Kazuhiro Hatta, Eri Muso, Mitsuhiro Takeno, Hidehiro Yamada, Shoichi Ozaki

  MODERN RHEUMATOLOGY 25 4 603 - 608 2015年07月 [査読有り][通常論文]
   

  Objectives. The safety and efficacy of rituximab were examined in a multicenter open-label pilot study in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. Methods. Patients with refractory AAV were administered a rituximab infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients also received oral daily prednisolone. The primary outcome was complete remission, which was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 or 1. Results. The mean age of the 7 patients was 57 (range, 34-71) years. The mean follow-up period after rituximab treatment was 62.9 (range, 4.8-81) months. The mean BVAS at entry was 16.7 (range, 2-34). Complete remission occurred in all cases, except in 1 case in which the patient died, with a significant decline in BVAS from baseline at 12 months after initiation of rituximab. Rituximab reduced granulomatous orbital involvement in a patient with granulomatosis with polyangiitis. Relapse occurred in five patients. Adverse events included de novo hepatitis B in one patient, cancer (hepatocellular carcinoma and prostate cancer) in two patients, and transient visual disturbance, atypical mycobacterial infection, urinary tract infection, sepsis, and cytomegalovirus infection. Two patients died due to recurrent infections and airway obstruction, caused by an AAV lesion. Conclusions. Rituximab had a beneficial effect on refractory AAV in Japanese patients, but several adverse effects occurred during rituximab treatment.
• Low levels of plasma protein S, protein C and coagulation factor XII during early pregnancy and adverse pregnancy outcome

  Yasuhiko Ebina, Masahiro Ieko, Sumiyoshi Naito, Gen Kobashi, Masashi Deguchi, Hisanori Minakami, Tatsuya Atsumi, Hideto Yamada

  THROMBOSIS AND HAEMOSTASIS 114 1 65 - 69 2015年07月 [査読有り][通常論文]
   

  It was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8-14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as <1st, <5th, and <10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of <10th percentile yielded risks of pregnancy-induced hypertension (PIN) and severe PIH, while free PS level of <5th percentile yielded a risk of pre-eclampsia. FXII level of <1st percentile yielded a risk of premature delivery (PD) at <34 GW. None was associated with PD at <37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of <10th percentile (odds ratio 5.9, 95% confidence interval 1.7-18.1) and body mass index (BMI) >= 25 kg/m(2) (4.3, 1 1.1-13.3) were independent risk factors for severe PIN. Similarly, free PS level of <5th percentile (4.4, 1.0-14.3) and BMI >= 25 kg/m(2) (4.0, 1.3-10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIN, severe PIN or pre-eclampsia. Women with low FXII level might have an increased risk of PD at <34 GW.
• 完全自動化測定器による抗リン脂質抗体測定の意義

  奥 健志, オルガ・アメングアル, 久田 諒, 大村 一将, 中川 育磨, 渡邊 俊之, 坊垣 暁之, 堀田 哲也, 保田 晋助, 渥美 達也

  日本臨床免疫学会会誌 38 3 157 - 163 日本臨床免疫学会 2015年06月 [査読有り][通常論文]
   

  抗リン脂質抗体症候群(APS)に出現する病原性自己抗体である抗リン脂質抗体(aPL)は免疫学的にも機能的にも多様な自己抗体群で,それらをどのように効率的・正確に同定するかはいまだに重大な問題である.更に,aPLの測定には多数の免疫学的・機能的検査が必要であり,検査部門の負担が大きく必要十分な検査が行われない事が多い.そこで,北海道大学病院内科IIおよび消化器内科,北海道医療大学内科に通院するAPS患者を含む膠原病及び非膠原病患者・健常人合計212例の保存検体を用い後方視的に完全自動化化学発光免疫測定器にてaPL(抗カルジオリピン抗体IgG/IgM,抗β2グリコプロテインI抗体IgG/IgM)を計測し,従来のELISA検査法と比較した.その結果,両者は同等の診断確度を有していた.また,APS患者では2種以上のaPL陽性となる症例が,41/61(67%)と全身性エリテマトーデス(SLE)(3/37,9%),非SLE膠原病(1/53,2%)等他患者群・健常人に比べ高率であった.これらの点から複数のaPLを同時に測定できる完全自動化化学発光免疫測定器はAPSの診断に有用であることが判明した.(著者抄録)
• An independent validation of the Global Anti-Phospholipid Syndrome Score in a Japanese cohort of patients with autoimmune diseases.

  Oku K, Amengual O, Bohgaki T, Horita T, Yasuda S, Atsumi T

  Lupus 24 7 774 - 775 2015年06月 [査読有り][通常論文]
  
• Comment on: The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis: reply

  Shinsuke Yasuda, Takashi Kurita, Tetsuya Horita, Tatsuya Atsumi

  RHEUMATOLOGY 54 6 1129 - 1129 2015年06月 [査読有り][通常論文]
  
• 腎移植前後の耐糖能の推移に関する検討

  中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 篠原 信雄, 渥美 達也

  糖尿病 58 Suppl.1 S - 355 (一社)日本糖尿病学会 2015年04月
• 腎移植が耐糖能に与える影響

  中村 昭伸, 岩見 大基, 三好 秀明, 森田 研, 篠原 信雄, 寺内 康夫, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 52回 71 - 71 日本臨床分子医学会 2015年04月
• 当院におけるリナグリプチンの2型糖尿病腎症に対する尿アルブミン量減少効果についての検討

  菅原 基, 宮 愛香, 野本 博司, 高橋 清彦, 檀浦 みどり, 橋本 玲奈, 北尾 直之, 三次 有奈, 山本 浩平, 山本 知穂, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 58 Suppl.1 S - 303 (一社)日本糖尿病学会 2015年04月
• β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome.

  Tanimura K, Jin H, Suenaga T, Morikami S, Arase N, Kishida K, Hirayasu K, Kohyama M, Ebina Y, Yasuda S, Horita T, Takasugi K, Ohmura K, Yamamoto K, Katayama I, Sasazuki T, Lanier LL, Atsumi T, Yamada H, Arase H

  Blood 125 18 2835 - 2844 2015年04月 [査読有り][通常論文]
   

  Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. beta 2-glycoprotein I (beta 2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact beta 2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize beta 2GPI/HLA class II complexes in the absence of phospholipids. In situ association between beta 2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against beta 2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that beta 2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis.
• [Programs for Continuing Medical Education: A session; 7. Antiphospholipid syndrome: diagnosis and treatment].

  Atsumi T

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 104 3 513 - 518 2015年03月 [査読有り][通常論文]
  
• リウマチ性疾患の新しい治療法 成人ループス腎炎患者におけるミコフェノール酸モフェチルの使用実態調査

  保田 晋助, 渥美 達也, 嶋村 抄苗, 廣村 桂樹, 佐田 憲映, 森 雅亮, 武井 修治, 川口 鎮司, 田村 直人, 高崎 芳成

  日本リウマチ学会総会・学術集会プログラム・抄録集 59回 439 - 439 (一社)日本リウマチ学会 2015年03月
• Clinical features and pregnancy outcome in antiphospholipid syndrome patients with history of severe pregnancy complications

  Yuko Matsuki, Tatsuya Atsumi, Koushi Yamaguchi, Michi Hisano, Naoko Arata, Kenji Oku, Noriyoshi Watanabe, Haruhiko Sago, Yoshinari Takasaki, Atsuko Murashima

  MODERN RHEUMATOLOGY 25 2 215 - 218 2015年03月 [査読有り][通常論文]
   

  Objective. To clarify the clinical significance of antiphospholipid antibody (aPL) profile in patients with obstetric antiphospholipid syndrome (APS). Methods. Clinical records of 13 pregnant patients (15 pregnancies) with obstetrical APS were reviewed over 10 years. Patients who met the Sapporo Criteria fully were studied, whereas those with only early pregnancy loss were excluded. In addition to classical aPL: lupus anticoagulant (LA), anticardiolipin antibody (aCL), and anti-beta(2)-glycoprotein I (a beta 2GPI); phosphatidylserine-dependent anti-prothrombin antibody (aPS/PT) and kininogen-dependent anti-phosphatidylethanolamine antibody (aPE) were also examined in each case. Results. Cases were divided into two groups according to patient response to standard treatment: good and poor outcome groups. All cases with poor outcome presented LA, with IgG a beta 2GPI and IgG aPS/PT were also frequently observed. IgG aPE did not correlate with pregnancy outcome. Conclusion. aPL profile may predict pregnancy outcome in patients with this subset of obstetric APS.
• リウマチ性滑膜炎の描出 従来型のコントラスト造影MRIに対する二重標識後待ち時間(PLD)測定を利用したASL画像分析法の利点(Depiction of Rheumatoid Synovitis: Advantage of ASL Imaging Analysis Using Dual Post Labeling Delay(PLD) Settings Over Conventional Contrast Enhanced MRI)

  Sakashita Taro, Kamishima Tamotsu, Sugimori Hiroyuki, Tou Meiki, Noguchi Atsushi, Kono Michihito, Atsumi Tatsuya

  日本放射線技術学会総会学術大会予稿集 71回 185 - 185 2015年02月
• 画素間演算と時間強度曲線の形状分析を用いた関節リウマチにおける滑膜炎の正確な定量評価(Accurate Quantitative Assessment of Synovitis in Rheumatoid Arthritis Using Pixel by Pixel, Time-intensity Curve Shape Analysis)

  Sugimori Hiroyuki, Tou Meiki, Noguchi Atsushi, Kono Michihito, Atsumi Tatsuya

  日本放射線技術学会総会学術大会予稿集 71回 185 - 185 2015年02月
• Ras Guanine Nucleotide-Releasing Protein 4 Is Aberrantly Expressed in the Fibroblast-like Synoviocytes of Patients With Rheumatoid Arthritis and Controls Their Proliferation

  Michihito Kono, Shinsuke Yasuda, Richard L. Stevens, Hideyuki Koide, Takashi Kurita, Yuka Shimizu, Yusaku Kanetsuka, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Tomohiro Shimizu, Tokifumi Majima, Takao Koike, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 67 2 396 - 407 2015年02月 [査読有り][通常論文]
   

  Objective. Ras guanine nucleotide-releasing protein 4 (RasGRP-4) is a calcium-regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP-4-null mice are resistant to arthritis induced by anti-glucose-6-phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP-4 in the pathogenesis of human and rat arthritis. Methods. Synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were evaluated immunohistochemically for the presence of RasGRP-4 protein. Fibroblast-like synoviocytes (FLS) were isolated from synovial samples, and expression of RasGRP-4 was evaluated by real-time quantitative reverse transcription-polymerase chain reaction analyses. The proliferation potency of FLS was evaluated by exposing the cells to a RasGRP-4-specific small interfering RNA (siRNA). Finally, the ability of RasGRP-4-specific siRNAs to hinder type II collagen-induced arthritis in rats was evaluated to confirm the importance of the signaling protein in the disease. Results. Unexpectedly, RasGRP-4 protein was detected in the synovial hyperplastic lining, where proliferating FLS preferentially reside. FLS isolated from tissues obtained from a subpopulation of RA patients expressed much more RasGRP-4 than did FLS from examined OA patients. Moreover, the level of RasGRP-4 transcript was correlated with the FLS proliferation rate. The ability of cultured FLS to divide was diminished when they were treated with RasGRP-4-specific siRNAs. The intraarticular injection of RasGRP-4-specific siRNAs also dampened experimental arthritis in rats. Conclusion. RasGRP-4 is aberrantly expressed in FLS and helps regulate their growth. This intracellular signaling protein is therefore a candidate target for dampening proliferative synovitis and joint destruction.
• Clinical Images: Coronary and mesenteric involvement in polyarteritis nodosa

  Kanako Watanabe, Shinsuke Yasuda, Atsushi Noguchi, Tetsuya Horita, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 67 2 583 - 583 2015年02月 [査読有り][通常論文]
  
• [Clinical significance of antiphospholipid antibody measured by EliA anticardiolipin antibodies and anti-β2Glycoprotein I antibodies in antiphospholipid syndrome].

  Fujieda Y, Shida H, Oku K, Bohgaki T, Amengual O, Horita T, Yasuda S, Atsumi T

  Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 37 5 430 - 436 2015年01月06日 [査読有り][通常論文]
   

  Anticardiolipin antibodies (aCL-IgG/IgM) and anti-β2-glycoprotein I antibodies (aβ2GPI-IgG/IgM) are laboratory tests included in the current classification criteria for definite antiphospholipid syndrome (APS). However, not all of these assays have been commercially available in Japan. We investigated the efficacy of aCL-IgG/IgM and aβ2GPI-IgG/IgM assays using fluorescence enzyme immunoassay (Phadia:EliATM) for the diagnosis of APS in Japan. This study comprised 229 sera from patients (100 with APS and 129 without APS). The diagnosis of APS was made according to Sydney revised Sapporo criteria. EliATMCardiolipin and EliATMβ2-Glycoprotein (Phadia AB. Uppsala Sweden) were used to detect aCL IgG/M and aβ2GPI IgG/M, respectively. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were as follows aCL-IgG (45%, 94%, 0.80), aCL-IgM (20%, 94%, 0.54), aβ2GPI-IgG (33%, 98%, 0.88) and aβ2GPI-IgM (16%, 99%, 0.64) respectively. aCL-IgM, aβ2GPI-IgG or aβ2GPI-IgM were detected in 10 patients (18%) with aCL-IgG negative. The use of Phadia:EliATMantiphospholipid antibodies assays improve the diagnostic yield of thrombotic risk in APS patients.
• Decreased expression of Runx1 and lowered proportion of Foxp3(+)CD25(+)CD4(+) regulatory T cells in systemic sclerosis

  Hiroshi Kataoka, Shinsuke Yasuda, Shinji Fukaya, Kenji Oku, Tetsuya Horita, Tatsuya Atsumi, Takao Koike

  MODERN RHEUMATOLOGY 25 1 90 - 95 2015年01月 [査読有り][通常論文]
   

  Objectives. To investigate the role of Foxp3(+)CD25(+)CD4(+) regulatory T cells (Treg) and their transcription factor, Runt-related transcription factor 1 (Runx1), in the pathogenesis and development of systemic sclerosis (SSc). Methods. We collected 23 blood samples from patients with SSc including 19 females and 4 males, 11 early-stage cases within 3 years from onset and 12 late-stage cases and 22 samples from age-matched healthy subjects (HS). Total CD4(+) T cells were assessed for the expression of Treg-related markers, CD25 and CD127, on their surface and intracellular Foxp3 using flow cytometry. Relative expression of Runx1 mRNA in magnetically purified Treg was analyzed using real-time PCR. Results. Proportion of Foxp3(+) cells in total CD4(+) T cells was decreased in patients with either early-or late-stage SSc compared with that in HS, and Runx1 mRNA expression in purified Treg was lower in patients with SSc than in HS. Runx1 mRNA expression level was related to the frequency of Treg in SSc. Conclusions. This is the first report on Runx1 expression in Treg of a human autoimmune disease. Low expression of Runx1 along with reduced proportion of Treg in CD4(+) T cells may be associated with development of SSc even in early disease.
• The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis.

  Takashi Kurita, Shinsuke Yasuda, Koji Oba, Toshio Odani, Michihito Kono, Kotaro Otomo, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Tatsuya Atsumi

  Rheumatology (Oxford, England) 54 1 39 - 44 2015年01月 [査読有り][通常論文]
   

  OBJECTIVE: Interstitial lung diseases (ILDs) complicated with PM or DM are frequently aggressive and refractory to treatment. Recently some reports have suggested the potential benefit of tacrolimus for severe ILD complicated with PM/DM. However, little evidence has yet shown the efficacy of tacrolimus in these settings. The aim of this study was to evaluate the efficacy of tacrolimus as a treatment for PM-/DM-related ILD. METHODS: This retrospective study comprised 49 previously untreated patients diagnosed as PM-/DM-related ILD admitted to Hokkaido University Hospital from January 2000 to July 2013. These patients were treated with tacrolimus plus conventional therapy or only with conventional therapy (prednisolone, i.v. CYC and/or ciclosporin). The primary endpoint was defined as the time to relapse or death of respiratory cause or a serious adverse event. The secondary endpoint was defined as the time from the initiation of immunosuppressive treatment to relapse or death of respiratory cause. Endpoints were compared by adjusted Cox regression model by using inverse probability of treatment weighting in order to reduce the impact of these selection biases and potential confounding factors. RESULTS: After adjustment, the tacrolimus group (n = 25) had significantly longer event-free survival as compared with the conventional therapy group (n = 24). The weighted hazard ratio (HR) was 0.32 (95% CI 0.14, 0.75, P = 0.008). In addition, the tacrolimus group had significantly longer disease-free survival as compared with the conventional therapy group. The weighted HR was 0.25 (95% CI 0.10, 0.66, P = 0.005). CONCLUSION: The addition of tacrolimus to conventional therapy significantly improved the prognosis of patients with PM-/DM-related ILD.
• The participations of the physicians on the diagnosis and treatments of antiphospholipid related pregnancy morbidities in Japan: from the result of nationwide survey.

  Oku K, Murashima A, Oomura K, Amengual O, Bohgaki T, Horita T, Yasuda S, Kaneko K, Nakanishi I, Nozawa K, Sugiura-Ogasawara M, Atsumi T

  Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 38 6 457 - 465 2015年 [査読有り][通常論文]
  
• [The function and the significance of full-automated tests for detecting antiphospholipid antibodies].

  Oku K, Amengual O, Hisada R, Oomura K, Nakagawa I, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T

  Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 38 3 157 - 163 2015年 [査読有り][通常論文]
  
• Dietary patterns and the risk of systemic lupus erythematosus in a Japanese population: The Kyushu Sapporo SLE (KYSS) Study

  Kiyohara C, Washio M, Horiuchi T, Takahashi H, Tada Y, Kobashi G, Asami T, Ide S, Atsumi T, Kodama H, Akashi K, Harada M, Tsukamoto H, Hotokebuchi T, Nagasawa K, Ushiyama O, Mori M, Oura A, Sinomura Y, Suzuki H, Yamamoto M, Abe T, Tanaka H, Yasuda S, Nogami N, Okamoto K, Sakamoto N, Sasaki S, Miyake Y, Yokoyama T, Inaba Y, Nagai M

  International Medical Journal 22 3 110 - 115 2015年 [査読有り][通常論文]
  
• The efficacy of calcineurin inhibitors for the treatment of interstitial lung disease associated with polymyositis/dermatomyositis.

  Kurita T, Yasuda S, Amengual O, Atsumi T

  Lupus 24 1 3 - 9 2015年01月 [査読有り][通常論文]
   

  Interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM) is often resistant to treatment and life threatening, being recognized as one of the severest complication in these autoimmune disorders. Patients with clinically amyopathic dermatomyositis (CADM) or those with anti-CADM140/MDA5 antibody are especially prone to develop rapidly progressive interstitial pneumonia. We retrospectively analyzed 46 patients with PM/DM admitted to our hospital and identified DM, rapidly progressive disease, honeycomb lung, CADM and extensive ILD as risk factors for recurrence or death. In the presence of two or more risk factors, the sensitivity and specificity for the prediction of death or relapse were 81.3% and 76.7%, respectively. Calcineurin inhibitors have been widely used as induction and maintenance therapy for PM/DM-associated ILD. Recently we reported the benefit of tacrolimus on the disease-free survival and event-free survival of the patients with PM/DM-associated ILD. Among those patients treated with tacrolimus, poor prognostic factors for death, recurrence or severe adverse event were identified as acute progression of the disease, honeycomb lung, forced vital capacity (FVC) less than 80% and having DM. The potential effectiveness of an intensive therapy protocol with triple therapy that comprises high-dose corticosteroids, calcineurin inhibitors and cyclophosphamide has been reported.
• Long-term outcome in Japanese patients with lupus nephritis

  Kono M, Yasuda S, Kato M, Kanetsuka Y, Kurita T, Fujieda Y, Otomo K, Horita T, Oba K, Kondo M, Mukai M, Yanai M, Fukasawa Y, Atsumi T

  Lupus 23 11 1124 - 1132 2015年 [査読有り][通常論文]
  
• Determination of clinically significant tests for antiphospholipid antibodies and cutoff levels for obstetric antiphospholipid syndrome

  Tamao Kitaori, Mayumi Sugiura-Ogasawara, Kenji Oku, Wolfgang Papisch, Takeshi Ebara, Yasuhiko Ozaki, Kinue Katano, Tatsuya Atsumi

  Lupus 2015年 [査読無し][通常論文]
  
• Real-world practice of obstetricians in respect of assays for antiphospholipid antibodies

  Mayumi Sugiura-Ogasawara, Tatsuya Atsumi, Hideto Yamada, Tamao Kitaori, Yasuhiko Ozaki, Kinue Katano, Atsuko Murashima

  MODERN RHEUMATOLOGY 25 6 883 - 887 2015年 [査読有り][通常論文]
   

  Objective. The international classification criteria (CC) for definite antiphospholipid syndrome (APS) recommend confirmation of the sustained presence, for at least 12 weeks, of both lupus anticoagulant (LA), as determined by aPTT and RVVT, and anti beta 2glycoprotein I (beta 2GPI) or anticardiolipin (aCL) IgG and/or IgM. However, it remains unclear whether obstetricians comply with the aforementioned CC for the diagnosis of APS in daily clinical practice. We performed a nationwide survey to examine the attitudes of Japanese obstetricians toward the use of assays for antiphospholipid antibodies (aPLs). Methods. A questionnaire was sent to 2,700 obstetric facilities where maternity checkups are car-ried out. The types of assays conducted for aPLs, ascertainment of persistence of the antibodies for at least 12 weeks, and the cutoff points used for the assays were examined. Results. Of the facilities surveyed, 61.5% carried out the assay(s) only once. In regard to the type of assay performed, 97.1% carried out the assay for aCL IgG and/or beta 2GPI-dependent aCL, while 67.9% performed the LA-aPTT and/or LA-RVVT assay. Only 8.8% carried out assays for both LA. As for the cutoff points used, 98% of the facilities used lower cutoff points described in the manufacturers' manuals rather than the cutoff values recommended in the CC. Conclusion. Thus, only a limited number of facilities adhered precisely to the CC for the diagnosis of APS. Inappropriate treatment and unnecessary expense are potentially major concerns when facilities overdiagnose APS using lower cutoff points or without ascertaining the persistence of the antibodies for at least 12 weeks. On the other hand, some patients miss the opportunity to be treated for APS because of the absence of testing for LA.
• Surveillance for the use of mycophenolate mofetil for adult patients with lupus nephritis in Japan

  Shinsuke Yasuda, Tatsuya Atsumi, Sanae Shimamura, Kota Ono, Keiju Hiromura, Kenei Sada, Masaaki Mori, Syuji Takei, Yasushi Kawaguchi, Naoto Tamura, Yoshinari Takasaki

  MODERN RHEUMATOLOGY 25 6 854 - 857 2015年 [査読有り][通常論文]
   

  Objectives. Mycophenolate mofetil (MMF) is used as one of the standard induction/maintenance protocols for lupus nephritis (LN). However, MMF has not been approved for treating LN in any country, resulting in worldwide off-label use of this immunosuppressant. In order to clarify the real-world use of MMF as a treatment for LN in Japan, Japan College of Rheumatology surveyed the use of MMF in daily clinical practice. Methods. Adult patients with LN who visited enrolled hospitals from October 2008 to September 2013 were surveyed for the initial, maximum, and maintenance doses of MMF. The safety and efficacy of MMF were retrospectively evaluated. Results. One hundred and thirty-seven LN patients including 116 females were enrolled. The median of initial, maximum, and maintenance doses of MMF were 1.0 g/day, 1.5 g/day, and 1.0 g/day, respectively. Sixty-one adverse events were reported in 39 patients during the follow-up period. Median urine protein level decreased from 1.89 g/gCr to 0.21 g/gCr, meanC3 level increased from 66.4 mg/dl to 80.3 mg/dl, and median anti-DNA antibody titer decreased from 40.6 IU/ml to 10.6 IU/ml. Conclusion. MMF was commonly used for the treatment of adult LN patients with acceptable efficacy and safety in Japan.
• A national survey on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan

  Ryoki Hara, Hirotaka Miyazawa, Kenichi Nishimura, Takahiro Momoi, Tomo Nozawa, Masako Kikuchi, Nodoka Sakurai, Toshitaka Kizawa, Sanae Shimamura, Shinsuke Yasuda, Keiju Hiromura, Ken-ei Sada, Yasushi Kawaguchi, Naoto Tamura, Syuji Takei, Yoshinari Takasaki, Tatsuya Atsumi, Masaaki Mori

  MODERN RHEUMATOLOGY 25 6 858 - 864 2015年 [査読有り][通常論文]
   

  Purpose. To conduct a national survey of systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Based on current information on the use of MMF, we aimed to evaluate its efficacy and safety for childhood-onset (c-) SLE. Target. We evaluated 115 patients by questionnaire on MMF use for c-SLE in medical facilities specializing in pediatric rheumatic and renal diseases.Results. Average age at SLE onset was 10.6 (range, 2-15) years; average age at the time of starting MMF was 12.3 (range, 2-15) years. Average dose per body surface area was 1,059.3 mg/m2/ day. Corticosteroid dosing was 20.9 mg/day before treatment but 7.7 mg/day after treatment. Laboratory values before and after MMF treatment were as follows: C3 increased from 67.0 to 84.9 mg/dl (p < 0.001), C4 increased from 10.2 to 15.1 mg/dl (p < 0.001), and anti-DNA antibody decreased from 154.2 to 18.4 IU/ml (p < 0.001). 24 adverse events in 21 cases were reported, but MMF was not discontinued in any.Conclusions. The amount of MMF for c-SLE in Japan is similar to the standard dose in other countries. Reduction of corticosteroid dose and improvement of laboratory values represent efficacy of MMF. The side effects recorded here indicated tolerability of the drug.
• A Comparison of the Effects of the GLP-1 Analogue Liraglutide and Insulin Glargine on Endothelial Function and Metabolic Parameters: A Randomized, Controlled Trial Sapporo Athero-Incretin Study 2 (SAIS2).

  Hiroshi Nomoto, Hideaki Miyoshi, Tomoo Furumoto, Koji Oba, Hiroyuki Tsutsui, Arina Miyoshi, Takuma Kondo, Kenichi Tsuchida, Tatsuya Atsumi, Naoki Manda, Yoshio Kurihara, Shin Aoki

  PloS one 10 8 e0135854  2015年 [査読有り][通常論文]
   

  OBJECTIVES: GLP-1 improves hyperglycemia, and it has been reported to have favorable effects on atherosclerosis. However, it has not been fully elucidated whether GLP-1 is able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of the GLP-1 analogue, liraglutide on endothelial function and glycemic metabolism compared with insulin glargine therapy. MATERIALS AND METHODS: In this multicenter, prospective randomized parallel-group comparison study, 31 diabetic outpatients (aged 60.3 ± 10.3 years with HbA1c levels of 8.6 ± 0.8%) with current metformin and/or sulfonylurea treatment were enrolled and randomly assigned to receive liraglutide or glargine therapy once daily for 14 weeks. Flow mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force Monitor), and serum metabolic markers were assessed before and after the treatment period. RESULTS: A greater reduction (worsening) in %FMD was observed in the glargine group, although this change was not statistically different from the liraglutide group (liraglutide; 5.7 to 5.4%, glargine 6.7 to 5.7%). The augmentation index, C-peptide index, derivatives of reactive oxygen metabolites and BMI were significantly improved in the liraglutide group. Central systolic blood pressure and NT-proBNP also tended to be improved in the liraglutide-treated group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. CONCLUSIONS: Regardless of glycemic improvement, early liraglutide therapy did not affect endothelial function but may provide favorable effects on beta-cell function and cardioprotection in type 2 diabetics without advanced atherosclerosis. TRIAL REGISTRATION: UMIN Clinical Trials Registry System as trial ID UMIN000005331.
• Overexpression of TNF-α converting enzyme promotes adipose tissue inflammation and fibrosis induced by high fat diet.

  Matsui Y, Tomaru U, Miyoshi A, Ito T, Fukaya S, Miyoshi H, Atsumi T, Ishizu A

  Experimental and molecular pathology 97 3 354 - 358 2014年12月 [査読有り][通常論文]
   

  Obesity is a state in which chronic low-grade inflammation persists in adipose tissues. Pro-inflammatory cytokines, including TNF-alpha, produced by adipose tissues have been implicated as active participants in the development of obesity-related diseases. Since TNF-alpha converting enzyme (TACE) is the major factor that induces soluble TNF-alpha, TACE has been noted as a pivotal regulator in this field. To reveal the role of TACE in adipose tissue inflammation, TACE-transgenic (TACE-Tg) and wild type (WT) mice were fed with high fat diet (HFD) or control diet for 16 weeks. At 13 weeks after the beginning of the diet, serum TNF-alpha and macrophage-related cytokine/chemokine levels were elevated in TACE-Tg mice fed with HFD (Tg-HFD mice), and the number of the so-called crown-like adipocyte was significantly increased in adipose tissues of Tg-HFD mice at the end of the experiment. Although macrophage infiltration was not detected in the adipose tissues at this time, fibrosis was observed around the crown-like adipocytes. These findings suggested that TACE overexpression induced macrophage infiltration and subsequent fibrosis in adipose tissues under HFD regimen. The collective evidence suggested that TACE could be a therapeutic target of HFD-induced obesity-related adipose tissue inflammation. (C) 2014 Elsevier Inc. All rights reserved.
• 副甲状腺癌による原発性副甲状腺機能亢進症に下垂体副腎偶発腫瘍を合併した一例

  宮 愛香, 山本 知穂, 一山 芽衣, 北尾 直之, 山本 浩平, 三次 有奈, 野本 博司, 中村 昭伸, 三好 秀明, 渥美 達也, 亀田 啓

  北海道医学雑誌 89 2 159 - 160 北海道医学会 2014年11月
• 抗リン脂質抗体症候群におけるエリア-抗リン脂質抗体測定試薬の臨床的有用性

  藤枝 雄一郎, 志田 玄貴, 奥 健志, 坊垣 暁之, Amengual Olga, 堀田 哲也, 保田 晋助, 渥美 達也

  日本臨床免疫学会会誌 37 5 430 - 436 (一社)日本臨床免疫学会 2014年10月 

  抗カルジオリピン抗体(抗CL)-IgG/IgM,抗β2-グリコプロテインI(抗β2GPI)-IgG/IgMは抗リン脂質抗体症候群(APS)の診断基準で認められた臨床検査であるが,本邦では抗CL-IgMや抗β2GPI-IgG/IgMはルーチン検査として確立していない.抗CL-IgG/IgM,抗β2GPI-IgG/IgM測定キット(Phadia:EliATM)を用いることによるAPSの診断における本邦での有用性を検討した.229例(APS群100例,非APS群129例)の保存血清を用い,EliATM抗CL(CL-IgG,CL-IgM)およびEliATM抗β2GPI(β2-IgG,β2-IgM)を測定した.感度,特異度,ROC曲線下面積はそれぞれ抗CL-IgG(45%,94%,0.80),抗CL-IgM(20%,94%,0.54),抗β2-IgG(33%,98%,0.88),抗β2-IgM(16%,99%,0.64)であった.APS100例で抗CL-IgG陰性55例のうち,抗CL-IgM,抗β2-IgG,抗β2-IgMのいずれかが陽性である症例は10例であった.複数の抗リン脂質抗体検査を組み合わせることで,APS診断の感度向上が確認された.(著者抄録)
• 頸動脈エコーと足関節上腕血圧比検査を用いた全身性エリテマトーデス患者の動脈硬化に関する検討

  渡邊 俊之, 西田 睦, 澁谷 斉, 重松 明男, 清水 力, 渥美 達也

  臨床病理 62 補冊 243 - 243 (一社)日本臨床検査医学会 2014年10月
• 下垂体副腎腫瘍合併副甲状腺癌を疑った原発性副甲状腺機能亢進症

  宮 愛香, 橋本 玲奈, 高橋 清彦, 菅原 基, 一山 芽衣, 山本 知穂, 北尾 直之, 山本 浩平, 野本 博司, 亀田 啓, 中村 昭伸, 三好 秀明, 菅野 宏美, 三橋 智子, 渥美 達也

  日本内分泌学会雑誌 90 3 946 - 946 (一社)日本内分泌学会 2014年10月
• 分娩後早期にSheehan症候群を発症し診断し得た1例

  澤谷 亮佑, 高橋 清彦, 菅原 基, 橋本 玲奈, 北尾 直之, 一山 芽衣, 宮 愛香, 山本 浩平, 山本 知穂, 野本 博司, 中村 昭伸, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 90 3 985 - 985 (一社)日本内分泌学会 2014年10月
• 短期加療における2型糖尿病の内臓脂肪面積の変化とその背景因子の検討

  宮 愛香, 三好 秀明, 山本 知穂, 野本 博司, 中村 昭伸, 渥美 達也

  肥満研究 20 Suppl. 206 - 206 (一社)日本肥満学会 2014年10月
• 【実臨床で使用されるリウマチ性疾患の自己抗体up-to-date】抗カルジオリピン抗体とループスアンチコアグラント

  大村 一将, 奥 健志, 渥美 達也

  リウマチ科 52 4 359 - 363 (有)科学評論社 2014年10月 [査読有り][通常論文]
  
• Antiphospholipid scoring: significance in diagnosis and prognosis

  K. Oku, O. Amengual, T. Atsumi

  LUPUS 23 12 1269 - 1272 2014年10月 [査読有り][通常論文]
   

  Recently our group introduced the antiphospholipid score (aPL-S), a quantitative marker that represents aPL profile. We have validated its efficacy for the diagnosis of antiphospholipid syndrome (APS) and predictive value for thrombosis. The study comprised two independent sets of patients with autoimmune diseases. In the first set of patients (n=233), the aPL-S was established by analyzing aPL profiles. In the second set of patients (n=411), the predictive value of the aPL-S for thrombosis was evaluated. To define aPL-S, we calculated the relative risks (approximated by odds ratios (ORs)) of having APS manifestations (thrombosis and/or pregnancy morbidity) for each of the aPL tests and devised an original formula in which aPL-S was determined by OR: aPL-S=5xexp ([OR] -5)/4. The receiver operating characteristic (ROC) curve showed a hyperbolic pattern and the area under the ROC curve value was 0.752 (0.686 for revised Sapporo criteria), implying that aPL-S is a potential quantitative marker for APS diagnosis. The OR for thrombosis in patients with a high aPL-S (30) was 5.27 (95% confidence interval (95% CI) 2.32-11.95, p<0.0001). By multivariate analysis, an aPL-S of 30 appeared to be an independent risk factor for thrombosis (hazard ratio 3.144 (95% CI 1.383-7.150), p=0.006). The aPL-S is a useful quantitative index for diagnosing APS and may be a predictive marker for thrombosis in autoimmune diseases.
• Upregulation of Myxovirus Resistance Protein 1 in Patients with Neuropsychiatric Systemic Lupus Erythematosus

  Yuka Shimizu, Shinsuke Yasuda, Takashi Kurita, Sanae Shimamura, Ikuma Nakagawa, Atsushi Noguchi, Haruki Shida, Toshiyuki Watanabe, Michihito Kono, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 66 S718 - S719 2014年10月 [査読有り][通常論文]
  
• Antiphospholipid-Associated Nephropathy Is a Risk for Developing Arterial Thromboses in Patients with Systemic Lupus Erythematosus

  Tomoko Fukui, Shinsuke Yasuda, Toshiyuki Watanabe, Kazumasa Ohmura, Sanae Shimamura, Ikuma Nakagawa, Atsushi Noguchi, Haruki Shida, Yuka Shimizu, Michihito Kono, Takashi Kurita, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 66 S3 - S3 2014年10月 [査読有り][通常論文]
  
• The Protective Effects of Statins for Thrombosis in Patients with Systemic Lupus Erythematosus Positive for Antiphospholipid Antibodies.

  Toshiyuki Watanabe, Kenji Oku, Olga Amengual, Eri Sugawara, Ryo Hisada, Kazumasa Ohmura, Tomoko Fukui, Sanae Shimamura, Ikuma Nakagawa, Atsushi Noguchi, Haruki Shida, Michihito Kono, Yuka Shimizu, Takashi Kurita, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 66 S1154 - S1155 2014年10月 [査読有り][通常論文]
  
• Efficacy of Tocilizumab in Patients with Rheumatoid Arthritis: Sequential Evaluation Using Whole-Body Magnetic Resonance Imaging.

  Michihito Kono, Shinsuke Yasuda, Kazumasa Ohmura, Tomoko Fukui, Sanae Shimamura, Ikuma Nakagawa, Atsushi Noguchi, Haruki Shida, Toshiyuki Watanabe, Yuka Shimizu, Takashi Kurita, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Keita Sakamoto, Tamotsu Kamishima, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 66 S518 - S518 2014年10月 [査読有り][通常論文]
  
• Markers of Thrombotic Events in Autoimmune Diseases: Comparison of Antiphospholipid Score (aPL-S) and Global Anti-Phospholipid Syndrome Score (GAPSS).

  Kenji Oku, Olga Amengual, Ryo Hisada, Kazumasa Oomura, Ikuma Nakagawa, Toshiyuki Watanabe, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 66 S1251 - S1252 2014年10月 [査読有り][通常論文]
  
• Decreased Levels of SRSF1 (Serin/Arginine-Rich Splicing Factor1) Induced Lower Levels of RasGRP1 in T Cells from Patients with Systemic Lupus Erythematosus.

  Takashi Kurita, Shinsuke Yasuda, Vaishali Moulton, Yuka Shimizu, Michihito Kono, Hideyuki Koide, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, George C. Tsokos, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 66 S1171 - S1171 2014年10月 [査読有り][通常論文]
  
• Thrombocytopenia in Primary Antiphospholipid Syndrome Is Related to Arterial Thrombosis

  Ikuma Nakagawa, Kenji Oku, Olga Amengual, Ryo Hisada, Eri Sugawara, Kazumasa Ohmura, Tomoko Fukui, Sanae Shimamura, Haruki Shida, Toshiyuki Watanabe, Yuka Shimizu, Michihito Kono, Takashi Kurita, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi

  ARTHRITIS & RHEUMATOLOGY 66 S1 - S1 2014年10月 [査読有り][通常論文]
  
• Comparative analysis of different enzyme immunoassays for assessment of phosphatidylserine-dependent antiprothrombin antibodies

  Olga Amengual, Tetsuya Horita, Walter Binder, Gary L. Norman, Zakera Shums, Masaru Kato, Kotaro Otomo, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Shinsuke Yasuda, Tatsuya Atsumi

  RHEUMATOLOGY INTERNATIONAL 34 9 1225 - 1230 2014年09月 [査読有り][通常論文]
   

  Phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) were strongly correlated with the presence of lupus anticoagulant showing a high specificity for the diagnosis of antiphospholipid syndrome. However, the main criticism for the clinical applicability of aPS/PT testing is the lack of reproducibility of the results among laboratories. In this study, we measured IgG and IgM aPS/PT using our original in-house enzyme-linked immunosorbent assays (ELISA) and commercial ELISA kits to assess the assay performance and to evaluate the accuracy of aPS/PT results. The study included 111 plasma samples collected from patients and stored at our laboratory for aPS/PT assessment. Sixty-one samples were tested for IgG aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite (TM) aPS/PT IgG ELISA kit (INOVA Diagnostics, Inc., USA). Fifty samples were evaluated for IgM aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite (TM) aPS/PT IgM ELISA kit (INOVA Diagnostics). Ninety-eight percent of samples yielded concordant results for IgG aPS/PT and 82 % for IgM aPS/PT. There was an excellent agreement between the IgG aPS/PT assays (Cohen kappa = 0.962) and moderate agreement between the IgM aPS/PT assays (kappa = 0.597). Statistically significant correlations in the aPS/PT results were obtained from both IgG and IgM aPS/PT assays (r = 0.749, r = 0.622, p < 0.001, respectively). In conclusion, IgG and IgM detection by ELISA is accurate. The performance of aPS/PT is reliable, and concordant results can be obtained using different ELISA methods.
• Structural deterioration of finger joints with ultrasonographic synovitis in rheumatoid arthritis patients with clinical low disease activity

  Jun Fukae, Masato Isobe, Akemi Kitano, Mihoko Henmi, Fumihiko Sakamoto, Akihiro Narita, Takeya Ito, Akio Mitsuzaki, Masato Shimizu, Kazuhide Tanimura, Megumi Matsuhashi, Tamotsu Kamishima, Tatsuya Atsumi, Takao Koike

  RHEUMATOLOGY 53 9 1608 - 1612 2014年09月 [査読有り][通常論文]
   

  Objective. In this study we investigated the relationship between synovial vascularity (SV) and structural alteration of finger joints in patients with RA and long-term sustained clinical low disease activity (CLDA). Methods. RA patients with CLDA of >2 years (minimum 1 year of CLDA for study entry plus 1 year of observation) were analysed. Quantitative SV values were sequentially measured in each finger joint using power Doppler ultrasonography (0, 8, 20 and 52 weeks). Radiological progression of local finger joints was evaluated according to the Genant-modified Sharp score (0-52 weeks). Results. Of the 25 patients enrolled, 15 patients were finally analysed after excluding 10 patients who failed to maintain CLDA during the observational period. Changes in radiological progression of MCP and PIP joints with positive SV were significantly greater than those in joints with negative SV. Joint space narrowing (JSN) was strongly related to structural alteration of finger joints. In joints with positive SV, changes in structural alteration did not relate to total SV values, which reflect total exposure to inflammation in an observational period. Conclusion. Even in patients with a long period of CLDA, finger joints with positive SV showed structural alteration, especially in the progression of JSN.
• 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends

  Maria Laura Bertolaccini, Olga Amengual, Laura Andreoli, Tatsuya Atsumi, Cecilia B. Chighizola, Ricardo Forastiero, Philip De Groot, Gabriella Lakos, Marc Lambert, Pierluigi Meroni, Thomas L. Ortel, Michelle Petri, Anisur Rahman, Robert Roubey, Savino Sciascia, Melissa Snyder, Anne E. Tebo, Angela Tincani, Rohan Willis

  AUTOIMMUNITY REVIEWS 13 9 917 - 930 2014年09月 [査読有り][通常論文]
   

  Current classification criteria for definite Antiphospholipid Syndrome CAPS) require the use of three laboratory assays to detect antiphospholipid antibodies (aCL, anti-beta 2GPI and LA) in the presence of at least one of the two major clinical manifestations (i.e. thrombosis or pregnancy morbidity) of the syndrome. However, several other autoantibodies shown to be directed to other proteins or their complex with phospholipids have been proposed to be relevant to APS but their clinical utility and their diagnostic value remains elusive. This report summarizes the findings, conclusions and recommendations of the "APS Task Force 3-Laboratory Diagnostics and Trends" meeting that took place during the 14th International Congress on Antiphospholipid Antibodies (APLA 2013, September 18-21, Rio de Janeiro, Rj, Brazil). (c) 2014 Elsevier B.V. All rights reserved.
• [111th Scientific Meeting of the Japanese Society of Internal Medicine: Educationnal Lecture: 2. Systemic lupus erythematosus: Diagnosis and treatment].

  Atsumi T

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 9 2236 - 2241 2014年09月 [査読有り][通常論文]
  
• 手関節のリウマチ滑膜炎におけるPixel-by-Pixel TIC解析

  坂下 太郎, 神島 保, 杉森 博行, 唐 明輝, 河野 通仁, 渥美 達也

  日本放射線技術学会雑誌 70 9 965 - 965 (公社)日本放射線技術学会 2014年09月
• 短期高脂肪食負荷と長期高脂肪食負荷による膵β細胞増殖機構の差異

  中村 昭伸, 北尾 直之, 野本 博司, 三好 秀明, 寺内 康夫, 渥美 達也

  糖尿病合併症 28 Suppl.1 135 - 135 (一社)日本糖尿病合併症学会 2014年09月
• 含糖酸化鉄投与と短腸症候群により多彩な電解質異常を呈した1例

  野本 博司, 北尾 直之, 高野 善成, 一山 芽衣, 小梁川 直秀, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 亀田 啓, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 90 Suppl.Update 39 - 41 (一社)日本内分泌学会 2014年09月 

  62歳女。38歳時にクローン病を発症し、複数回の小腸切除を受け、近年はアダリムマブ投与にて症状安定していた。また、経過中に鉄欠乏性貧血と診断され含糖酸化鉄注射液の間歇投与を受けていた。今回、手足のしびれが出現し、低Ca血症にてCa製剤投与を受けるも改善ないため当科紹介となった。初診時の採血で低Ca血症に加え低P血症、更に低Mg血症の併存が明らかとなり、FGF23の測定を行った。入院後に各種内服薬ならびにグルコン酸Caの投与を一旦中止し、電解質の推移を確認したところ、血清Ca・血清Pの経時的な減少を認めたため、速やかに服薬を再開し精査を行った。低Mg血症はMg製剤の経静脈的な補充にて血清濃度が正常域に回復したため、経口剤に切り替え再発は認めなかった。後日、初診時にFGF23が高値であったことが判明し、前医での含糖酸化鉄投与歴も考慮して、同鉄剤によるFGF23上昇が病態に関与していると考えた。同鉄剤中止後にFGF23の経時的な低下ならびに正常化を認め、それに伴い血清Pも正常化した。最終的に含糖酸化鉄の中止と活性型ビタミンD製剤、経口Ca製剤、Mg製剤の経口投与のみで多彩な電解質異常は是正され、軽快退院した。
• Modifying Effect of N-Acetyltransferase 2 Genotype on the Association Between Systemic Lupus Erythematosus and Consumption of Alcohol and Caffeine-Rich Beverages

  Chikako Kiyohara, Masakazu Washio, Takahiko Horiuchi, Toyoko Asami, Saburo Ide, Tatsuya Atsumi, Gen Kobashi, Hiroki Takahashi, Yoshifumi Tada

  ARTHRITIS CARE & RESEARCH 66 7 1048 - 1056 2014年07月 [査読有り][通常論文]
   

  Objective. N-acetyltransferase 2 (NAT2) is involved in the metabolism of various environmental substances, both with and without carcinogenic potential. Alcoholic and nonalcoholic caffeine-rich beverages may be associated with markers of inflammation. Systemic lupus erythematosus (SLE) is a chronic, multifaceted inflammatory disease. We investigated the effects of alcoholic and nonalcoholic caffeine-rich beverages on risk of SLE and determined whether the effects were modified by NAT2 status. Methods. The NAT2 polymorphism was genotyped in 152 SLE cases and 427 healthy controls, all women and Japanese. We assessed effect modification by testing an interaction term for the NAT2 polymorphism and consumption of beverages. Results. Consumption of black tea (odds ratio [OR] 1.88, 95% confidence interval [95% CI] 1.03-3.41) and coffee (OR 1.57, 95% CI 0.95-2.61), but not green tea, was associated with an increased risk of SLE, while alcohol use (OR 0.33, 95% CI 0.20-0.55) was associated with a decreased risk of SLE. There were significant interactions between the NAT2 polymorphism and either alcohol use (P-interaction = 0.026) or consumption of black tea (P-interaction = 0.048). Conclusion. The NAT2 polymorphism significantly modified the effects of alcohol use and black tea consumption on SLE, emphasizing the importance of incorporating genetic and metabolic information in studies on management of SLE. Additional studies are warranted to confirm the findings suggested in this study.
• Expression and Regulation of Neuromedin B in Pituitary Corticotrophs of Male Melanocortin 2 Receptor-Deficient Mice

  Hiraku Kameda, Hideaki Miyoshi, Chikara Shimizu, So Nagai, Akinobu Nakamura, Takuma Kondo, Dai Chida, Tatsuya Atsumi

  ENDOCRINOLOGY 155 7 2492 - 2499 2014年07月 [査読有り][通常論文]
   

  The hypothalamic-pituitary-adrenal (HPA) axis is a major part of the neuroendocrine system that controls responses to stress, and has an important function in the regulation of various body processes. We previously created a mouse line deficient in the melanocortin 2 receptor (MC2R). MC2R-deficient mice (MC2R(-/-) mice) have high adrenocorticotropic hormone (ACTH) levels because of undetectable corticosterone levels. Increased neuromedin B (NMB) expression was recently reported in the pituitary gland of adrenalectomized mice, a model for acute adrenal insufficiency. To investigate gene expression in the pituitary gland under chronic adrenal deficiency, we examined the pituitary gland of MC2R(-/-) mice, a model of chronic adrenal insufficiency. To understand the molecular background of pituitary cells under chronic adrenal deficiency, we first performed DNA microarray analyses using the pituitary glands of the MC2R(-/-) mice. The DNA microarray analysis and real-time polymerase chain reaction showed that NMB expression was higher in the MC2R(-/-) than in the wild-type (WT) mice. We detected NMB expression in the MC2R(-/-) pituitary corticotrophs by immunohistochemistry using the specific antibodies for ACTH and NMB. In addition, the plasma NMB concentration was significantly higher in the MC2R(-/-) mice than in the WT mice. Subcutaneous implantation of a sustained-release corticosterone pellet decreased the expression of NMB mRNA as well as pituitary proopiomelanocortin mRNA. In isolated anterior pituitary cells, NMB mRNA expression was increased by the administration of corticotropin-releasing hormone (CRH) and was suppressed by dexamethasone treatment. In this study, we first demonstrate NMB expression in corticotrophs and its regulation by CRH and glucocorticoids. Furthermore, corticotrophs seemed to secrete NMB into the systemic circulation.
• [Recent progress of diagnosis and treatment for immune-mediated hematological diseases. Topics: II. Differential diagnosis; 1. Idiopathic thrombocytopenic purpura and antiphospholipid syndrome].

  Atsumi T

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 7 1580 - 1585 2014年07月 [査読有り][通常論文]
  
• [The pathogenesis, diagnosis and treatment of antiphospholipid syndrome].

  Ohmura K, Oku K, Atsumi T

  Nihon rinsho. Japanese journal of clinical medicine 72 7 1309 - 1313 2014年07月 [査読有り][通常論文]
  
• 【血栓・塞栓症-治療・予防の最新動向-】臨床研究の進歩 抗リン脂質抗体症候群の病態と診断・治療

  大村 一将, 奥 健志, 渥美 達也

  日本臨床 72 7 1309 - 1313 (株)日本臨床社 2014年07月 [査読有り][通常論文]
  
• シタグリプチンとグリメピリドの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study(1)

  野本 博司, 三好 秀明, 古本 智夫, 井上 篤, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 渥美 達也, 萬田 直紀, 栗原 義夫, 青木 伸

  日本動脈硬化学会総会プログラム・抄録集 46回 236 - 236 (一社)日本動脈硬化学会 2014年06月
• リラグルチドとグラルギンの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study(2)

  野本 博司, 三好 秀明, 古本 智夫, 土田 健一, 三次 有奈, 中村 昭伸, 近藤 琢磨, 渥美 達也, 萬田 直紀, 栗原 義夫, 青木 伸

  日本動脈硬化学会総会プログラム・抄録集 46回 237 - 237 (一社)日本動脈硬化学会 2014年06月
• Psychological stress in a Japanese population with systemic lupus erythematosus: Finding from KYSS study

  Hiroki Takahashi, Masakazu Washio, Chikako Kiyohara, Yoshifumi Tada, Toyoko Asami, Saburo Ide, Tatsuya Atsumi, Gen Kobashi, Motohisa Yamamoto, Takahiko Horiuchi

  MODERN RHEUMATOLOGY 24 3 448 - 452 2014年05月 [査読有り][通常論文]
   

  Objectives. Daily psychological stress has been proposed as a risk factor for systemic lupus erythematosus (SLE) in Western countries. However, there is little information about the relationship between daily psychological stress and the risk of SLE in a Japanese population. We examined the association between SLE and daily psychological stress. Methods. A case-control study was conducted to examine the relationship between daily psychological stress and SLE in Japanese females. The participants were 160 female SLE patients and 660 female volunteers. Unconditional logistic regression was used to compute OR and 95% confi dence interval (CI), with adjustment for several covariates. Results. Smoking (OR = 2.59; 95% CI, 1.74-3.86), walking (OR = 1.75; 95% CI, 1.81-2.56) and daily psychological stress (OR = 1.88; 95% CI, 1.14-3.10) were increased in patients with SLE after adjusting for age, region and all factors. Smokers with daily psychological stress (OR = 4.70; 95% CI = 2.53-8.77) were more prevalent than nonsmokers without daily psychological stress in SLE. The multiplicative interaction measures between smoking status and daily psychological stress did not reach statistical significance. Conclusions. The present study suggests the possibility that daily psychological stress as well as smoking might be associated with an increased risk of SLE.
• Enhanced Formation and Disordered Regulation of NETs in Myeloperoxidase-ANCA-Associated Microscopic Polyangiitis

  Daigo Nakazawa, Haruki Shida, Utano Tomaru, Masaharu Yoshida, Saori Nishio, Tatsuya Atsumi, Akihiro Ishizu

  JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 25 5 990 - 997 2014年05月 [査読有り][通常論文]
   

  AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired post-ischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.
• 多時相造影MRIのTIC解析を用いた滑膜炎抽出

  小野 雅人, 神島 保, 杉森 博行, 唐 明輝, 河野 通仁, 渥美 達也

  北海道医学雑誌 89 1 93 - 93 北海道医学会 2014年05月
• 1型糖尿病患者における25-(OH)ビタミンDの充足状況に関する検討

  亀田 啓, 三次 有奈, 山本 浩平, 野本 博司, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 南 昭子, 清水 力, 渥美 達也

  日本骨形態計測学会雑誌 24 2 S123 - S123 日本骨形態計測学会 2014年05月
• 産科抗リン脂質抗体測定標準化に関する検討

  北折 珠央, 奥 健志, 林 裕子, 片野 衣江, 尾崎 康彦, 渥美 達也, 杉浦 真弓

  日本産婦人科・新生児血液学会誌 24 1 S - 68 日本産婦人科・新生児血液学会 2014年05月
• 【関節リウマチ-生物学的製剤の登場から10年、今後の10年-】生物学的製剤 使い方と安全性 セルトリズマブペゴル

  大村 一将, 渥美 達也

  Mebio 31 5 46 - 52 (株)メジカルビュー社 2014年05月 [査読有り][通常論文]
  
• Sonographic synovial vascularity of synovitis in rheumatoid arthritis

  Jun Fukae, Kazuhide Tanimura, Tatsuya Atsumi, Takao Koike

  RHEUMATOLOGY 53 4 586 - 591 2014年04月 [査読有り][通常論文]
   

  RA is a condition of multiple synovitis. Abnormal synovial vascularity (SV) is evident with the onset of joint inflammation. The idea of estimating the level of joint inflammation by sonographic SV was conceived with the advancement of US. The ideal treatment strategy, called treat to target (T2T), requires early diagnosis and assessment of RA. Detection of positive SV can be useful for proving the presence of synovitis and finally diagnosing RA. In the assessment of RA, US-based global scores aimed at assessing overall disease activity have the potential to be useful for the achievement of T2T because US can directly detect changes in synovitis. Remaining SV in local joints increases the risk of structural deterioration. RA requires both improvement of overall disease activity and the disappearance of local SV for remission. The evaluation of SV provides various information and contributes to the clinical treatment of RA.
• 先端巨大症に対するオクトレオチド徐放性製剤の術前投与成績

  山本 浩平, 亀田 啓, 野本 博司, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 90 1 308 - 308 (一社)日本内分泌学会 2014年04月
• リラグルチドとグラルギンの抗動脈硬化作用及び膵β細胞機能改善効果における比較研究Sapporo Athero-Incretin Study 2

  三好 秀明, 野本 博司, 古本 智夫, 曹 圭龍, 土田 健一, 三次 有奈, 中村 昭伸, 近藤 琢磨, 渥美 達也, 萬田 直樹, 栗原 義夫, 青木 伸

  糖尿病 57 Suppl.1 S - 128 (一社)日本糖尿病学会 2014年04月
• 短期高脂肪食が膵β細胞増殖に与える影響

  北尾 直之, 中村 昭伸, 高野 善成, 一山 芽衣, 小梁川 直秀, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 近藤 琢磨, 三好 秀明, 寺内 康夫, 渥美 達也

  糖尿病 57 Suppl.1 S - 141 (一社)日本糖尿病学会 2014年04月
• インスリンデグルデクのContinuous Glucose Monitoring Systemsによる血糖変動の検討

  山本 知穂, 北尾 直之, 高野 善成, 一山 芽衣, 宮 愛香, 小梁川 直秀, 山本 浩平, 三次 有奈, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 57 Suppl.1 S - 147 (一社)日本糖尿病学会 2014年04月
• 膵β細胞におけるsmall Maf転写因子群の意義とインクレチン効果に関する検討

  野本 博司, 近藤 琢磨, 中村 昭伸, 三好 秀明, 渥美 達也

  糖尿病 57 Suppl.1 S - 263 (一社)日本糖尿病学会 2014年04月
• 2型糖尿病患者におけるインスリンをベースとしたシタグリプチン高用量とビルダグリプチン標準用量の血糖変動におよぼす効果

  小梁川 直秀, 北尾 直之, 高野 善成, 一山 芽衣, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 57 Suppl.1 S - 309 (一社)日本糖尿病学会 2014年04月
• 2型糖尿病合併骨粗鬆症患者の、ビスホスホネート製剤とSERMによる骨質マーカーへの影響

  三次 有奈, 野本 博司, 亀田 啓, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 57 Suppl.1 S - 318 (一社)日本糖尿病学会 2014年04月
• 24週にわたる自己血糖測定(SMBG)を用いたシタグリプチンとビルダグリプチン投与下の血糖変動の交差比較

  耒海 公彦, 三好 秀明, 相川 望美, 野本 博司, 亀田 啓, 曹 圭龍, 永井 聡, 近藤 琢磨, 渥美 達也

  糖尿病 57 Suppl.1 S - 400 (一社)日本糖尿病学会 2014年04月
• 高脂肪食負荷期間による膵β細胞増殖メカニズムの差異

  北尾 直之, 中村 昭伸, 野本 博司, 亀田 啓, 近藤 琢磨, 三好 秀明, 寺内 康夫, 渥美 達也

  日本臨床分子医学会学術総会プログラム・抄録集 51回 79 - 79 日本臨床分子医学会 2014年04月
• インスリノーマ手術症例に対するSSTR2発現とオクトレオチド負荷試験との関連性の検討

  高野善成, 中村昭伸, 野本博司, 亀田啓, 近藤琢磨, 三好秀明, 三橋智子, 清水力, 寺内康夫, 渥美達也

  日本内分泌学会雑誌 90 1 319  2014年04月01日 [査読無し][通常論文]
  
• Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility.

  Hui Jin, Noriko Arase, Kouyuki Hirayasu, Masako Kohyama, Tadahiro Suenaga, Fumiji Saito, Kenji Tanimura, Sumiko Matsuoka, Kosuke Ebina, Kenrin Shi, Noriko Toyama-Sorimachi, Shinsuke Yasuda, Tetsuya Horita, Ryosuke Hiwa, Kiyoshi Takasugi, Koichiro Ohmura, Hideki Yoshikawa, Takashi Saito, Tatsuya Atsumi, Takehiko Sasazuki, Ichiro Katayama, Lewis L Lanier, Hisashi Arase

  Proceedings of the National Academy of Sciences of the United States of America 111 10 3787 - 92 2014年03月11日 [査読有り][通常論文]
   

  Specific HLA class II alleles are strongly associated with susceptibility to rheumatoid arthritis (RA); however, how HLA class II regulates susceptibility to RA has remained unclear. Recently, we found a unique function of HLA class II molecules: their ability to aberrantly transport cellular misfolded proteins to the cell surface without processing to peptides. Rheumatoid factor (RF) is an autoantibody that binds to denatured IgG or Fc fragments of IgG and is detected in 70-80% of RA patients but also in patients with other diseases. Here, we report that intact IgG heavy chain (IgGH) is transported to the cell surface by HLA class II via association with the peptide-binding groove and that IgGH/HLA class II complexes are specifically recognized by autoantibodies in RF-positive sera from RA patients. In contrast, autoantibodies in RF-positive sera from non-RA individuals did not bind to IgGH/HLA class II complexes. Of note, a strong correlation between autoantibody binding to IgG complexed with certain HLA-DR alleles and the odds ratio for that allele's association with RA was observed (r = 0.81; P = 4.6 × 10(-5)). Our findings suggest that IgGH complexed with certain HLA class II alleles is a target for autoantibodies in RA, which might explain why these HLA class II alleles confer susceptibility to RA.
• 【神経症候群(第2版)-その他の神経疾患を含めて-】自己免疫性疾患 膠原病に伴う神経障害 全身性エリテマトーデスに伴う神経障害(精神神経ループス)

  神田 真聡, 渥美 達也

  日本臨床 別冊 神経症候群II 563 - 567 (株)日本臨床社 2014年03月
• 無症状で発見された1型糖尿病の1例

  北尾 直之, 小梁川 直秀, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 57 3 211 - 211 (一社)日本糖尿病学会 2014年03月
• インスリンデグルデクのContinuous Glucose Monitoring Systemsによる血糖変動の検討

  山本 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 57 3 213 - 213 (一社)日本糖尿病学会 2014年03月
• 糖尿病患者における無症候性心筋虚血罹患率の観察研究

  小梁川 直秀, 三次 有奈, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 57 3 215 - 215 (一社)日本糖尿病学会 2014年03月
• silent somatotroph adenoma術後に耐糖能障害が改善した1例

  宮 愛香, 中村 昭伸, 山本 知穂, 小梁川 直秀, 北尾 直之, 野本 博司, 亀田 啓, 曹 圭龍, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 57 3 223 - 223 (一社)日本糖尿病学会 2014年03月
• [NETs in pathogenesis of vasculitis].

  Nakazawa D, Nishio S, Tomaru U, Atsumi T, Ishizu A

  Nihon Jinzo Gakkai shi 56 2 117 - 123 2 2014年 [査読有り][通常論文]
  
• Autophagy in autoimmune disease

  Toshiyuki Bohgaki, Tatsuya Atsumi

  Japanese Journal of Clinical Immunology 37 3 125 - 132 2014年 [査読有り][通常論文]
   

  Cell death process can be involved in the development, differentiation, inflammation, immunity and tumorigenesis. Molecular mechanism of apoptotic cell death has been unveiled while molecular mechanisms of the other programmed cell death, especially necroptosis and autophagy, also have been elucidated. Autophagy is a highly conserved lysosome-mediated catabolic process and a homeostatic process to degrade unnecessary or dysfunctional cellular organelles and to recycle nutrients. The relation between autophagy and human disease has been reported. Here, we describe about the role of autophagy in autoimmune disease. © 2014 The Japan Society for Clinical Immunology.
• 1．特発性血小板減少性紫斑病（免疫性血小板減少症）と抗リン脂質抗体症候群

  渥美 達也

  日本内科学会雑誌 103 7 1580 - 1585 The Japanese Society of Internal Medicine 2014年 

  特発性血小板減少性紫斑病（免疫性血小板減少症：ITP）の鑑別のひとつが，抗リン脂質抗体症候群または抗リン脂質抗体関連血小板減少症である．抗リン脂質抗体は血小板減少症と関連した自己抗体であり，陽性の場合は血栓症のリスクをもつ．すなわち，抗リン脂質抗体が陽性の血小板減少症は，出血と血栓の両者のリスクとしてのマネージメントが必要なので，鑑別の意味は大きい．
• P9-002 産科抗リン脂質抗体症候群における測定法の標準化の試み

  北折 珠央, 奥 健志, 片野 衣江, 尾崎 康彦, 杉浦 真弓, 渥美 達也

  日本臨床免疫学会会誌 37 4 371b - 371b 日本臨床免疫学会 2014年 

  【目的】抗リン脂質抗体は不育症の原因の10％を占め唯一治療可能な原因であるが，抗リン脂質抗体は多様な抗体の集まりであるため多くの測定法があるが，陽性例に対する抗凝固療法が出産率を改善する産科的有用性は確立されていない．11種類の測定法の有用性を調べ，産科抗リン脂質抗体測定法標準化を目的とする．【方法】同意を得た560名の不育症患者を対象とした．従来法β2GPI依存性抗カルジオリピン（aCL）抗体，ループスアンチコアグラントLA-希釈ラッセル蛇毒（RVVT）法，LA-aPTT法とLA-リン脂質PL中和法，フォスファチジルセリンプロトロンビン（aPS/PT）IgG・M，古典的aCL IgG・M，aCL IgG・M・A，β2GPI IgG・M・A（Phadia）を測定し，その後の出産率と胎児染色体を調べ，相関，APS特異度，産科的有用性を調べた．【結果】β2GPI aCL，古典的CL IgG, β2GPI IgG, CL IgGまたLA-aPTT，LA- RVVT，PL中和法の間に強い相関を認めた．陽性治療・無治療の出産率はPL中和法（98percentile基準）では85.7％ vs 59.3％（p＝0.024），aPS/PT-IgG（99percentile基準）では，治療による出産率改善を認めた．CL IgG, IgMはいずれの基準を用いても有用性はなかった．【結論】PL中和法は98percentileでも有用であった．aPS/PT IgGも有用であり，抗リン脂質抗体症候群診断基準に加える必要がある．陽性率が低くても特異度の高い検査を複数組み合わせて行うことで過不足の少ない不育症医療ができると考えられた．
• Testing for Antiphospholipid antibodies with Solid Phase Assays: Guidance from the SSC of the ISTH

  K. M.J. Devreese, S. S. Pierangeli, B. de Laat, A. Tripodi, T. Atsumi, T. L. Ortel

  Journal of Thrombosis and Haemostasis 12 5 792 - 795 2014年 [査読有り][通常論文]
  
• 含糖酸化鉄投与と短腸症候群により多彩な電解質異常を呈した1例

  野本 博司, 北尾 直之, 小梁川 直秀, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 亀田 啓, 曹 圭龍, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 89 3 956 - 956 (一社)日本内分泌学会 2013年12月
• 術後に耐糖能障害が改善したsilent somatotroph adenomaの一例

  続木 惇, 宮 愛香, 中村 昭伸, 山本 知穂, 小梁川 直秀, 北尾 直之, 高野 善成, 野本 博司, 亀田 啓, 曹 圭龍, 近藤 琢磨, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 89 3 967 - 967 (一社)日本内分泌学会 2013年12月
• 中毒性多結節性甲状腺腫とパラガングリオーマを合併した一例

  山本 浩平, 亀田 啓, 野本 博司, 中村 昭伸, 近藤 琢磨, 三好 秀明, 永井 聡, 清水 力, 渥美 達也

  日本内分泌学会雑誌 89 3 982 - 982 (一社)日本内分泌学会 2013年12月
• 手指・足趾形成異常を伴った中枢性性腺機能低下症の一例

  比嘉 逸人, 小梁川 直秀, 山本 千穂, 宮 愛香, 山本 浩平, 三次 有奈, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也

  日本内分泌学会雑誌 89 3 1006 - 1006 (一社)日本内分泌学会 2013年12月
• The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery.

  Kyu Yong Cho, Hideaki Miyoshi, Satoshi Kuroda, Hiroshi Yasuda, Kenji Kamiyama, Joji Nakagawara, Masayoshi Takigami, Takuma Kondo, Tatsuya Atsumi

  Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 22 7 910 - 8 2013年10月 [査読有り][通常論文]
   

  BACKGROUND: Proinflammatory (M1) macrophages and anti-inflammatory (M2) macrophages have been identified in atherosclerotic plaques. While these macrophages have been speculated to be related to plaque vulnerability, there are limited studies investigating this relationship. Therefore, we examined the association between macrophage phenotype (M1 versus M2) and plaque vulnerability and clinical events. METHODS: Patients undergoing carotid endarterectomy received an ultrasound of the carotid artery before surgery. Plaques were processed for analysis by immunohistochemistry, Western blotting, and real-time polymerase chain reaction studies. Medical history and clinical data were obtained from medical records. RESULTS: Patients were divided into 2 groups: those suffering from acute ischemic attack (symptomatic, n = 31) and those that did not present with symptoms (asymptomatic, n = 34). Ultrasound analysis revealed that plaque vulnerability was greater in the symptomatic group (P= .033; Chi-square test). Immunohistochemistry revealed that plaques from the symptomatic group had a greater concentration of M1 macrophages (CD68-, CD11c-positive) while plaques from the asymptomatic group had more M2 macrophages (CD163-positive). This observation was confirmed by Western blotting. Characterization by real-time polymerase chain reaction studies revealed that plaques from the symptomatic group had increased expression of the M1 markers CD68 and CD11c, as well as monocyte chemoattractive protein-1, interleukin-6, and matrix metalloproteinase-9. In addition, more M1 macrophages expressed in unstable plaques were defined by ultrasound analysis, while more M2 macrophages were expressed in stable plaques. CONCLUSIONS: Our data show that M1 macrophage content of atherosclerotic plaques is associated with clinical incidence of ischemic stroke and increased inflammation or fibrinolysis. We also show the benefits of using ultrasound to evaluate vulnerability in the plaques.
• Decreased Levels Of Splicing Factor 2/Alternative Splicing Factor (SF2/ASF) Correlate With Lower Transcript Levels Of The RasGRP1 Normal Isoform In Lupus T Cells.

  Kurita Takashi, Yasuda Shinsuke, Moulton Vaishali R, Kono Michihito, Koide Hideyuki, Oku Kenji, Bohgaki Toshiyuki, Amengual Olga, Horita Tetsuya, Tsokos George C, Atsumi Tatsuya

  ARTHRITIS AND RHEUMATISM 65 S691  2013年10月 [査読有り][通常論文]
  
• Autoantibodies Against Component Of Complement One Contribute To The Complement Activation and Clinical Manifestation Of Antiphospholipid Syndrome (APS) Especially In Refractory Cases

  Oku Kenji, Amengual Olga, Nakagawa Ikuma, Watanabe Toshiyuki, Kanetsuka Yusaku, Bohgaki Toshiyuki, Horita Tetsuya, Yasuda Shinsuke, Atsumi Tatsuya

  ARTHRITIS AND RHEUMATISM 65 S7 - S8 2013年10月 [査読有り][通常論文]
  
• Essential role of the p38 mitogen-activated protein kinase pathway in tissue factor gene expression mediated by the phosphatidylserine-dependent antiprothrombin antibody

  Kenji Oku, Olga Amengual, Polona Zigon, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi

  RHEUMATOLOGY 52 10 1775 - 1784 2013年10月 [査読有り][通常論文]
   

  Objective. The aim of this study was to investigate the effects of phosphatidylserine-dependent antiprothrombin antibody (aPS/PT) on the expression of tissue factor (TF) and the signal transduction pathway in procoagulant cells. Methods. Peripheral blood mononuclear cells (PBMCs) from a healthy donor, murine monocyte RAW264.7 cells and human umbilical vein endothelial cells (HUVECs) were treated with either IgG fractions obtained from APS patients who were positive for aPS/PT or a murine monoclonal aPS/PT antibody, 231D, in the presence of prothrombin. The levels of TF mRNA were measured using real-time PCR. TF function, as measured by procoagulant activity, was determined with a clotting assay. 231D binding on the surface of treated cells was determined by flow cytometric analysis. Screening for phosphorylation of intracellular signalling proteins was conducted using an array assay. Phosphorylation of p38 MAPK was quantitatively analysed with ELISA, and SB203580 was used as a specific inhibitor of p38 MAPK. Specific siRNA for p38 MAPK was used for the knockdown assay. Results. The IgG fractions from APS patients and 231D induced TF mRNA overexpression and shortening of coagulation time in cells in the presence of prothrombin. The 231D moiety induced phosphorylation of p38 MAPK after binding to the cell surface of RAW264.7 cells. SB203580 or p38 siRNA significantly hampered TF overexpression. Conclusion. Expression of TF in procoagulant cells was induced by aPS/PT via p38MAPK phosphorylation. This phenomenon may be correlated with the thrombogenicity of APS.
• DPP4阻害薬投与後に増悪したバセドウ病の2例

  亀田 啓, 高野 善成, 北尾 直之, 一山 芽衣, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 小梁川 直秀, 野本 博司, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也, 永井 聡, 清水 力

  北海道医学雑誌 88 4-5 171 - 172 北海道医学会 2013年09月
• パラガングリオーマと中毒性多結節性甲状腺腫を合併した一例

  山本 浩平, 亀田 啓, 野本 博司, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 三好 秀明, 渥美 達也, 永井 聡, 清水 力

  北海道医学雑誌 88 4-5 174 - 174 北海道医学会 2013年09月
• β型T3受容体遺伝子解析により診断し得た甲状腺ホルモン不応症の1例

  三次 有奈, 小梁川 直秀, 村田 善晴, 山本 浩平, 野本 博司, 亀田 啓, 永井 聡, 近藤 琢磨, 三好 秀明, 秋川 和聖, 清水 力, 渥美 達也

  日本内分泌学会雑誌 89 2 474 - 474 (一社)日本内分泌学会 2013年09月
• 重症成人成長ホルモン分泌不全症患者へのGH補充による代謝への影響の検討

  野本 博司, 三次 有奈, 亀田 啓, 曹 圭龍, 中村 昭伸, 近藤 琢磨, 清水 力, 三好 秀明, 渥美 達也

  肥満研究 19 Suppl. 207 - 207 (一社)日本肥満学会 2013年09月
• 潜在性甲状腺機能低下症ならびに抗甲状腺ペルオキシダーゼ抗体が糖尿病合併症に与える影響についての検討

  亀田 啓, 高野 善成, 北尾 直之, 一山 芽衣, 宮 愛香, 三次 有奈, 山本 浩平, 山本 知穂, 小梁川 直秀, 野本 博司, 曹 圭龍, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 和田 典男, 柳澤 克之, 渥美 達也

  糖尿病合併症 27 Suppl.1 143 - 143 (一社)日本糖尿病合併症学会 2013年08月
• 糖尿病教育入院患者における重症慢性歯周病と臨床パラメータの関連性

  三次 有奈, 小梁川 直秀, 山本 浩平, 山本 知穂, 野本 博司, 亀田 啓, 曹 圭龍, 中村 昭伸, 永井 聡, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病合併症 27 Suppl.1 176 - 176 (一社)日本糖尿病合併症学会 2013年08月
• 内頸動脈剥離術後プラークを用いたマクロファージ炎症バランスとプラークの脆弱性・破綻に関する検討

  曹 圭龍, 三好 秀明, 小梁川 直秀, 山本 知穂, 野本 博司, 亀田 啓, 中村 昭伸, 近藤 琢磨, 渥美 達也

  糖尿病合併症 27 Suppl.1 178 - 178 (一社)日本糖尿病合併症学会 2013年08月
• The involvement of CD36 in monocyte activation by antiphospholipid antibodies.

  Kato M, Atsumi T, Oku K, Amengual O, Nakagawa H, Fujieda Y, Otomo K, Horita T, Yasuda S, Koike T

  Lupus 22 8 761 - 771 Sage publications ltd 2013年07月 [査読有り][通常論文]
   

  Background CD36, known as a scavenger receptor, is a transmembrane glycoprotein expressed on monocytes, platelets and endothelial cells, recognizes multiple ligands, including phosphatidylserine, and regulates atherogenesis and thrombosis. The objective of this study is to investigate the possible involvement of CD36 in the pathophysiology of thrombosis in patients with antiphospholipid syndrome (APS). Methods First, rs3765187, a missense mutation linked to CD36 deficiency, was investigated by TaqMan polymerase chain reaction (PCR) genotyping method in 819 Japanese, including 132 patients with APS, 265 with systemic lupus erythematosus (SLE) in the absence of APS, and 422 healthy subjects. Then, the involvement of CD36 in antiphospholipid antibody (aPL)-induced tissue factor (TF) expression was examined using CD36-null mice or anti-CD36. Purified IgG from patients with APS and a monoclonal phosphatidylserine-dependent antiprothrombin antibody were used in these experiments. TF expression was tested by real-time PCR and flow cytometry. Results Minor allele carrier of rs3765187 was less frequent in patients with APS (3.8% p=0.032), but not in patients with SLE in the absence of APS (7.9% p=0.32), compared with healthy subjects (10.2%). The aPL-induced TF expression was significantly suppressed on peritoneal macrophages from CD36-null mice compared to wild type and significantly inhibited by anti-CD36 on human monocytes. Conclusions The gene mutation linked to CD36 deficiency was less frequent in patients with APS. The deficient or suppressed CD36 function significantly reduced aPL-induced TF expression invitro. Taken together, in a susceptible background CD36 scavenger receptor function may be involved in the thrombotic pathophysiology in patients with APS.
• 血清IgG4高値を示した甲状腺原発MALTリンパ腫の1例

  野本 博司, 小梁川 直秀, 三次 有奈, 山本 浩平, 山本 知穂, 相川 望美, 亀田 啓, 田島 一樹, 野田 学, 曹 圭龍, 中垣 整, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 89 Suppl.Update 43 - 45 (一社)日本内分泌学会 2013年06月 

  52歳女。2年前頃より周囲の人から頸部の腫脹を指摘されるようになり、同時期より易疲労感を自覚し始めた。1年前に近医受診したところ、橋本病による甲状腺機能低下症・甲状腺腫大と診断され、レボチロキシンの補充を開始されたが、甲状腺機能・腫大とも改善に乏しく、当院に紹介された。外来でレボチロキシンの漸増を行ったが、甲状腺機能の改善に乏しく、一方で高度の高γグロブリン血症を認めたためIgG4の測定を行った。その結果、816mg/dlと高値であったことからIgG4関連疾患の可能性を考え、精査加療目的に入院となった。PET-CTを含む各種画像検査にて全身精査を行ったが、甲状腺以外には明らかな病変は指摘しえなかった。確定診断のため甲状腺生検を行ったところリンパ濾胞の形成を認め、濾胞間にはリンパ球・形質細胞を主体とする炎症細胞の密な浸潤が認められた。免疫染色では濾胞に一致してCD20陽性細胞が確認され、CD79a染色では、CD20陽性のB細胞とともに濾胞間に増生する形質細胞に広く陽性を示した。大部分の形質細胞がIgG陽性を示し、IgG4も全体の40%ほどが陽性であったものの、一方でIgκ優位に軽鎖制限が確認されたことからMALTリンパ腫と診断した。
• Prediction of Response to Treatment by Gene Expression Profiling of Peripheral Blood in Patients with Microscopic Polyangiitis

  Akihiro Ishizu, Utano Tomaru, Taichi Murai, Tomohiro Yamamoto, Tatsuya Atsumi, Takashi Yoshiki, Wako Yumura, Kunihiro Yamagata, Hidehiro Yamada, Shunichi Kumagai, Manae S. Kurokawa, Machi Suka, Hirofumi Makino, Shoichi Ozaki

  PLOS ONE 8 5 e63182  2013年05月 [査読有り][通常論文]
   

  The JMAAV study was an open-labeled prospective clinical trial, which proposed severity-based treatment protocols for patients with microscopic polyangiitis (MPA). The results suggest that the proposed protocols are useful (remission rate: 89.4%), but are also indicative of relapse or patient demise regardless of the treatment (recurrence rate: 19.0%; mortality rate: 10.6%). The aim of this study is to develop the method to predict response to the treatment in patients with MPA. In the present study, transcriptome analysis was performed using peripheral blood from patients enrolled in the JMAAV study before and 1-week after the beginning of treatment. The gene expression profile before treatment was not directly related to the response to the treatment. However, when the samples from 9 patients with good response (persistent remission for 18 months) were examined, the expression of 88 genes was significantly altered by the treatment. Thirty statistically reliable genes were selected, and then the alteration of expression by the treatment was examined among 22 patients, including 17 with good response, which was defined as persistent remission for 18 months and 5 with poor response, which was defined as relapse after remission or no remission. Discrimination analysis between the alteration of expression of the 30 genes by the treatment and the response identified a combination of 16 genes as the most valuable gene set to predict the response to the treatment. This preliminary study identified IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2 as the important genes that can predict the response to the treatment in patients with MPA at an early point during the therapy.
• [Case report; A case of familial focal segmental glomerulosclerosis with a mutation in the formin INF2].

  Yamamoto J, Nakazawa D, Tsukaguchi H, Toyoyama T, Sato A, Nakagaki T, Ishikawa Y, Shibazaki S, Nishio S, Atsumi T

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 102 5 1220 - 1222 5 2013年05月 [査読有り][通常論文]
  
• Ovarian morphology and prevalence of polycystic ovary syndrome in japanese women with type 1 diabetes mellitus

  Arina Miyoshi, So Nagai, Masamitsu Takeda, Takuma Kondo, Hiroshi Nomoto, Hiraku Kameda, Amiko Hirai, Kyuyong Cho, Kimihiko Kimachi, Chikara Shimizu, Tatsuya Atsumi, Hideaki Miyoshi

  Journal of Diabetes Investigation 4 3 326 - 329 2013年05月 [査読有り][通常論文]
   

  Aims/Introduction: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder including polycystic ovary morphology (PCOM), ovulatory dysfunction and hyperandrogenism. PCOS is frequently associated with type 2 diabetes mellitus however, it is unknown whether PCOM and PCOS are prevalent in Japanese patients with type 1 diabetes mellitus. The purpose of our study was to determine the frequency of PCOM and PCOS in women with type 1 diabetes mellitus. Materials and Methods: We evaluated clinical, hormonal and ovarian ultrasound data from 21 type 1 diabetes mellitus patients whose average glycated hemoglobin levels were 7.9 ± 1.5%. Results: Ultrasound identified PCOM in 11 patients (52.4%) and these patients also had higher levels of the androgen dehydroepiandrosterone sulfate (DHEA-S) than those without PCOM (P < 0.05). Of the patients with PCOM, five presented menstrual irregularities (45.5%) and three met the Japanese criteria for PCOS (27.2%) whereas all patients without PCOM had a normal menstrual cycle (P < 0.05). Conclusions: Japanese premenopausal women with type 1 diabetes mellitus had a high frequency of PCOM as well as PCOS. This is the first research of this area carried out in an Asian population. © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.
• 【分子標的療法による炎症制御の現状と未来】B細胞阻害薬 BAFF阻害薬 ベリムマブへの期待

  神田 真聡, 坊垣 暁之, 渥美 達也

  別冊Bio Clinica: 慢性炎症と疾患 2 1 120 - 125 (株)北隆館 2013年04月 

  B cell Activating Factor(BAFF)はB細胞の増殖・分化に関わるサイトカインであり、種々の自己免疫性疾患における病態形成への関与が示唆されている。BAFF阻害薬であるベリムマブは、長らく成果の乏しかった自己免疫性疾患に対する新規B細胞阻害薬として期待されている。ベリムマブは全身性エリテマトーデスの新規分子標的療法として2011年にFDAに認可され、クラススイッチしたメモリーB細胞を直接障害しないため感染症のリスクが少ないとされる。(著者抄録)
• 先端巨大症に対するオクトレオチド徐放性製剤の長期投与による治療効果・糖代謝への影響の検討

  野本 博司, 小梁川 直秀, 三次 有奈, 山本 浩平, 山本 知穂, 亀田 啓, 田島 一樹, 野田 学, 曹 圭龍, 中垣 整, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 89 1 291 - 291 (一社)日本内分泌学会 2013年04月
• メラノコルチン2受容体欠損マウスにおける下垂体遺伝子発現の検討

  亀田 啓, 野本 博司, 中垣 整, 永井 聡, 近藤 琢磨, 三好 秀明, 渥美 達也, 千田 大, 岩倉 洋一郎, 清水 力

  日本内分泌学会雑誌 89 1 295 - 295 (一社)日本内分泌学会 2013年04月
• 糖尿病教育入院患者における重症慢性歯周病と動脈硬化の指標を含む臨床パラメータの関連性

  三次 有奈, 小梁川 直秀, 山本 知穂, 山本 浩平, 野本 博司, 亀田 啓, 田島 一樹, 曹 圭龍, 野田 学, 中垣 整, 永井 聡, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 56 Suppl.1 S - 220 (一社)日本糖尿病学会 2013年04月
• ピオグリタゾンを対照薬としたインスリン療法へのDPP-4阻害薬の追加投与効果の検討

  野本 博司, 小梁川 直秀, 三次 有奈, 山本 知穂, 山本 浩平, 相川 望美, 亀田 啓, 田島 一樹, 野田 学, 曹 圭龍, 中垣 整, 近藤 琢磨, 清水 力, 三好 秀明, 渥美 達也

  糖尿病 56 Suppl.1 S - 285 (一社)日本糖尿病学会 2013年04月
• 抗TPO抗体陽性の2型糖尿病患者における腎機能と糖尿病合併症についての検討

  亀田 啓, 山本 浩平, 山本 知穂, 小梁川 直秀, 三次 有奈, 相川 望美, 野本 博司, 野田 学, 曹 圭龍, 中垣 整, 永井 聡, 近藤 琢磨, 三好 秀明, 和田 典男, 柳澤 克之, 清水 力, 渥美 達也

  糖尿病 56 Suppl.1 S - 308 (一社)日本糖尿病学会 2013年04月
• 高血圧症と脂質異常症を合併した2型糖尿病患者におけるCa拮抗薬とHMG-CoA還元酵素阻害剤合剤投与による検討

  中垣 整, 山本 知穂, 山本 浩平, 三次 有奈, 小梁川 直秀, 野田 学, 野本 博司, 田島 一樹, 亀田 啓, 曹 圭龍, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 56 Suppl.1 S - 399 (一社)日本糖尿病学会 2013年04月
• 動脈硬化進展におけるマクロファージ泡沫化と脂肪滴周囲蛋白の評価

  曹 圭龍, 三好 秀明, 山本 浩平, 山本 知穂, 小梁川 直秀, 三次 有奈, 野本 博司, 亀田 啓, 田島 一樹, 野田 学, 中垣 整, 近藤 琢磨, 渥美 達也

  糖尿病 56 Suppl.1 S - 435 (一社)日本糖尿病学会 2013年04月
• Positive synovial vascularity in patients with low disease activity indicates smouldering inflammation leading to joint damage in rheumatoid arthritis: time-integrated joint inflammation estimated by synovial vascularity in each finger joint

  Jun Fukae, Masato Isobe, Akemi Kitano, Mihoko Henmi, Fumihiko Sakamoto, Akihiro Narita, Takeya Ito, Akio Mitsuzaki, Masato Shimizu, Kazuhide Tanimura, Megumi Matsuhashi, Tamotsu Kamishima, Tatsuya Atsumi, Takao Koike

  RHEUMATOLOGY 52 3 523 - 528 2013年03月 [査読有り][通常論文]
   

  Objective. To investigate the relationship between synovial vascularity and joint damage progression in each finger joint of patients with RA under low disease activity during treatment with biologic agents. Methods. We studied 310 MCP and 310 PIP joints of 31 patients with active RA who were administered adalimumab (ADA) or tocilizumab (TCZ). Patients were examined with clinical and laboratory assessments. Power Doppler sonography was performed at baseline and at weeks 8, 20 and 40. Synovial vascularity was evaluated according to quantitative measurement. Hand and foot radiography was performed at baseline and at week 50. Results. Composite scores of the DAS with 28 joints and the Simplified Disease Activity Index (SDAI) were significantly decreased from baseline to week 8, being sustained at a low level by biologic agents during the observational period. MCP and PIP joints with positive synovial vascularity after week 8 showed more subsequent joint damage progression than joints without synovial vascularity throughout the follow-up. The changes in radiographic progression in these joints were independent of the sum of synovial vascularity from baseline to week 40 or the occasional occurrence of positive synovial vascularity. Conclusion. Smouldering inflammation reflected by positive synovial vascularity under low disease activity was linked to joint damage. The damage progressed irrespective of the severity of positive synovial vascularity. Even with a favourable overall therapeutic response, monitoring of synovial vascularity has the potential to provide useful joint information to tailor treatment strategies. Trial registration. University Hospital Medical Information Network Clinical Trials Registry; ext-link-type="uri" xlink:href="http://www.umin.ac.jp/ctr/" xmlns:xlink="http://www.w3.org/1999/xlink">http://www.umin.ac.jp/ctr/; UMIN000004476.
• A retrospective study of serum KL-6 levels during treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: a report from the Ad Hoc Committee for Safety of Biological DMARDs of the Japan College of Rheumatology.

  Takamura A, Hirata S, Nagasawa H, Kameda H, Seto Y, Atsumi T, Dohi M, Koike T, Miyasaka N, Harigai M

  Modern rheumatology / the Japan Rheumatism Association 23 2 297 - 303 2 2013年03月 [査読有り][通常論文]
   

  We investigated associations between treatment with methotrexate (MTX) or biological disease-modifying antirheumatic drugs (DMARDs) and elevation of serum Krebs von den Lungen-6 (KL-6) levels in Japanese patients with rheumatoid arthritis (RA). Using a standardized form, data were collected retrospectively from medical records and analyzed descriptively. Of a total of 198 RA patients with KL-6 serum levels measured at initiation of treatment (month 0) and two or more times by month 12, 27 (17.9 %) of 151 RA patients treated with biological DMARDs, including infliximab, etanercept, adalimumab, and tocilizumab (the biological DMARDs group), and 5 (10.6 %) of 47 patients treated without biological DMARDs but with MTX (MTX group), met criterion B (max. KL-6 a parts per thousand yen500 U/ml and > 1.5-fold from baseline) by 12 months. The majority of patients (n = 28) meeting criterion B had no apparent interstitial lung disease or malignancy. Of these 28 patients, 21 had serum KL-6 levels available after reaching their maximum level, and 13 (61.9 %) of the 21 then met criterion R [decrease to less than 500 U/ml or to less than (baseline + 0.5 x (maximum - baseline))] by month 12. Serum KL-6 levels may increase during treatment with MTX or these biological DMARDs without significant clinical events.
• Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: A report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs

  Masayoshi Harigai, Akito Takamura, Tatsuya Atsumi, Makoto Dohi, Shintaro Hirata, Hideto Kameda, Hayato Nagasawa, Yohei Seto, Takao Koike, Nobuyuki Miyasaka

  Modern Rheumatology 23 2 284 - 296 2013年03月 [査読有り][通常論文]
   

  Objective: The associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials. Methods: Percentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated. Results: In RISING, a clinical trial for infliximab, 15.6 % of the enrolled patients met criterion B (KL-6 ≥500 U/ml and < 1.5-fold increase over the baseline value) by week 54. In HIKARI, 7.8 % of the certolizumab pegol (CZP) group and 0 % of the placebo group met criterion B during the double-blind (DB) period (p = 0.003). In J-RAPID, 8.4 % of the methotrexate (MTX) + CZP and 3.9 % of the MTX + placebo groups met criterion B during the DB period. In GO-MONO, 1.8 % of the golimumab (GLM) and 1.3 % of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period (p = 0.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7 % of these patients. Conclusion: Serum KL-6 levels may increase during anti- TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option. © Japan College of Rheumatology 2012.
• A merged presentation of clinical and radiographic data using probability plots in a clinical trial, the JESMR study

  Hideto Kameda, Katsuaki Kanbe, Eri Sato, Yukitaka Ueki, Kazuyoshi Saito, Shouhei Nagaoka, Toshihiko Hidaka, Tatsuya Atsumi, Michishi Tsukano, Tsuyoshi Kasama, Shunichi Shiozawa, Yoshiya Tanaka, Hisashi Yamanaka, Tsutomu Takeuchi

  ANNALS OF THE RHEUMATIC DISEASES 72 2 310 - 312 2013年02月 [査読有り][通常論文]
  
• [The antiphospholipid syndrome].

  Oku K, Atsumi T

  [Rinsho ketsueki] The Japanese journal of clinical hematology 54 2 179 - 188 2 2013年02月 [査読有り][通常論文]
  
• Phospholipid scramblase 1 expression is enhanced in patients with antiphospholipid syndrome

  Olga Amengual, Tatsuya Atsumi, Kenji Oku, Eriko Suzuki, Tetsuya Horita, Shinsuke Yasuda, Takao Koike

  Modern Rheumatology 23 1 81 - 88 2013年01月 [査読有り][通常論文]
   

  Objective: Thrombus formation is the key event of vascular manifestations in antiphospholipid syndrome (APS). Phosphatidylserine (PS) is normally sequestered in the inner leaflet of cell membranes. Externalization of PS occurs during cell activation and is essential for promoting blood coagulation and for the binding of antiphospholipid antibodies (aPL) to cells. One of the molecules involved in PS externalization is phospholipid scramblase 1 (PLSCR1). We evaluated PLSCR1 expression on monocytes from APS patients and analyzed the in vitro effect of monoclonal aPL on PLSCR1 expression. Patients and methods: Forty patients with APS were investigated. In vitro experiments were performed in monocyte cell lines incubated with monoclonal aPL. PLSCR1 expression was determined by quantitative real-time polymerase chain reactions. PS exposure on CD14+ cell surface was analyzed by flow cytometry. Results: Levels of full-length PLSCR1 messenger RNA (mRNA) were significantly increased in APS patients compared with healthy controls (2.4 ± 1.2 vs. 1.3 ± 0.4, respectively, p < 0.001). In cultured monocytes, interferon alpha enhanced tissue-factor expression mediated by β2-glycoprotein-I-dependent monoclonal anticardiolipin antibody. Conclusions: Monocytes in APS patients had increased PLSCR1 mRNA expression. © 2012 Japan College of Rheumatology.
• Contrast-enhanced whole body joint MR Imaging in rheumatoid patients on tumour necrosis factor-alpha agents: a pilot study to evaluate novel scoring system for MR synovitis

  T. Kamishima, M. Kato, T. Atsumi, T. Koike, Y. Onodera, S. Terae

  CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 31 1 154 - 154 2013年01月 [査読有り][通常論文]
  
• Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation.

  Fukaya S, Matsui Y, Tomaru U, Kawakami A, Sogo S, Bohgaki T, Atsumi T, Koike T, Kasahara M, Ishizu A

  Laboratory investigation; a journal of technical methods and pathology 93 1 72 - 80 1 2013年01月 [査読有り][通常論文]
   

  TNF-alpha-converting enzyme (TACE) can cleave transmembrane proteins, such as TNF-alpha, TNF receptors, and epidermal growth factor receptor (EGFR) ligands, to release the extracellular domains from the cell surface. Recent studies have suggested that overexpression of TACE may be associated with the pathogenesis of inflammation and fibrosis. To determine the roles of TACE in inflammation and fibrosis, TACE transgenic (TACE-Tg) mice, which overexpressed TACE systemically, were generated. As the transgene-derived TACE was expressed as an inactive form, no spontaneous phenotype developed in TACE-Tg mice. However, the transgene-derived TACE could be converted to an active form by furin in vitro and by phorbol myristate acetate (PMA) in vivo. Subcutaneous injection of PMA into mice induced inflammatory cell infiltration 1 day later and subsequent dermal fibrosis 7 days later. Interestingly, the degree of dermal fibrosis at day 7 was significantly higher in TACE-Tg mice than in wild-type mice. Correspondingly, PMA increased the expression of type I collagen in the primary culture of dermal fibroblasts derived from TACE-Tg mice. Furthermore, phosphorylated EGFR was increased in the fibroblasts by the PMA treatment. The collective findings suggest that TACE overexpression and activation in fibroblasts could shed off putative EGFR ligands. Subsequently, the soluble EGFR ligands could bind and activate EGFR on fibroblasts, and then increase the type I collagen expression resulting in induction of dermal fibrosis. These results also suggest that TACE and EGFR on fibroblasts may be novel therapeutic targets of dermal fibrosis, which is induced after diverse inflammatory disorders of the skin. Laboratory Investigation (2013) 93, 72-80; doi:10.1038/labinvest.2012.153; published online 12 November 2012
• The significance of antiphospholipid antibodies tests

  Kotaro Otomo, Tatsuya Atsumi

  Japanese Journal of Clinical Immunology 36 2 63 - 70 2013年 [査読有り][通常論文]
   

  Antiphospholipid syndrome (APS) is an autoimmune disease defined by the presence of antiphospholipid antibodies (APL) in plasma of patients with thrombosis and/or pregnancy morbidity. In the classification criteria of APS, the presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL) or anti-β2-glycoprotein I antibodies (aβ2GPI) is necessary to diagnose APS. Recently, we defined "antiphospholipid score (aPL-S)" and evaluate the predictive value for thrombosis. In the study, aPL-S may be a predictive marker for developing thrombosis in patients with autoimmune diseases. In this article, we explain various APL assays for diagnosing APS in a clinical practice, introduce the study of "aPL-S", and discuss the significance of APL tests not only for a diagnosis of APS but also for a predictive marker of thrombosis in patients with autoimmune diseases. © 2013 The Japan Society for Clinical Immunology.
• AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration.

  Kazuki Tajima, Jun Shirakawa, Yu Togashi, Hideaki Inoue, Koichiro Sato, Kazuki Orime, Yuzuru Ito, Mitsuyo Kaji, Eri Sakamoto, Akinobu Nakamura, Kazutaka Aoki, Yoshio Goshima, Tatsuya Atsumi, Yasuo Terauchi

  PloS one 8 5 e64633  2013年 [査読有り][通常論文]
   

  The precise role of AMP-activated protein kinase (AMPK), a target of metformin, in pancreatic β cells remains controversial, even though metformin was recently shown to enhance the expression of incretin receptors (GLP-1 and GIP receptors) in pancreatic β cells. In this study, we investigated the effect of AMPK in the regulation of incretin receptors expression in pancreatic islets. The phosphorylation of AMPK in the mouse islets was decreased by increasing glucose concentrations. We showed the expression of incretin receptors in bell-shaped response to glucose. Expression of the incretin receptors in the isolated islets showed higher levels under a medium glucose concentration (11.1 mM) than that under a low glucose concentration (2.8 mM), but was suppressed under a high glucose concentration (22.2 mM). Both treatment with an AMPK inhibitor and DN-AMPK expression produced a significant increase of the incretin receptors expression under a low glucose concentration. By contrast, in hyperglycemic db/db islets, the enhancing effect of the AMPK inhibitor on the expression of incretin receptors was diminished under a low glucose concentration. Taken together, AMPK is involved in the regulation of incretin receptors expression in pancreatic islets under a low glucose concentration.
• 糖尿病教育入院患者における重症慢性歯周病と動脈硬化の指標を含む臨床パラメータの関連性

  三次 有奈, 相川 望美, 野本 博司, 亀田 啓, 田嶋 一樹, 曹 圭龍, 中垣 整, 永井 聡, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 56 1 39 - 39 (一社)日本糖尿病学会 2013年01月
• インスリンアレルギーの1例

  山本 浩平, 亀田 啓, 相川 望美, 野本 博司, 田島 一樹, 曹 圭龍, 中垣 整, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 56 1 45 - 45 (一社)日本糖尿病学会 2013年01月
• 2型糖尿病患者における持効型インスリンを用いたBOTの有効性および使用単位数の検討

  山本 知穂, 中垣 整, 野本 博司, 亀田 啓, 田島 一樹, 曹 圭龍, 近藤 琢磨, 三好 秀明, 渥美 達也

  糖尿病 56 1 45 - 45 (一社)日本糖尿病学会 2013年01月
• Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice.

  Tajima K, Nakamura A, Shirakawa J, Togashi Y, Orime K, Sato K, Inoue H, Kaji M, Sakamoto E, Ito Y, Aoki K, Nagashima Y, Atsumi T, Terauchi Y

  Am J Physiol Endocrinol Metab. 8 5 e64633  2013年 [査読有り][通常論文]
   

  The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing with the growing epidemics of obesity and diabetes. NAFLD encompasses a clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to NASH, which is a more aggressive form of fatty liver disease, to cirrhosis and, finally, hepatocellular carcinoma (HCC). The exact mechanism behind the development of HCC in NASH remains unclear; however, it has been established that hepatic steatosis is the important risk factor in the development of HCC. Metformin has recently drawn attention because of its potential antitumor effect. Here, we investigated the effects of metformin on high-fat diet (HFD)-induced liver tumorigenesis, using a mouse model of NASH and liver tumor. Metformin prevented long-term HFD-induced liver tumorigenesis in C57Bl/6 mice. Of note, metformin failed to protect against liver tumorigenesis in mice that had already begun to develop NAFLD. Metformin improved short-term HFD-induced fat accumulation in the liver, associated with the suppression of adipose tissue inflammation. Collectively, these results suggest that metformin may prevent liver tumorigenesis via suppression of liver fat accumulation in the early stage, before the onset of NAFLD, which seems to be associated with a delay in the development of inflammation of the adipose tissue.
• 左副腎原発メトトレキサート関連悪性リンパ腫の一例

  亀田啓, 中垣整, 永井聡, 近藤琢磨, 三橋智子, 松野吉宏, 安部崇重, 篠原信雄, 野々村克也, 白鳥聡一, 豊嶋崇徳, 三好秀明, 清水力, 清水力, 渥美達也

  日本内分泌学会雑誌 88 3 1034  2012年12月20日 [査読無し][通常論文]
  
• 低Na血症を契機に腎癌転移による下垂体機能低下症を診断した1例

  三次 有奈, 永井 聡, 亀田 啓, 小梁川 直秀, 山本 浩平, 山本 知穂, 野本 博司, 田島 一樹, 曹 圭龍, 野田 学, 中垣 整, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 88 3 1053 - 1053 (一社)日本内分泌学会 2012年12月
• 血清IgG4高値を示した甲状腺原発MALTリンパ腫の1例

  野本 博司, 小梁川 直秀, 三次 有奈, 山本 浩平, 山本 知穂, 相川 望美, 亀田 啓, 田島 一樹, 野田 学, 曹 圭龍, 中垣 整, 近藤 琢磨, 三好 秀明, 清水 力, 渥美 達也

  日本内分泌学会雑誌 88 3 1057 - 1057 (一社)日本内分泌学会 2012年12月
• Predominant prevalence of arterial thrombosis in Japanese patients with antiphospholipid syndrome.

  Fujieda Y, Atsumi T, Amengual O, Odani T, Otomo K, Kato M, Oku K, Kon Y, Horita T, Yasuda S, Koike T

  Lupus 21 14 1506 - 1514 14 2012年12月 [査読有り][通常論文]
   

  Objective: To study the clinical and immunological manifestations of the antiphospholipid syndrome (APS) in Japanese population by a single center registration. Methods: In this retrospective cohort study, 141 consecutive patients with APS, fulfilling the Sydney revised Sapporo criteria for definite APS, who visited to our Autoimmune Clinic from 1988 to 2010 were recruited and followed up. All the patients were interviewed and underwent a general physical examination by qualified rheumatologists on the day of blood sampling. Results: The population comprised 119 woman and 22 men with a mean age at diagnosis of 44 years (range 11-83 years). Seventy patients (49.6%) had primary APS, and 71 (50.4%) had systemic lupus erythematosus. The prevalence of thrombosis was 85.8%, arterial thrombosis was found in 93 patients (66.0%) and venous thrombosis in 46 (32.6%). The most common thrombosis was cerebral infarction [86/141 (61.0%)] followed by deep vein thrombosis [33/141 (23.4%)]. Among 70 pregnant women, 45 (64.3%) had obstetric complications. Lupus anticoagulant was detected in 116 patients (82.3%), anticardiolipin antibodies in 83 (58.9%), anti-β2Glycoprotein I antibodies in 73 (51.8%) and phosphatidylserine-dependent antiprothrombin antibodies in 98 (69.5%). Conclusion: High prevalence of arterial thrombosis was noted in Japanese patients with APS. The profile of heterogeneous and complex clinical manifestations in was substantiated in Japanese patients with APS.
• Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules

  Ryoko Sakai, Michi Tanaka, Toshihiro Nanki, Kaori Watanabe, Hayato Yamazaki, Ryuji Koike, Hayato Nagasawa, Koichi Amano, Kazuyoshi Saito, Yoshiya Tanaka, Satoshi Ito, Takayuki Sumida, Atsushi Ihata, Yoshiaki Ishigatsubo, Tatsuya Atsumi, Takao Koike, Atsuo Nakajima, Naoto Tamura, Takao Fujii, Hiroaki Dobashi, Shigeto Tohma, Takahiko Sugihara, Yukitaka Ueki, Akira Hashiramoto, Atsushi Kawakami, Noboru Hagino, Nobuyuki Miyasaka, Masayoshi Harigai

  ANNALS OF THE RHEUMATIC DISEASES 71 11 1820 - 1826 2012年11月 [査読有り][通常論文]
   

  Objective To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA). Method This prospective cohort study included Japanese RA patients who started infliximab (n = 412, 636.0 patient-years (PY)), etanercept (n = 442, 765.3 PY), or tocilizumab (n = 168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan-Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied. Results The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE. Conclusions Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.
• Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease

  Toshio Odani, Shinsuke Yasuda, Yuko Ota, Yuichiro Fujieda, Yujiro Kon, Tetsuya Horita, Yasushi Kawaguchi, Tatsuya Atsumi, Hisashi Yamanaka, Takao Koike

  RHEUMATOLOGY 51 10 1765 - 1774 2012年10月 [査読有り][通常論文]
   

  Objective. Interstitial lung disease (ILD) is a serious complication of SSc. We aimed to identify markers associated with SSc-related ILD. Methods. RNA was prepared from the peripheral blood mononuclear cells of 14 SSc patients, divided into four different RNA pools according to the presence or absence of ILD and to the treatment, and subjected to microarray analysis. Real-time quantitative PCR was used to confirm the microarray results in 43 SSc patients, 42 autoimmune controls and 10 healthy controls. Genomic DNA samples were collected from 149 patients with SSc (70 in Hokkaido and 79 in Tokyo) who underwent a high-resolution CT for the evaluation of ILD and from 230 healthy controls. Genotyping was performed using sequence-specific primers. Results. The microarray analysis revealed HLA-DRB5 to be the only gene commonly up-regulated in patients with ILD compared with those without ILD in both comparison groups. High expression levels of HLA-DRB5 in SSc patients with ILD were confirmed by real-time quantitative PCR. The prevalence of HLA-DRB5 gene carriers increased in the SSc patients with ILD relative to those without ILD or to healthy controls in both cohorts. Among the four detected alleles, the HLA-DRB5*01:05 allele was significantly more frequent in SSc patients with ILD than in SSc patients without ILD or in healthy controls. These associations were confirmed in the second cohort. Conclusion. HLA-DRB5 was highly expressed in PBMCs from patients with SSc-related ILD. The HLA-DRB5*01:05 allele is a risk factor for ILD in patients with SSc.
• Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome

  Kenji Oku, Olga Amengual, Tatsuya Atsumi

  EUROPEAN JOURNAL OF CLINICAL INVESTIGATION 42 10 1126 - 1135 2012年10月 [査読有り][通常論文]
   

  Eur J Clin Invest 2012; 42 (10): 11261135 Abstract In patients with the antiphospholipid syndrome (APS), the presence of a group of pathogenic autoantibodies called antiphospholipid antibodies causes arteriovenous thrombosis and pregnancy complications. To date, the pathogenicity of the antiphospholipid antibodies has been the focus of analysis. Recently, the antibodies were reported to be capable of direct cell activation, and research on the underlying mechanism is ongoing. The antiphospholipid antibodies bind to the membranes of vascular endothelial cells, monocytes and platelets, provoking tissue factor expression and platelet aggregation. This activation functions as intracellular signalling, independent of the cell type, to activate p38MAPK and the transcription factor NF?B. Currently, there are multiple candidates for the membrane receptors of the antiphospholipid antibodies that are being tested for potential in specific therapy. Recently, APS was reported to have significant comorbidity with complement activation, and it was proposed that this results in placental damage and cell activation and, therefore, could be the primary factor for the onset of pregnancy complications and thrombosis. The detailed mechanism of complement activation remains unknown; however, an inflammation-inducing substance called anaphylatoxin, which appears during the activation process of the classical complement pathway, is thought to be a key molecule. Complement activation occurs in tandem, regardless of the pathology of APS or the type of antiphospholipid antibody, and it is thought that this completely new understanding of the mechanism will contribute greatly to comprehension of the pathology of APS.
• [Discussion meeting on rheumatoid arthritis: progress in diagnosis and treatment].

  Takeuchi T, Atsumi T, Nagaoka S, Oribe M, Kikuchi J

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 101 10 2926 - 2942 10 2012年10月 [査読有り][通常論文]
  
• Dual Antiplatelet Therapy As Prophylaxis of Recurrent Arterial Thrombosis in Patients with antiphospholipid Syndrome.

  Fujieda Yuichiro, Amengual Olga, Watanabe Toshiyuki, Kono Michihito, Kanetsuka Yusaku, Kurita Takashi, Odani Toshio, Otomo Kotaro, Bohgaki Toshiyuki, Horita Tetsuya, Yasuda Shinsuke, Atsumi Tatsuya

  ARTHRITIS AND RHEUMATISM 64 10 S1036  2012年10月 [査読有り][通常論文]
  
• Ribophorin II Is Involved in the Tissue Factor Expression Mediated by Phosphatidylserine-Dependent Antiprothrombin Antibody On Monocytes.

  Fujieda Yuichiro, Amengual Olga, Kanetsuka Yusaku, Odani Toshio, Otomo Kotaro, Oku Kenji, Bohgaki Toshiyuki, Horita Tetsuya, Yasuda Shinsuke, Kuroki Kimiko, Maenaka Katsumi, Matsumoto Masaki, Hatakeyama Shigetsugu, Atsumi Tatsuya

  ARTHRITIS AND RHEUMATISM 64 10 S741  2012年10月 [査読有り][通常論文]
  
• A case of catastrophic antiphospholipid antibody syndrome complicated with systemic lupus erythematosus, double positive for anti-cardiolipin/β₂ glycoprotein I and anti-phosphatidylserine/prothrombin autoantibodies.

  Hirakawa E, Saito K, Hirata S, Atsumi T, Koike T, Tanaka Y

  Modern rheumatology / the Japan Rheumatism Association 22 5 769 - 773 5 2012年09月 [査読有り][通常論文]
   

  A 16-year-old male with severe thrombocytopenia and progressive multiple organ infarctions was diagnosed as having catastrophic antiphospholipid syndrome (CAPS) complicated with systemic lupus erythematosus, and was successfully treated with combination of anticoagulants, corticosteroids, plasma exchange, and intravenous cyclophosphamide. Antibodies to phosphatidylserine/prothrombin (PS/PT) complex and cardiolipin (CL)/beta(2)-glycoprotein I (beta(2)GPI) were simultaneously detected, indicating that the different pathways of both PS/PT and CL/beta(2)GPI might be associated with the radical manifestation of CAPS.
• Factor XI is a substrate for oxidoreductases: Enhanced activation of reduced FXI and its role in antiphospholipid syndrome thrombosis

  Bill Giannakopoulos, Lu Gao, Miao Qi, Jason W. Wong, Demin M. Yu, Panayiotis G. Vlachoyiannopoulos, Harry M. Moutsopoulos, Tatsuya Atsumi, Takao Koike, Philip Hogg, Jian C. Qi, Steven A. Krilis

  JOURNAL OF AUTOIMMUNITY 39 3 121 - 129 2012年09月 [査読有り][通常論文]
   

  Factor XI (FXI), a disulfide-linked covalent homodimer, circulates in plasma, and upon activation initiates the intrinsic/consolidation phase of coagulation. We present evidence that disulfide bonds in FXI are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). We identified that Cys362-Cys482 and Cys118-Cys147 disulfide bonds are reduced by TRX-1. The activation of TRX-1-treated FXI by thrombin, FXIIa or FXIa was significantly increased compared to non-reduced FXI, indicating that the reduced factor is more efficiently activated than the oxidized protein. Using a novel ELISA system, we compared the amount of reduced FXI in antiphospholipid syndrome (APS) thrombosis patients with levels in healthy controls, and found that APS patients have higher levels of reduced FXI. This may have implication for understanding the contribution of FXI to APS thrombosis, and the predisposition to thrombosis in patients with elevated plasma levels of reduced FXI. (c) 2012 Elsevier Ltd. All rights reserved.
• IgG4高値を示しIgG4関連疾患との鑑別を要した甲状腺原発MALTリンパ腫の1例

  野本 博司, 三次 有奈, 山本 浩平, 亀田 啓, 田島 一樹, 曹 圭龍, 中垣 整, 近藤 琢磨, 三好 秀明, 渥美 達也, 清水 力

  日本内分泌学会雑誌 88 2 532 - 532 (一社)日本内分泌学会 2012年09月
• 抗TPO抗体陽性の2型糖尿病患者における腎機能と糖尿病合併症の頻度についての検討

  亀田 啓, 山本 浩平, 三次 有奈, 野本 博司, 曹 圭龍, 永井 聡, 三好 秀明, 和田 典男, 柳澤 克之, 清水 力, 渥美 達也

  日本内分泌学会雑誌 88 2 537 - 537 (一社)日本内分泌学会 2012年09月
• Time-Dependent Increased Risk for Serious Infection From Continuous Use of Tumor Necrosis Factor Antagonists Over Three Years in Patients With Rheumatoid Arthritis

  Ryoko Sakai, Yukiko Komano, Michi Tanaka, Toshihiro Nanki, Ryuji Koike, Hayato Nagasawa, Koichi Amano, Atsuo Nakajima, Tatsuya Atsumi, Takao Koike, Atsushi Ihata, Yoshiaki Ishigatsubo, Kazuyoshi Saito, Yoshiya Tanaka, Satoshi Ito, Takayuki Sumida, Shigeto Tohma, Naoto Tamura, Takao Fujii, Takahiko Sugihara, Atsushi Kawakami, Noboru Hagino, Yukitaka Ueki, Akira Hashiramoto, Kenji Nagasaka, Nobuyuki Miyasaka, Masayoshi Harigai

  ARTHRITIS CARE & RESEARCH 64 8 1125 - 1134 2012年08月 [査読有り][通常論文]
   

  Objective. To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long-Term Safety (REAL) database. Methods. We analyzed 727 RA patients who had started either infliximab or etanercept (the anti-TNF group; 1,480.1 patient-years [PY]) and 571 RA patients who had started conventional nonbiologic disease-modifying antirheumatic drugs (the unexposed group; 1,104.1 PY) at the time of enrollment in the REAL. We assessed the occurrence of SIs within a 3-year observation period, including the period after switching to other TNF antagonists, and all SIs, unlimited to the first one in each patient as reported in other studies, to evaluate the real safety of TNF antagonists in daily practice. Results. The incidence rate of SIs per 100 PY was 5.54 (95% confidence interval [95% CI] 4.44-6.84) in the anti-TNF group and 2.72 (95% CI 1.87-3.83) in the unexposed group. Poisson regression analysis revealed that the relative risk (RR) of continuous use of TNF antagonists for SIs after adjusting for baseline and time-dependent covariates was significantly elevated both overall (1.97, 95% CI 1.25-3.19) and for the first year (2.40, 95% CI 1.20-5.03), but not for the second and third years combined (1.38, 95% CI 0.80-2.43). The adjusted RR for SIs of etanercept compared to infliximab was not significantly elevated. Conclusion. Continuous anti-TNF therapy was significantly associated with increased risks for developing SIs during, but not after, the first year.
• Cigarette Smoking, Alcohol Consumption, and Risk of Systemic Lupus Erythematosus: A Case-control Study in a Japanese Population

  Chikako Kiyohara, Masakazu Washio, Takahiko Horiuchi, Toyoko Asami, Saburo Ide, Tatsuya Atsumi, Gen Kobashi, Yoshifumi Tada, Hiroki Takahashi

  JOURNAL OF RHEUMATOLOGY 39 7 1363 - 1370 2012年07月 [査読有り][通常論文]
   

  Objective. Cigarette smoking may be associated with increased risk of systemic lupus erythematosus (SLE), whereas the role of alcohol consumption is unknown. We examined the association between SLE risk and smoking or drinking. Methods. We investigated the relationship of smoking and drinking compared to SLE risk among 171 SLE cases and 492 healthy controls in female Japanese subjects. Unconditional logistic regression was used to compute OR and 95% Cl, with adjustments for several covariates. Results. Compared with nonsmoking, current smoking was significantly associated with increased risk of SLE (OR 3.06, 95% Cl 1.86-5.03). The higher the level of exposure to cigarette smoke, the higher the risk of SLE. Inhalation was also associated with increased SLE risk (OR 3.73, 95% Cl 1.46-9.94 for moderate inhalation; OR 3.06, 95% Cl 1.81-5.15 for deep inhalation). In contrast, light/moderate alcohol consumption had a protective effect on SLE risk (OR 0.38,95% CI 0.19-0.76). As for beer, the risks for non-beer drinkers and beer drinkers were similar. This also applies to alcoholic beverages other than beer. Conclusion. Our results suggest that smoking was positively associated with increased SLE risk whereas light/moderate alcohol consumption was inversely associated with SLE risk, irrespective of the type of alcoholic beverage. Additional studies are warranted to confirm these findings. (First Release May 15 2012; J Rheumatol 2012;39:1363-70; doi:10.3899/jrheum.111609)
• Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study

  Shoichi Ozaki, Tatsuya Atsumi, Taichi Hayashi, Akihiro Ishizu, Shigeto Kobayashi, Shunichi Kumagai, Yasuyuki Kurihara, Manae S. Kurokawa, Hirofumi Makino, Hiroko Nagafuchi, Kimimasa Nakabayashi, Norihiro Nishimoto, Machi Suka, Yasuhiko Tomino, Hidehiro Yamada, Kunihiro Yamagata, Masaharu Yoshida, Wako Yumura

  MODERN RHEUMATOLOGY 22 3 394 - 404 2012年06月 [査読有り][通常論文]
   

  We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.
• Thrombotic microangiopathy due to multiple autoantibodies related to antiphospholipid syndrome

  Shunsuke Noda, Masao Ogura, Akiko Tsutsumi, Tomohiro Udagawa, Koichi Kamei, Kentaro Matsuoka, Hiroshi Kitamura, Tatsuya Atsumi, Shuichi Ito

  PEDIATRIC NEPHROLOGY 27 4 681 - 685 2012年04月 [査読有り][通常論文]
   

  Antiphospholipid syndrome (APS) is a rare disorder in children. More than half of childhood APS occurs as secondary APS complicated by systemic lupus erythematosus (SLE) and other autoimmune diseases. We encountered a boy with SLE who presented with thrombotic microangiopathy (TMA) due to APS. He was initially diagnosed with SLE and treated with methylprednisolone pulse therapy. However, his renal function rapidly deteriorated. Since poikilocytes were detected, we suspected that his condition was complicated by TMA or APS. Urgent plasma exchange, continuous hemodialysis, and intravenous cyclophosphamide saved the patient and his renal failure ameliorated. A renal biopsy performed at the onset of disease showed multiple microvascular thrombi, diffuse mesangiolysis, and cortical necrosis compatible with TMA. He was positive for anticardiolipin antibody, anti-beta 2-glycoprotein I antibody, and lupus anticoagulant as well as anti-phosphatidylserine-prothrombin complex IgG antibody (aPS/PT). Anti-a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) antibody was negative and ADAMTS13 activity was normal. The aPS/PT is thrombogenic and is a newly discovered lupus anticoagulant. Childhood TMA due to APS has rarely been reported. To the best of our knowledge this is the first report of pediatric TMA due to APS with positive aPS/PT. Physicians need to be aware of aPS/PT in pediatric APS and/or SLE.
• Improvement of the Quality of Life of a Patient with Colon Ulceration of Systemic Lupus Erythematosus by Successful Surgical Treatment: Report of a Case

  Keita Noguchi, Norihiko Takahashi, Shigenori Homma, Akihiko Kataoka, Yujiro Kon, Tatsuya Atsumi, Toshiya Kamiyama

  AMERICAN SURGEON 78 4 E209 - E210 2012年04月 [査読有り][通常論文]
  
• Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events

  Kotaro Otomo, Tatsuya Atsumi, Olga Amengual, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Tetsuya Horita, Shinsuke Yasuda, Takao Koike

  ARTHRITIS AND RHEUMATISM 64 2 504 - 512 2012年02月 [査読有り][通常論文]
   

  Objective To define the antiphospholipid score (aPL-S) by testing multiple antiphospholipid antibodies (aPL) and to evaluate its efficacy for the diagnosis of antiphospholipid syndrome (APS) and predictive value for thrombosis. Methods. This study comprised 2 independent sets of patients with autoimmune diseases. In the first set of patients (n = 233), the aPL profiles were analyzed. Five clotting assays for testing lupus anticoagulant and 6 enzyme-linked immunosorbent assays (IgG/IgM anticardiolipin antibodies, IgG/IgM anti-beta(2)-glycoprotein I, and IgG/IgM phosphatidylserine-dependent antiprothrombin antibodies) were included. The association of the aPL-S with a history of thrombosis/ pregnancy morbidity was assessed. In the second set of patients (n = 411), the predictive value of the aPL-S for thrombosis was evaluated retrospectively. Two hundred ninety-six of these patients were followed up for > 2 years. The relationship between the aPL-S and the risk of developing thrombosis was analyzed. Results. In the first set of patients, the aPL-S was higher in those with thrombosis/pregnancy morbidity than in those without manifestations of APS (P < 0.00001). For the aPL-S, the area under the receiver operating characteristic curve value was 0.752. In the second set of patients, new thromboses developed in 32 patients. The odds ratio (OR) for thrombosis in patients with an aPL-S of > 30 was 5.27 (95% confidence interval [ 95% CI] 2.32-11.95, P < 0.0001). By multivariate analysis, an aPL-S of > 30 appeared to be an independent risk factor for thrombosis (hazard ratio 3.144 [ 95% CI 1.383-7.150], P = 0.006). Conclusion. The aPL-S is a useful quantitative index for diagnosing APS and may be a predictive marker for thrombosis in autoimmune diseases.
• A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese

  Yukinori Okada, Kenichi Shimane, Yuta Kochi, Tomoko Tahira, Akari Suzuki, Koichiro Higasa, Atsushi Takahashi, Tetsuya Horita, Tatsuya Atsumi, Tomonori Ishii, Akiko Okamoto, Keishi Fujio, Michito Hirakata, Hirofumi Amano, Yuya Kondo, Satoshi Ito, Kazuki Takada, Akio Mimori, Kazuyoshi Saito, Makoto Kamachi, Yasushi Kawaguchi, Katsunori Ikari, Osman Wael Mohammed, Koichi Matsuda, Chikashi Terao, Koichiro Ohmura, Keiko Myouzen, Naoya Hosono, Tatsuhiko Tsunoda, Norihiro Nishimoto, Tsuneyo Mimori, Fumihiko Matsuda, Yoshiya Tanaka, Takayuki Sumida, Hisashi Yamanaka, Yoshinari Takasaki, Takao Koike, Takahiko Horiuchi, Kenshi Hayashi, Michiaki Kubo, Naoyuki Kamatani, Ryo Yamada, Yusuke Nakamura, Kazuhiko Yamamoto

  PLOS GENETICS 8 1 e1002455  2012年01月 [査読有り][通常論文]
   

  Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3x10(-9), odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4(+) and CD19(+) peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.
• [Impaired expression of Act1mRNA in B cells of patients with Sjögren's syndrome].

  Nakagawa Y, Kataoka H, Kurita T, Nakagawa H, Yasuda S, Horita T, Atsumi T, Koike T

  Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 35 1 75 - 80 1 2012年 [査読有り][通常論文]
   

  Sjögren's syndrome (SS) is a systemic autoimmune disorder characterized by profound lymphocytic infiltration into the lacrimal and salivary glands, thereby diminished secretory function. B cell hyper-activation is a predominant feature of SS related to hypergammaglobulinemia and production of autoantibodies. The adaptor molecule NF-kB activator 1 (Act1) plays an important role in the homeostasis of B cells by attenuating CD40 and B cell-activating factor belonging to the tumor necrosis factor family receptor (BAFFR) signaling. Act1-deficient mice develop autoimmune manifestations similar to SS, which are hypergammaglobulinemia, high levels of anti-SSA and anti-SSB autoantibodies. In this study, to investigate the role of Act1 in the pathogenesis of SS, we examined Act1mRNA expressions in B cells from patients with SS and discussed the association of Act1 with parameters and clinical manifestations of SS. We showed the low level of Act1mRNA expression in patients with SS and reciprocal association of Act1 with serum IgG level. Diminished Act1mRNA expression in SS may be associated with B cell hyperactivity and elevated immunoglobulin production in SS by uncontrolled B cell activation signal through CD40 and BAFFR. © 2012, The Japan Society for Clinical Immunology. All rights reserved.
• Task force report on “non-criteria” antiphospholipid antibody tests

  Maria LaurA. Bertolaccini, OlgA. Amengual, TatsuyA. Atsumi, Walter L. Binder, William H. Kutteh, Bas De Laat, Ricardo Forastiero, Marc Lambert, Hidehiko Matsubayashi, Vijaya L. Murthy, Michelle Petri, Jacob H. Rand, Marielle Sanmarco, Anne E. Tebo, Silvia S. Pierangeli

  Antiphospholipid Syndrome: Insights and Highlights from the 13Th International Congress on Antiphospholipid Antibodies 134 - 146 2012年01月01日 [査読有り][通常論文]
   

  Current classification criteria for antiphospholipid syndrome (APS) recommend the use of one or more of three positive standardized laboratory assays to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity). However, several other autoantibodies shown to be directed against phospholipids other than cardiolipin and/or their complexes with proteins of the coagulation cascade have also been proposed to be important in APS. This chapter summarizes the recommendations of a Task Force of worldwide scientists who discussed and analyzed critical questions related to “noncriteria” aPL tests in an evidence-based manner, during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13–16, 2010, Galveston, TX).
• Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population

  C. Kiyohara, M. Washio, T. Horiuchi, T. Asami, S. Ide, T. Atsumi, G. Kobashi, H. Takahashi, Y. Tada

  SCANDINAVIAN JOURNAL OF RHEUMATOLOGY 41 2 103 - 109 2012年 [査読有り][通常論文]
   

  Objectives: Exposure to reactive oxygen species (ROS) through cigarette smoking is thought to contribute to the development of systemic lupus erythematosus (SLE). Metabolic enzymes are involved in ROS production. The aim of this study was to evaluate the modifying effect of metabolic polymorphisms on the association of cigarette smoking with SLE risk in a Japanese population. Methods: We investigated the relationship of the cytochrome P450 (CYP) 1A1 rs4646903 and glutathione S-transferase (GST) M1 deletion polymorphisms to SLE risk with attention to interaction with cigarette smoking among 151 SLE cases and 421 controls in female Japanese subjects. Unconditional logistic regression was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for several covariates. Results: Smokers with the CC genotype of CYP1A1 rs4646903 were significantly associated with increased risk of SLE (OR 9.72, 95% CI 2.73-34.6). Similarly, smokers with the combined CYP1A1 rs4646903/GSTM1 'at-risk' genotype were significantly associated with increased risk of SLE (OR 17.5, 95% CI 3.20-95.9). More than 60% of the excess risk for SLE in smokers with the CC genotype and smokers with the combined 'at-risk' genotype was due to an additive interaction. A lack of association of the GSTM1 genotypes with smoking was observed. Conclusions: Our results suggest that a combination of smoking and either the CYP1A1 rs4646903 genotype or the combined metabolic genotype plays an important role in SLE susceptibility in our Japanese population. Additional studies are warranted to confirm the metabolic polymorphism-smoking interaction suggested in the present study.
• A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese

  Okada Y, Shimane K, Kochi Y, Tahira T, Suzuki A, Higasa K, Takahashi A, Horita T, Atsumi T, Ishii T, Okamoto A, Fujio K, Hirakata M, Amano H, Kondo Y, Ito S, Takada K, Mimori A, Saito K, Kamachi M, Kawaguchi Y, Ikari K, Mohammed O. W, Matsuda K, Terao C, Ohmura K, Myouzen K, Hosono N, Tsunoda T, Nishimoto N, Mimori T, Matsuda F, Tanaka Y, Sumida T, Yamanaka H, Takasaki Y, Koike T, Horiuchi T, Hayashi K, Kubo M, Kamatani N, Yamada R, Nakamura Y, Yamamoto K

  PLoS Genet 8 1 e1002455  2012年 [査読有り][通常論文]
  
• Hepatitis B Virus Reactivation by Immunosuppressive Therapy in Patients with Autoimmune Diseases: Risk Analysis in Hepatitis B Surface Antigen-negative Cases

  Masaru Kato, Tatsuya Atsumi, Takashi Kurita, Toshio Odani, Yuichiro Fujieda, Kotaro Otomo, Tetsuya Horita, Shinsuke Yasuda, Takao Koike

  JOURNAL OF RHEUMATOLOGY 38 10 2209 - 2214 2011年10月 [査読有り][通常論文]
   

  Objective. To evaluate the risk of reactivation of resolved hepatitis B virus (HBV) by immunosuppressive therapy in patients with autoimmune diseases. Methods. Thirty-five patients with autoimmune diseases were included in our study; all were hepatitis B surface antigen (HBsAg)-negative and antibody against hepatitis B core antigen-positive. They were followed for 8-124 weeks and clinical outcomes were analyzed, including serum levels of HBV-DNA and aminotransferase every 4 weeks during their immunosuppressive therapy for underlying autoimmune diseases. If HBV-DNA was detected during the immunosuppressive therapy. HBsAg, antibody against HBsAg (anti-HBs), hepatitis B e antigen (HBeAg), and antibody against HBeAg were also monitored every 4 weeks. Results. HBV-DNA was detected in 6 out of 35 patients. Anti-HBs titer was significantly lower in the patients in whom HBV-DNA was detected compared with the others at baseline: 2.83 (range 0.24-168.50) mIU/ml vs 99.94 (range 0.00-5342.98) mIU/ml, respectively (p = 0.036). Outcomes of the 6 patients with HBV reactivation were as follows: HBV-DNA turned negative in 2 patients without nucleic acid analog (NAA) and 1 with NAA; 2 died due to bacterial sepsis; and I died due to autoimmune hemolytic anemia. Significant elevation of aminotransferase was found in only 1 patient, but HBsAg converted to positive in 2 patients and HBeAg converted to positive in I patient. Conclusion. Reactivation of resolved HBV can occur during standard immunosuppressive therapy for autoimmune diseases. The low titer of baseline anti-HBs may carry its risk. (First Release Aug 15 2011; J Rheumatol 2011;38:2209-14; doi:10.3899/jrheum.110289)
• [Treatment of rheumatic diseases: current status and future prospective. Topics: II. Immunosuppressant/antirheumatic drugs: 9. Mycophenolate mofetil].

  Kono M, Atsumi T

  Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 100 10 2954 - 2959 10 2011年10月 [査読有り][通常論文]
  
• HLA-DRB5*01:05 Is a Risk Factor for Systemic Sclerosis with Interstitial Lung Disease

  Odani Toshio, Yasuda Shinsuke, Kubota Ayaka, Nakagawa Hisako, Fujieda Yuichiro, Otomo Kotaro, Kato Masaru, Horita Tetsuya, Atsumi Tatsuya, Koike Takao

  ARTHRITIS AND RHEUMATISM 63 10 S902 - S903 2011年10月 [査読有り][通常論文]
  
• Role of Apolipoprotein B100 and Oxidized Low-Density Lipoprotein in Anti-beta2 Glycoprotein I Induced Tissue Factor Expression on Monocytes

  Otomo Kotaro, Atsumi Tatsuya, Fujieda Yuichiro, Nakagawa Hisako, Kato Masaru, Amengual Olga, Horita Tetsuya, Yasuda Shinsuke, Matsumoto Masaki, Hatakeyama Shigetsugu, Koike Takao

  ARTHRITIS AND RHEUMATISM 63 10 S6  2011年10月 [査読有り][通常論文]
  
• Remission Induction by Etanercept (ETN) Plus Methotrexate (MTX) Combination Therapy Versus ETN Monotherapy in Patients with Active Rheumatoid Arthritis Despite MTX Treatment

  Kameda Hideto, Ueki Ukitaka, Saito Kazuyoshi, Nagaoka Shouhei, Hidaka Toshihiko, Atsumi Tatsuya, Tsukano Michishi, Kasama Tsuyoshi, Shiozawa Shunichi, Tanaka Yoshiya, Kanbe Katsuaki, Sato Eri, Yamanaka Hisashi, Takeuchi Tsutomu

  ARTHRITIS AND RHEUMATISM 63 10 S855 - S855 2011年10月 [査読有り][通常論文]
  
• The short-term role of corticosteroid therapy for pulmonary arterial hypertension associated with connective tissue diseases: Report of five cases and a literature review

  M. Kato, H. Kataoka, T. Odani, Y. Fujieda, K. Otomo, K. Oku, T. Horita, S. Yasuda, T. Atsumi, H. Ohira, I. Tsujino, M. Nishimura, T. Koike

  Lupus 20 1047 - 1056 2011年10月01日 [査読無し][通常論文]
   

  Pulmonary arterial hypertension (PAH) is a life-threatening complication in connective tissue diseases (CTD). It remains controversial whether immunosuppressive therapy is useful for PAH associated with CTD (PAH-CTD). The Dana Point algorithm does not refer such treatments in patients with PAH-CTD due to the lack of evidence. However, some case reports have shown the potential efficacy of immunosuppression for PAH-CTD. Here we report five cases of PAH-CTD treated with corticosteroids and discuss the current management of PAH-CTD with immunosuppressive agents. Our cases consisted of three active systemic lupus erythematosus (SLE), a quiescent SLE and an active polymyositis. WHO functional classes at baseline were class III in three cases and class II in two. Median follow-up period was 44 (28-92) weeks. PAH was diagnosed by right heart catheterization in all cases (median pulmonary arterial pressure was 45 (29-49) mmHg). All patients received 1 mg/kg of prednisolone (PSL) for 2-4 weeks, followed by appropriate dose reduction. Methylprednisolone pulse therapy was performed in patients resistant to the high dosage of PSL. Four patients received vasodilators in combination. The therapy as above improved WHO functional class 4 weeks after the initiation of PSL in all the patients. Two patients required dose increase or additional administration of vasodilators due to the dose reduction of PSL. Corticosteroid therapy may be effective for PAH-CTD at least in the short term, even in low general activity of CTD or moderate PAH. Our experience suggests that corticosteroid therapy, by itself or in conjunction with standard vasodilators, is effective for PAH-CTD patients. © The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav.
• Novel assays of thrombogenic pathogenicity in the antiphospholipid syndrome based on the detection of molecular oxidative modification of the major autoantigen β2-glycoprotein I.

  Ioannou Y, Zhang JY, Qi M, Gao L, Qi JC, Yu DM, Lau H, Sturgess AD, Vlachoyiannopoulos PG, Moutsopoulos HM, Rahman A, Pericleous C, Atsumi T, Koike T, Heritier S, Giannakopoulos B, Krilis SA

  Arthritis and rheumatism 63 9 2774 - 2782 9 2011年09月 [査読有り][通常論文]
   

  Objective. Beta-2-glycoprotein I (beta(2)GPI) constitutes the major autoantigen in the antiphospholipid syndrome (APS), a common acquired cause of arterial and venous thrombosis. We recently described the novel observation that beta(2)GPI may exist in healthy individuals in a free thiol (biochemically reduced) form. The present study was undertaken to quantify the levels of total, reduced, and posttranslationally modified oxidized beta(2)GPI in APS patients compared to various control groups. Methods. In a retrospective multicenter analysis, the proportion of beta(2)GPI with free thiols in serum from healthy volunteers was quantified. Assays for measurement of reduced as well as total circulating beta(2)GPI were developed and tested in the following groups: APS (with thrombosis) (n = 139), autoimmune disease with or without persistent antiphospholipid antibodies (aPL) but without APS (n = 188), vascular thrombosis without APS or aPL (n = 38), and healthy volunteers (n = 91). Results. Total beta(2)GPI was significantly elevated in patients with APS (median 216.2 mu g/ml [interquartile range 173.3-263.8]) as compared to healthy subjects (median 178.4 mu g/ml [interquartile range 149.4-227.5] [P < 0.0002]) or control patients with autoimmune disease or vascular thrombosis (both P < 0.0001). The proportion of total beta(2)GPI in an oxidized form (i.e., lacking free thiols) was significantly greater in the APS group than in each of the 3 control groups (all P < 0.0001). Conclusion. This large retrospective multicenter study shows that posttranslational modification of beta(2)GPI via thiol-exchange reactions is a highly specific phenomenon in the setting of APS thrombosis. Quantification of posttranslational modifications of beta(2)GPI in conjunction with standard laboratory tests for APS may offer the potential to more accurately predict the risk of occurrence of a thrombotic event in the setting of APS.
• Radiographic Prognosis of Finger Joint Damage Predicted by Early Alteration in Synovial Vascularity in Patients With Rheumatoid Arthritis: Potential Utility of Power Doppler Sonography in Clinical Practice

  Jun Fukae, Masato Isobe, Akemi Kitano, Mihoko Henmi, Fumihiko Sakamoto, Akihiro Narita, Takeya Ito, Akio Mitsuzaki, Masato Shimizu, Kazuhide Tanimura, Megumi Matsuhashi, Tamotsu Kamishima, Tatsuya Atsumi, Takao Koike

  ARTHRITIS CARE & RESEARCH 63 9 1247 - 1253 2011年09月 [査読有り][通常論文]
   

  Objective. To investigate the relationship between synovial vascularity and progression of structural bone damage in each finger joint in patients with rheumatoid arthritis (RA) and to demonstrate synovial vascularity as a potential therapeutic marker. Methods. We studied 250 metacarpophalangeal (MCP) and 250 proximal interphalangeal (PIP) joints of 25 patients with active RA who were administered adalimumab or tocilizumab. Patients were examined with clinical and laboratory assessments. Power Doppler sonography was performed at baseline and at the fourth and eighth weeks. Synovial vascularity was evaluated according to quantitative measurement. Hand and foot radiography was performed at baseline and the twentieth week. Results. Clinical indices such as the 28-joint Disease Activity Score, the Clinical Disease Activity Index, and the Simplified Disease Activity Index were significantly decreased by biologic agents. The MCP and PIP joints with no response in synovial vascularity between baseline and the eighth week (vascularity improvement of <= 70% at the eighth week) showed a higher risk of radiographic progression compared with responsive joints (vascularity improvement of >70% at the eighth week; relative risk 2.33-9). Radiographic progression at the twentieth week was significantly lower in responsive joints than in nonresponsive joints. Conclusion. The improvement of synovial vascularity following treatment with biologic agents led to suppression of radiographic progression of RA in each finger joint. The alteration in synovial vascularity numerically reflected therapeutic efficacy. Using vascularity as a marker to determine the most suitable therapeutic approach would be beneficial for patients with active RA.
• Pathophysiology of Thrombosis and Potential Targeted Therapies in Antiphospholipid Syndrome

  Olga Amengual, Tatsuya Atsumi, Takao Koike

  CURRENT VASCULAR PHARMACOLOGY 9 5 606 - 618 2011年09月 [査読有り][通常論文]
   

  The antiphospholipid syndrome (APS) is an autoimmune disease in which recurrent vascular thrombosis, pregnancy morbidity or a combination of these events is associated with the persistent presence of circulating antiphospholipid antibodies (aPL). Evidence shows that the dominant antigenic targets for aPL in APS are phospholipid-binding plasma proteins such as beta 2glycoprotein I and prothrombin. The pathogenic role of aPL in thrombosis is widely accepted but the mechanisms by which these antibodies mediate disease are only partially understood. aPL may affect the normal procoagulant and anticoagulant reactions occurring on cell surface, and also may interact with certain cells, altering the expression and secretion of procoagulant substances. The intracellular signal transduction triggered by aPL has been a focus of intensive research and the p38 mitogen activated protein kinase (MAPK) pathway has been revealed as a major player in the aPL-mediated cell activation. In addition, some candidates as cell-receptor for phospholipid-binding plasma proteins have been identified. The recognition of the intracellular signaling triggered by aPL is a step forward in the design of new modalities of targeted therapies for thrombosis in APS including specific inhibitors of MAPK pathway or antagonists of the putative receptors. Furthermore, novel findings regarding the role of aPL in T-cells responses mark new advances in the understanding of the immunological reactions in APS and open new insights into possible therapeutic approaches to APS. In this article, we review the pathophysiological mechanisms of thrombosis and the specific new targeted therapies for the treatment in APS.
• Radiographic prognosis of finger joint damage predicted by early alteration in synovial vascularity in patients with rheumatoid arthritis: Potential utility of power doppler sonography in clinical practice

  Jun Fukae, Masato Isobe, Akemi Kitano, Mihoko Henmi, Fumihiko Sakamoto, Akihiro Narita, Takeya Ito, Akio Mitsuzaki, Masato Shimizu, Kazuhide Tanimura, Megumi Matsuhashi, Tamotsu Kamishima, Tatsuya Atsumi, Takao Koike

  Arthritis Care and Research 63 9 1247 - 1253 2011年09月 [査読有り][通常論文]
   

  Objective To investigate the relationship between synovial vascularity and progression of structural bone damage in each finger joint in patients with rheumatoid arthritis (RA) and to demonstrate synovial vascularity as a potential therapeutic marker. Methods We studied 250 metacarpophalangeal (MCP) and 250 proximal interphalangeal (PIP) joints of 25 patients with active RA who were administered adalimumab or tocilizumab. Patients were examined with clinical and laboratory assessments. Power Doppler sonography was performed at baseline and at the fourth and eighth weeks. Synovial vascularity was evaluated according to quantitative measurement. Hand and foot radiography was performed at baseline and the twentieth week. Results Clinical indices such as the 28-joint Disease Activity Score, the Clinical Disease Activity Index, and the Simplified Disease Activity Index were significantly decreased by biologic agents. The MCP and PIP joints with no response in synovial vascularity between baseline and the eighth week (vascularity improvement of ≤70% at the eighth week) showed a higher risk of radiographic progression compared with responsive joints (vascularity improvement of > 70% at the eighth week relative risk 2.33-9). Radiographic progression at the twentieth week was significantly lower in responsive joints than in nonresponsive joints. Conclusion The improvement of synovial vascularity following treatment with biologic agents led to suppression of radiographic progression of RA in each finger joint. The alteration in synovial vascularity numerically reflected therapeutic efficacy. Using vascularity as a marker to determine the most suitable therapeutic approach would be beneficial for patients with active RA. Copyright © 2011 by the American College of Rheumatology.
• The REAL database reveals no significant risk of serious infection during treatment with a methotrexate dose of more than 8 mg/week in patients with rheumatoid arthritis.

  Sakai R, Komano Y, Tanaka M, Nanki T, Koike R, Nakajima A, Atsumi T, Yasuda S, Tanaka Y, Saito K, Tohma S, Fujii T, Ihata A, Tamura N, Kawakami A, Sugihara T, Ito S, Miyasaka N, Harigai M

  Modern rheumatology / the Japan Rheumatism Association 21 4 444 - 448 4 2011年08月 [査読有り][通常論文]
  
• Continuation of Methotrexate Resulted in Better Clinical and Radiographic Outcomes Than Discontinuation upon Starting Etanercept in Patients with Rheumatoid Arthritis: 52-week Results from the JESMR Study

  Hideto Kameda, Katsuaki Kanbe, Eri Sato, Yukitaka Ueki, Kazuyoshi Saito, Shouhei Nagaoka, Toshihiko Hidaka, Tatsuya Atsumi, Michishi Tsukano, Tsuyoshi Kasama, Shunichi Shiozawa, Yoshiya Tanaka, Hisashi Yamanaka, Tsutomu Takeuchi

  JOURNAL OF RHEUMATOLOGY 38 8 1585 - 1592 2011年08月 [査読有り][通常論文]
   

  Objective. The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA). Methods. In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 1112 twice a week with 6-8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score. Results. The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (-0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively). Conclusion. MTX should be continued when starting ETN in patients with active RA. (ClinicalTrials.gov: NCT00688103) (First Release May 15 2011; J Rheumatol 2011;38:1585-92; doi:10.3899/jrheum.110014)
• Incidence and Risk Factors for Serious Infection in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor Inhibitors: A Report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety

  Yukiko Komano, Michi Tanaka, Toshihiro Nanki, Ryuji Koike, Ryoko Sakai, Hideto Kameda, Atsuo Nakajima, Kazuyoshi Saito, Mitsuhiro Takeno, Tatsuya Atsumi, Shigeto Tohma, Satoshi Ito, Naoto Tamura, Takao Fujii, Tetsuji Sawada, Hiroaki Ida, Akira Hashiramoto, Takao Koike, Yoshiaki Ishigatsubo, Katsumi Eguchi, Yoshiya Tanaka, Tsutomu Takeuchi, Nobuyuki Miyasaka, Masayoshi Harigai

  JOURNAL OF RHEUMATOLOGY 38 7 1258 - 1264 2011年07月 [査読有り][通常論文]
   

  Objective. To compare tumor necrosis factor-alpha (TNF-alpha) inhibitors to nonbiological disease-modifying antirheumatic drugs (DMARD) for the risk of serious infection in Japanese patients with rheumatoid arthritis (RA). Methods. Serious infections occurring within the first year of the observation period were examined using the records for patients recruited to the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety (REAL), a hospital-based prospective cohort of patients with RA. The analysis included 1144 patients, 646 of whom were treated with either infliximab or etanercept [exposed group: 592.4 patient-years (PY)]. The remaining 498 patients received nonbiological DMARD with no biologics (unexposed group: 454.7 PY). Results. In the unexposed group, the incidence rate for all serious adverse events (SAE) was 9.02/100 PY and for serious infections, 2.64/100 PY. In the exposed group, SAE occurred in 16.04/100 PY and serious infections in 6.42/100 PY. The crude incidence rate ratio comparing serious infections in the exposed group with the unexposed group was 2.43 (95% Cl 1.27-4.65), a significant increase. A multivariate analysis revealed that the use of TNF inhibitors is a significant independent risk factor for serious infection (relative risk 2.37, 95% Cl 1.11-5.05, p = 0.026). Conclusion. Our study has provided the first epidemiological data on Japanese patients with RA for the safety of TNF inhibitors compared to nonbiological DMARD for up to 1 year of treatment. Anti-TNF therapy was associated with a significantly increased risk for serious infections, compared to treatment with nonbiological DMARD. (First Release April 15 2011; J Rheumatol 2011; 38:1258-64; doi:10.3899/jrheum.101009)
• Monitoring anti-interleukin 6 receptor antibody treatment for rheumatoid arthritis by quantitative magnetic resonance imaging of the hand and power Doppler ultrasonography of the finger

  Tamotsu Kamishima, Kazuhide Tanimura, Masato Shimizu, Megumi Matsuhashi, Jun Fukae, Yujiro Kon, Hiromi Hagiwara, Akihiro Narita, Yuko Aoki, Naoki Kosaka, Tatsuya Atsumi, Hiroki Shirato, Satoshi Terae

  SKELETAL RADIOLOGY 40 6 745 - 755 2011年06月 [査読有り][通常論文]
   

  To compare quantitative magnetic resonance imaging (MRI) and power Doppler ultrasonography (PDUS) with conventional measures of disease activity in rheumatoid arthritis (RA) patients treated with the anti-interleukin 6 (anti-IL 6) receptor antibody tocilizumab in terms of responsiveness at a few months to disease activity and ability to predict structural damage at 1 year. A cohort of patients with RA (n = 29) was evaluated clinically including disease activity score 28 (DAS28) and by semiquantitative (SQ-) and quantitative (Q-) PDUS (bilateral metacarpophalangeal joints) and MRI (one hand and wrist) at initiation of treatment with anti-IL 6 receptor antibody agents and after 2 and 5 months. Conventional radiography for both hands and wrists was performed at baseline and at 12 months. Responsiveness was assessed by standardized response means (SRM). Areas under the curve (AUC) for measures at baseline, 2 and 5 months were correlated with structural damage at 1 year. Among the laboratory and clinical parameters, DAS28-ESR was the most responsive with a large effect size of SRM. Structural damage progressions for radiography and MR erosion were correlated with AUC of MR bone erosion and Q-PDUS, respectively. In the evaluation of disease activity in RA patients in the first few months after starting anti-IL 6 receptor antibody tocilizumab treatment, the semiquantitative MR bone erosion score of the hand and quantitative value for power Doppler signal in the finger joint were both responsive and predictive of structural damage progression at 1 year.
• Clinical features of reversible posterior leukoencephalopathy syndrome in patients with systemic lupus erythematosus

  Yuichiro Fujieda, Hiroshi Kataoka, Toshio Odani, Kotaro Otomo, Masaru Kato, Shinji Fukaya, Kenji Oku, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi, Takao Koike

  MODERN RHEUMATOLOGY 21 3 276 - 281 2011年06月 [査読有り][通常論文]
   

  To characterize reversible posterior leukoencephalopathy syndrome (RPLS) in systemic lupus erythematosus (SLE) in terms of treatments for resolution and its clinical course, we reviewed 28 cases of RPLS in SLE including our cases in view of the treatment. Of these, 15 cases improved with blood pressure control and 13 required immunosuppressive therapy for activity of SLE presenting neurological manifestations. Patients without immunosuppressants at onset of RPLS more frequently required immunosuppressive therapy to recover it than those precedingly using these agents [31% (4/13) versus 87% (13/15), p = 0.008, chi-square test]. Brain magnetic resonance imaging (MRI) is important for diagnosis of RPLS-SLE in the patient with SLE who develops neurological disturbance and rapidly increasing blood pressure. When 7-day therapy for hypertension and convulsion does not reverse the manifestations, immunosuppressive treatments would be recommended to reverse RPLS.
• 'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010

  M. L. Bertolaccini, O. Amengual, T. Atsumi, W. L. Binder, B. de laat, R. Forastiero, W. H. Kutteh, M. Lambert, H. Matsubayashi, V. Murthy, M. Petri, J. H. Rand, M. Sanmarco, A. E. Tebo, S. S. Pierangeli

  LUPUS 20 2 191 - 205 2011年02月 [査読有り][通常論文]
   

  Current classification criteria for definite APS recommend the use of one or more of three positive standardized laboratory assays, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed to beta(2)glycoprotein I (anti-beta(2)GPI) to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity) of the syndrome. Several other autoantibodies shown to be directed to phospholipids and/or their complexes with phospholipids and/or to proteins of the coagulation cascade, as well as a mechanistic test for resistance to annexin A5 anticoagulant activity, have been proposed to be relevant to APS. A task force of worldwide scientists in the field discussed and analyzed critical questions related to 'non-criteria' aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13-16 April 2010, Galveston, Texas, USA). This report summarizes the findings, conclusions, and recommendations of this task force. Lupus (2011) 20, 191-205.
• Plasma gelsolin facilitates interaction between β2 glycoprotein I and α5β1 integrin.

  Bohgaki M, Matsumoto M, Atsumi T, Kondo T, Yasuda S, Horita T, Nakayama KI, Okumura F, Hatakeyama S, Koike T

  Journal of cellular and molecular medicine 15 1 141 - 151 1 2011年01月 [査読有り][通常論文]
   

  Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL) that directly recognizes plasma beta(2)-glycoprotein I (beta(2)GPI). Tissue factor (TF), the major initiator of the extrinsic coagulation system, is induced on monocytes by aPL in vitro, explaining in part the pathophysiology in APS. We previously reported that the mitogen-activated protein kinase (MAPK) pathway plays an important role in aPL-induced TF expression on monocytes. In this study, we identified plasma gelsolin as a protein associated with beta(2)GPI by using immunoaffinity chromatography and mass spectrometric analysis. An in vivo binding assay showed that endogenous beta(2)GPI interacts with plasma gelsolin, which binds to integrin a(5)beta(1) through fibronectin. The tethering of beta(2)GPI to monoclonal anti-beta(2)GPI autoantibody on the cell surface was enhanced in the presence of plasma gelsolin. Immunoblot analysis demonstrated that p38 MAPK protein was phosphorylated by monoclonal anti-beta(2)GPI antibody treatment, and its phosphorylation was attenuated in the presence of anti-integrin a(5)beta(1) antibody. Furthermore, focal adhesion kinase, a downstream molecule of the fibronectin-integrin signalling pathway, was phosphorylated by anti-beta(2)GPI antibody treatment. These results indicate that molecules including gelsolin and integrin are involved in the anti-beta(2)GPI antibody-induced MAPK pathway on monocytes and that integrin is a possible therapeutic target to modify a prothrombotic state in patients with APS.
• Aberrant splicing of the hRasGRP4 transcript and decreased levels of this signaling protein in the peripheral blood mononuclear cells in a subset of patients with rheumatoid arthritis

  Toko Hashimoto, Shinsuke Yasuda, Hideyuki Koide, Hiroshi Kataoka, Tetsuya Horita, Tatsuya Atsumi, Takao Koike

  ARTHRITIS RESEARCH & THERAPY 13 5 R154  2011年 [査読有り][通常論文]
   

  Introduction: An unidentified population of peripheral blood mononuclear cells (PBMCs) express Ras guanine nucleotide releasing protein 4 (RasGRP4). The aim of our study was to identify the cells in human blood that express hRasGRP4, and then to determine if hRasGRP4 was altered in any patient with rheumatoid arthritis (RA). Methods: Monocytes and T cells were purified from PBMCs of normal individuals, and were evaluated for their expression of RasGRP4 mRNA/protein. The levels of RasGRP4 transcripts were evaluated in the PBMCs from healthy volunteers and RA patients by real-time quantitative PCR. The nucleotide sequences of RasGRP4 cDNAs were also determined. RasGRP4 protein expression in PBMCs/monocytes was evaluated. Recombinant hRasGRP4 was expressed in mammalian cells. Results: Circulating CD14(+) cells in normal individuals were found to express hRasGRP4. The levels of the hRasGRP4 transcript were significantly higher in the PBMCs of our RA patients relative to healthy individuals. Sequence analysis of hRasGRP4 cDNAs from these PBMCs revealed 10 novel splice variants. Aberrantly spliced hRasGRP4 transcripts were more frequent in the RA patients than in normal individuals. The presence of one of these abnormal splice variants was linked to RA. The levels of hRasGRP4 protein in PBMCs tended to be lower. As expected, the defective transcripts led to altered and/or nonfunctional protein in terms of P44/42 mitogen-activated protein (MAP) kinase activation. Conclusions: The identification of defective isoforms of hRasGRP4 transcripts in the PBMCs of RA patients raises the possibility that dysregulated expression of hRasGRP4 in developing monocytes plays a pathogenic role in a subset of RA patients.
• Antiphospholipid Syndrome: Pathogenesis

  Tatsuya Atsumi, Olga Amengual, Takao Koike

  Systemic Lupus Erythematosus 945 - 965 2011年 [査読有り][通常論文]
   

  Antiphospholipid antibodies (aPLs) include a heterogeneous group of circulating immunoglobulins present in a wide range of infectious and autoimmune diseases. In particular, anticardiolipin antibodies (aCL) and lupus anticoagulants (LA) are associated with the antiphospholipid syndrome (APS). APS is recognized as a condition that is a frequent cause of acquired thrombophilia. They react with a complex of phospholipid and plasma proteins, including β2GPI, prothrombin, annexin V, high- and low-molecular-weight kininogen, protein S, and protein C, previously known as "cofactors." Because of their strong relationship with clinical symptoms, aPLs have been considered pathogenic antibodies. It is recognized that the inhibition of the natural anticoagulant systems, the impairment of fibrinolytic activity, and the direct effect of aPLs on cell functions are some of the mechanisms of aPL-mediated thrombosis. Studies on the pathogenicity of aPLs have been carried out mainly on the corresponding antigens, especially on the function of β2GPI and their modifications by the antibodies. Evidence suggests that complement activation is also required for aPL-mediated tissue injury, and findings have revealed that aPLs play a role in the T-cell responses. © 2011 Elsevier Inc. All rights reserved.
• 世界のリウマチガイドラインをみわたす ３）各国の治療ガイドライン ｢欧州各国の抗TNF薬使用のためのリコメンデーション｣.

  アメングアル オルガ

  分子リウマチ治療 4 4 16 - 20 2011年 [査読有り][通常論文]
  
• Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: a randomized trial

  Hideto Kameda, Yukitaka Ueki, Kazuyoshi Saito, Shouhei Nagaoka, Toshihiko Hidaka, Tatsuya Atsumi, Michishi Tsukano, Tsuyoshi Kasama, Shunichi Shiozawa, Yoshiya Tanaka, Tsutomu Takeuchi

  MODERN RHEUMATOLOGY 20 6 531 - 538 2010年12月 [査読有り][通常論文]
   

  The superiority of the combination therapy of methotrexate (MTX) and anti-tumor necrosis factor (TNF) biological agents over anti-TNF monotherapy in MTX-na < ve patients with rheumatoid arthritis (RA) has been demonstrated. We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept (ETN) in patients with active RA despite MTX therapy. In total, 151 patients with active RA despite treatment with MTX were randomized to either ETN 25 mg twice a week and MTX 6-8 mg/week (the E + M group) or ETN alone (the E group). Co-primary endpoints included the European League Against Rheumatism (EULAR) good response rate and the American College of Rheumatology (ACR) 50 response rate at week 24. Demographic and clinical features between groups at baseline were similar. The EULAR good response rates were significantly higher in the E + M group (52%) than in the E group (33%) at week 24 (p = 0.0001). Although the ACR50 response rate, one of the co-primary endpoints, and the ACR70 response rate at week 24 were not significantly greater in the E + M group (64 and 38%, respectively) than in the E group (48 and 26%, respectively), the ACR20 response rate was significantly greater in the E + M group (90%) than in the E group (64%; p = 0.0002). Safety profiles were similar for the groups. Thus, MTX should be continued at the commencement of ETN therapy, even in RA patients who show an inappropriate response to MTX.
• 全身性エリテマトーデス

  加藤 将, 渥美 達也, 小池 隆夫

  日本内科学会雑誌 99 10 2401 - 2406 The Japanese Society of Internal Medicine 2010年10月10日 

  全身性エリテマトーデスの治療は従来からステロイド薬による非特異的な治療が中心であったが，近年，免疫抑制薬や生物学的製剤を用い，効果的で副作用の少ない治療が試みられている．全身性エリテマトーデスの関節炎の特徴は「非破壊性関節炎」と表現され，関節リウマチの「破壊性関節炎」とは多くの点で対照的である．このような対照的な病態を理解することは関節炎全般の診療をより深いものにすると考えられる．
  
• Contrast-Enhanced Whole-Body Joint MRI in Patients With Unclassified Arthritis Who Develop Early Rheumatoid Arthritis Within 2 Years: Feasibility Study and Correlation With MRI Findings of the Hands

  Tamotsu Kamishima, Yuichiro Fujieda, Tatsuya Atsumi, Rie Mimura, Takao Koike, Satoshi Terae, Hiroki Shirato

  AMERICAN JOURNAL OF ROENTGENOLOGY 195 4 W287 - W292 2010年10月 [査読有り][通常論文]
   

  OBJECTIVE. The purpose of this article is to examine the feasibility of whole-body joint MRI for detecting systemic joint synovitis and for analyzing the relationship between the hands and systemic joint involvement in patients with unclassified arthritis who later develop early rheumatoid arthritis (RA). MATERIALS AND METHODS. The study included 17 patients (five men and 12 women; median age, 65 years [range, 38-77 years]; median symptom duration, 3 months [range, 1-6 months]). MRI of the systemic joints was performed for patients with unclassified arthritis without radiographic evidence of RA and who were diagnosed as having RA according to 1987 revised classification criteria within 2 years. RESULTS. The chosen 4-point scale for image quality was moderate to excellent. MRI findings of systemic joints were in accordance with joint swelling and tenderness (chi-square test, p < 0.0001). Sixty percent (45/75) of hand joints and 67% (12/18) of systemic joints other than hands showed MR synovitis without swelling. With regard to the correlation of MRI findings between hands and joints other than hands, there was a statistically significant positive correlation in the joint count (r = 0.5514 and p = 0.0218) and semiquantitative value of hand synovitis (r = 0.5382 and p = 0.0258). CONCLUSION. Whole-body joint MRI in early RA is feasible in terms of image quality and agreement with the results of clinical examination. MRI may be more sensitive for depicting synovitis-positive joints than clinical examination. Estimation of the systemic burden of synovitis detected by MRI may be possible via MRI of the hands.
• Increased Expression of Phospholipid Scramblase 1 in Monocytes from Patients with Systemic Lupus Erythematosus

  Eriko Suzuki, Olga Amengual, Tatsuya Atsumi, Kenji Oku, Toko Hashimoto, Hiroshi Kataoka, Tetsuya Horita, Shinsuke Yasuda, Masahiro Ieko, Kazuaki Fukushima, Takao Koike

  JOURNAL OF RHEUMATOLOGY 37 8 1639 - 1645 2010年08月 [査読有り][通常論文]
   

  Objective. A high incidence of thromboembolic events has been reported in patients with systemic lupus erythematosus (SLE). Phosphatidylserine (PS) is normally sequestered in the inner leaflet of cell membranes. Externalization of PS during cell activation is mediated by phospholipid scramblase 1 (PLSCR1) and has a central role in promoting blood coagulation. We investigated the underlying pathogenic status of thrombophilia in SLE by analyzing PLSCR1 expression on monocytes from patients with SLE. Methods. Sixty patients with SLE were evaluated. Twenty-three patients had antiphospholipid syndrome (APS/SLE). Plasma D-dimer levels were measured as a marker of fibrin turnover. The cDNA encoding human PLSCR1 was cloned from the total RNA extract from monocytes, and independent clones were sequenced. PLSCR1 mRNA expression in CD14+ cells was determined by real-time polymerase chain reaction. PS exposure on CD14+ cell surface was analyzed by flow cytometry. Results. Elevated D-dimer levels were found in plasma from SLE patients. Three splice variants of PLSCR1 mRNA were identified in all subjects, and levels of full-length PLSCR1 mRNA were significantly increased in SLE compared to healthy controls (2.9 +/- 1.5 vs 1.3 +/- 0.4, respectively; p < 0.0001). Flow-cytometry analysis showed relative enhancement of PS exposure in the surface of CD14+ cells in SLE patients compared to healthy controls. Conclusion. Novel PLSCR1 splice variants were identified. Monocytes in SLE patients had enhanced PLSCR1 mRNA expression, as well as increased fibrin turnover and cell-surface PS exposure, indicating that PLSCR1 may, in part, contribute to the prothrombotic tendency in SLE. (First Release June 1 2010; J Rheumatol 2010;37:1639-45; doi:10.3899/jrheum.091420)
• 関節リウマチ患者における肺病変の検討

  藤枝 雄一郎, 保田 晋助, 栗田 崇史, 小谷 俊雄, 加藤 将, 大友 耕太郎, 堀田 哲也, 渥美 達也, 南須原 康行, 小池 隆夫

  Inflammation and Regeneration 30 4 351 - 351 (一社)日本炎症・再生医学会 2010年07月
• Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus

  Keiko Myouzen, Yuta Kochi, Kenichi Shimane, Keishi Fujio, Tomohisa Okamura, Yukinori Okada, Akari Suzuki, Tatsuya Atsumi, Satoshi Ito, Kazuki Takada, Akio Mimori, Shiro Ikegawa, Ryo Yamada, Yusuke Nakamura, Kazuhiko Yamamoto

  HUMAN MOLECULAR GENETICS 19 11 2313 - 2320 2010年06月 [査読有り][通常論文]
   

  Systemic lupus erythematosus (SLE) is an autoimmune disease induced by the combinations of environmental and genetic factors. Recently, mice in which the early growth response 2 (EGR2) gene, a zinc-finger transcription factor, is conditionally knocked out in CD2(+) T cells have been shown to develop a lupus-like autoimmune disease. Here, we evaluated if polymorphisms in the EGR2 gene influence SLE susceptibility in humans. We first analyzed the effect of SNPs in the EGR2 region on EGR2 expression, and a significant positive correlation with expression was identified in an SNP located at the 5' flanking region of EGR2 (rs10761670, R=0.23, P=0.00072). We then performed a case-control association study using three sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region. A peak of association with SLE susceptibility was observed for rs10761670 [Pooled: OR = 1.23 (95% CI 1.10-1.37), P=0.00023). This SNP was also associated with susceptibility to rheumatoid arthritis (RA) [OR = 1.15 (95% CI 1.05-1.26), P = 0.0019), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670 (r(2) = 1.0), two SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.
• Increase in plasma thrombin-activatable fibrinolysis inhibitor may not contribute to thrombotic tendency in antiphospholipid syndrome because of inhibitory potential of antiphospholipid antibodies toward TAFI activation

  Masahiro Ieko, Mika Yoshida, Sumiyoshi Naito, Toru Nakabayashi, Kaoru Kanazawa, Kazuhiro Mizukami, Masaya Mukai, Tatsuya Atsumi, Takao Koike

  INTERNATIONAL JOURNAL OF HEMATOLOGY 91 5 776 - 783 2010年06月 [査読有り][通常論文]
   

  The causes of thrombosis in antiphospholipid syndrome (APS) remain unknown, though several hypotheses in regard to hypofibrinolysis have been proposed. To clarify the mechanism, we measured plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) in APS patients. Both the TAFI antigen (TAFI:Ag) level measured with an ELISA, and thrombin-thrombomodulin-dependent TAFI activity (TAFI:Ac) were elevated in 68 APS patients as compared with those in 66 healthy controls, though they were lower than those in 46 patients with autoimmune diseases. As for the influence of antiphospholipid antibodies (aPL) on TAFI levels, the mean TAFI:Ac level in 39 SLE patients positive for APS was significantly lower than that in 27 SLE patients without APS, whereas there was no difference in TAFI:Ag between those groups. Furthermore, purified IgG from patients positive for aPL, and monoclonal aPL (EY2C9 and 23-1D) inhibited the activation of TAFI in a concentration dependent manner. These results suggest that aPL inhibits TAFI activation by affecting the function of thrombomodulin-thrombin complex through phospholipids. Although TAFI in plasma is elevated in autoimmune diseases including APS, we concluded that an elevated level is not likely a risk factor for thrombosis in APS patients, because of the inhibition of TAFI activation by aPL.
• Change of Synovial Vascularity in a Single Finger Joint Assessed by Power Doppler Sonography Correlated With Radiographic Change in Rheumatoid Arthritis: Comparative Study of a Novel Quantitative Score With a Semiquantitative Score

  Jun Fukae, Yujiro Kon, Mihoko Henmi, Fumihiko Sakamoto, Akihiro Narita, Masato Shimizu, Kazuhide Tanimura, Megumi Matsuhashi, Tamotsu Kamishima, Tatsuya Atsumi, Takao Koike

  ARTHRITIS CARE & RESEARCH 62 5 657 - 663 2010年05月 [査読有り][通常論文]
   

  Objective. To investigate the relationship between synovial vascularity assessed by quantitative power Doppler sonography (PDS) and progression of structural bone damage in a single finger joint in patients with rheumatoid arthritis (RA). Methods. We studied 190 metacarpophalangeal (MCP) joints and 190 proximal interphalangeal (PIP) joints of 19 patients with active RA who had initial treatment with disease-modifying antirheumatic drugs (DMARDs). Patients were examined by clinical and laboratory assessments throughout the study. Hand and foot radiography was performed at baseline and the twentieth week. Magnetic resonance imaging (MRI) was performed at baseline. PDS was performed at baseline and the eighth week. Synovial vascularity was evaluated according to both quantitative and semiquantitative methods. Results. Quantitative PDS was significantly correlated with the enhancement rate of MRI in each single finger joint. Comparing quantitative synovial vascularity and radiographic change in single MCP or PIP joints, the level of vascularity at baseline showed a significant positive correlation with radiographic progression at the twentieth week. The change of vascularity in response to DMARDs, defined as the percentage change in vascularity by the eighth week from baseline, was inversely correlated with radiographic progression in each MCP joint. The quantitative PDS method was more useful than the semiquantitative method for the evaluation of synovial vascularity in a single finger joint. Conclusion. The change of synovial vascularity in a single finger joint determined by quantitative PDS could numerically predict its radiographic progression. Using vascularity as a guide to consider a therapeutic approach would have benefits for patients with active RA.
• Change of synovial vascularity in a single finger joint assessed by power doppler sonography correlated with radiographic change in rheumatoid arthritis: Comparative study of a novel quantitative score with a semiquantitative score

  Jun Fukae, Yujiro Kon, Mihoko Henmi, Fumihiko Sakamoto, Akihiro Narita, Masato Shimizu, Kazuhide Tanimura, Megumi Matsuhashi, Tamotsu Kamishima, Tatsuya Atsumi, Takao Koike

  Arthritis Care and Research 62 5 657 - 663 2010年05月 [査読有り][通常論文]
   

  Objective. To investigate the relationship between synovial vascularity assessed by quantitative power Doppler sonography (PDS) and progression of structural bone damage in a single finger joint in patients with rheumatoid arthritis (RA). Methods. We studied 190 metacarpophalangeal (MCP) joints and 190 proximal interphalangeal (PIP) joints of 19 patients with active RA who had initial treatment with disease-modifying antirheumatic drugs (DMARDs). Patients were examined by clinical and laboratory assessments throughout the study. Hand and foot radiography was performed at baseline and the twentieth week. Magnetic resonance imaging (MRI) was performed at baseline. PDS was performed at baseline and the eighth week. Synovial vascularity was evaluated according to both quantitative and semiquantitative methods. Results. Quantitative PDS was significantly correlated with the enhancement rate of MRI in each single finger joint. Comparing quantitative synovial vascularity and radiographic change in single MCP or PIP joints, the level of vascularity at baseline showed a significant positive correlation with radiographic progression at the twentieth week. The change of vascularity in response to DMARDs, defined as the percentage change in vascularity by the eighth week from baseline, was inversely correlated with radiographic progression in each MCP joint. The quantitative PDS method was more useful than the semiquantitative method for the evaluation of synovial vascularity in a single finger joint. Conclusion. The change of synovial vascularity in a single finger joint determined by quantitative PDS could numerically predict its radiographic progression. Using vascularity as a guide to consider a therapeutic approach would have benefits for patients with active RA. © 2010, American College of Rheumatology.
• Nicked β2 Glycoprotein Iの血管新生に与える影響

  中川 久子, 保田 晋助, 松浦 栄次, 小林 和子, 家子 正裕, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本臨床分子医学会学術総会プログラム・抄録集 47回 52 - 52 日本臨床分子医学会 2010年04月
• ニックβ2-糖蛋白質Iはアンギオスタチン4.5と結合しその血管新生阻害を減弱化する(Nicked β2-glycoprotein I binds angiostatin 4.5 and attenuates its anti-angiogenic property)

  中川 久子, 保田 晋助, 松浦 栄次, 小林 和子, 家子 正裕, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本血栓止血学会誌 21 2 92 - 92 2010年04月
• Angiostatin 4.5を介したNicked β2GlycoproteinIの血管新生に与える影響

  中川 久子, 保田 晋助, 松浦 栄次, 小林 和子, 家子 正裕, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本血栓止血学会誌 21 2 234 - 234 (一社)日本血栓止血学会 2010年04月
• RAの病因・病態 関節リウマチ患者におけるRas guanyl nucleotide-releasing protein 4(RasGRP4)発現

  橋本 陶子, 保田 晋助, 片岡 浩, 堀田 哲也, 渥美 達也, 眞島 任史, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 534 - 534 (一社)日本リウマチ学会 2010年03月
• 血管炎・APS 「抗リン脂質抗体スコア(aPL-S)」と血栓症発症リスクの検討

  大友 耕太郎, 渥美 達也, 藤枝 雄一郎, 加藤 将, 奥 健志, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 546 - 546 (一社)日本リウマチ学会 2010年03月
• 血管炎・APS CD36遺伝子多型と抗リン脂質抗体症候群との関連

  加藤 将, 堀田 哲也, 渥美 達也, 藤枝 雄一郎, 大友 耕太郎, 奥 健志, 片岡 浩, 保田 晋助, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 547 - 547 (一社)日本リウマチ学会 2010年03月
• 肺病変 高分解能CTにおいて間質性肺病変が認められた膠原病患者99例の検討

  栗田 崇史, 保田 晋助, 小谷 俊雄, 藤枝 雄一郎, 大友 耕太郎, 加藤 将, 奥 健志, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 572 - 572 (一社)日本リウマチ学会 2010年03月
• MCTD・強皮症 強皮症患者の間質性肺病変に対する自家末梢血幹細胞移植(aPBSCT)の有効性

  小谷 俊雄, 保田 晋助, 藤枝 雄一郎, 奥 健志, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 578 - 578 (一社)日本リウマチ学会 2010年03月
• シェーグレン症候群患者における全身性エリテマトーデスの疾患感受性遺伝子の解析

  中川 久子, 堀田 哲也, 中川 靖子, 片岡 浩, 奥 健志, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 635 - 635 (一社)日本リウマチ学会 2010年03月
• 口腔乾燥患者の唾液腺病変評価におけるMRシアログラフィーの有用性

  片岡 浩, 中川 靖子, 奥 健志, 保田 晋助, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 708 - 708 (一社)日本リウマチ学会 2010年03月
• The Association of a Nonsynonymous Single-Nucleotide Polymorphism in TNFAIP3 With Systemic Lupus Erythematosus and Rheumatoid Arthritis in the Japanese Population

  Kenichi Shimane, Yuta Kochi, Tetsuya Horita, Katsunori Ikari, Hirofumi Amano, Michito Hirakata, Akiko Okamoto, Ryo Yamada, Keiko Myouzen, Akari Suzuki, Michiaki Kubo, Tatsuya Atsumi, Takao Koike, Yoshinari Takasaki, Shigeki Momohara, Hisashi Yamanaka, Yusuke Nakamura, Kazuhiko Yamamoto

  ARTHRITIS AND RHEUMATISM 62 2 574 - 579 2010年02月 [査読有り][通常論文]
   

  Objective. Genome-wide association (GWA) studies in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Caucasian populations have independently identified risk variants in and near the tumor necrosis factor alpha (TNF alpha)-induced protein 3 gene (TNFAIP3), which is crucial for the regulation of TNF-mediated signaling and Toll-like receptor signaling. The aim of this study was to assess the role of TNFAIP3 in the development of SLE and RA in Japanese subjects. Methods. We selected 2 single-nucleotide polymorphisms (SNPs) from previous GWA studies. Rs2230926 is a nonsynonymous SNP in TNFAIP3 and is associated with SLE, while rs10499194 is an intergenic SNP associated with RA. We then performed 2 independent sets of SLE case-control comparisons (717 patients and 1,362 control subjects) and 3 sets of RA case-control comparisons (3,446 patients and 2,344 control subjects) using Japanese subjects. We genotyped SNPs using TaqMan assays. Results. We observed a significant association between rs2230926 and an increased risk of SLE and RA in the Japanese population (for SLE, odds ratio [OR] 1.92, 95% confidence interval [95% CI] 1.53-2.41, P = 1.9 x 10(-8); for RA, OR 1.35, 95% CI 1.18-1.56, P = 2.6 x 10(-5)). The intergenic SNP rs10499194 was also associated with SLE and RA, while the risk allele for RA in Caucasians was protective against the diseases in our population. Conclusion. We demonstrated a significant association between the nonsynonymous variant in TNFAIP3 and the risk for SLE and RA in the Japanese population. TNFAIP3, similar to STAT4 and IRF5, may be a common genetic risk factor for SLE and RA that is shared between the Caucasian and Japanese populations.
• Anti-beta 2 glycoprotein-I antibody increases the risk of pregnancy-induced hypertension: a case-controlled study

  Hideto Yamada, Tatsuya Atsumi, Olga Amengual, Takao Koike, Itsuko Furuta, Kaori Ohta, Gen Kobashi

  JOURNAL OF REPRODUCTIVE IMMUNOLOGY 84 1 95 - 99 2010年01月 [査読有り][通常論文]
   

  The aim of this study was to evaluate whether anti-beta 2 glycoprotein-I antibody (anti-beta 2GPI) of the IgG or IgM classes is associated with the development of pregnancy-induced hypertension (PIH) or preeclampsia in the Japanese population. In a case-controlled cohort study, peripheral blood was obtained at 8-14 weeks of gestation from a consecutive series of 1155 women. The case group comprised 36 patients who later developed PIH during the pregnancy. Of the 36 PIH patients, 13 had severe PIH, 18 had preeclampsia and 11 had severe preeclampsia. One hundred and eleven age- and parity-matched women whose pregnancies ended in normal delivery without obstetric complications were selected as controls. We found that a titer of anti-beta 2GPI IgG >= 1.0 U/ml was a risk factor for severe PIH (P = 0.023, OR 5.7 95%CI 1.4-22.8). In addition, titers of anti-beta 2GPI IgM >= 1.2 U/ml was found to be a risk factor for PIH (P = 0.001, OR 8.8 95%CI 1.6-47.5). In women positive for anti-beta 2GPI but negative for lupus anticoagulant, anti-cardiolipin, phosphatidylserine-dependent anti-prothrombin, or kininogen-dependent anti-phosphatidylethanolamine antibodies, the presence of anti-beta 2GPI was not a significant risk factor for development of PIH or preeclampsia. In conclusion, the presence of anti-beta 2GPI antibody represents a risk factor for developing PIH and severe PIH. This finding Supports the utility of anti-beta 2GPI determination as one of the laboratory criteria for anti-phospholipid syndrome classification. The usefulness of anti-beta 2GPI measurement among women without other anti-phospholipid antibodies requires further study. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
• Intravenous immunoglobulin therapy for aspirin-heparinoid-resistant antiphospholipid syndrome

  Shigeki Shimada, Hideto Yamada, Tatsuya Atsumi, Takashi Yamada, Noriaki Sakuragi, Hisanori Minakami

  Reproductive Medicine and Biology 9 4 217 - 221 2010年 [査読有り][通常論文]
   

  We encountered a woman who had a history of repeated fetal losses and positive tests for lupus anticoagulant, phosphatidylserine-dependent antiprothrombin (aPS/PT) IgG, IgM and kininogen-dependent antiphosphatidylethanolamine (aPE) IgG, IgM. Her previous pregnancy had ended in intrauterine fetal death at 24 weeks of gestation despite a therapy of low-dose aspirin, prednisolone and danaparoid. During the present pregnancy, she was treated with repeated intravenous infusions of immunoglobulin (IVIg) together with low-dose aspirin, prednisolone and heparin. When thrombocytopenia developed, she delivered a female baby weighing 2,152 g at 34 weeks of gestation by cesarean section. Titers of aPS/PT IgM and aPE IgM were reduced or maintained at low levels by repeated IVIg therapies. The IVIg therapy might be effective for aspirin-heparinoid-resistant antiphospholipid syndrome. © 2010 Japan Society for Reproductive Medicine.
• 造影超音波による関節リウマチの活動性評価

  神島 保, 西田 睦, 渥美 達也

  IVR: Interventional Radiology 25 1 109 - 109 (一社)日本インターベンショナルラジオロジー学会 2010年01月
• Cigarette Smoking, STAT4 and TNFRSF1B Polymorphisms, and Systemic Lupus Erythematosus in a Japanese Population

  Chikako Kiyohara, Masakazu Washio, Takahiko Horiuchi, Yoshifumi Tada, Toyoko Asami, Saburo Ide, Tatsuya Atsumi, Gen Kobashi, Hiroki Takahashi

  JOURNAL OF RHEUMATOLOGY 36 10 2195 - 2203 2009年10月 [査読有り][通常論文]
   

  Objective. Recent studies have identified signal transducer and activator of transcription 4 (STAT4) as a Susceptibility gene for systemic lupus erythematosus (SLE) in different populations. Similarly, tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B) has been reported to be associated with SLE risk in Japanese populations. Along with environmental factors Such as smoking, both polymorphisms may modulate an individual's susceptibility to SLE. We investigated these relationships in it case-control study to evaluate risk factors for SLE among Japanese women. Methods. We investigated the relationship of the STAT4 rs7574865 and TNFRSF1B rs1061622 polymorphisms to SLE risk with special reference to their combination and interaction with cigarette smoking among 152 SLE cases and 427 controls. Results. The TT genotype of STAT4 rs7574865 was significantly associated with increased risk of SLE (OR 2.21, 95% CI 1.10-4.68). Subjects with at least one G allele of TNFRSF1B rs 1061622 had an increased risk of SLE (OR 1.56 95% CI 0.99-2.47). The attributable proportion due to the interaction between the TNFRSF1B rs 1061622 genotypes and smoking was estimated to be 0.49 (95% CI 0.07-0.92), indicating that 49% of the excess risk for SLE in smokers with at least one G allele was due to an additive interaction. A lack of significant associations of STAT4 with smoking was observed. No significant gene-gene interactions were found among polymorphisms of STAT4 and TNFRSF1B. Conclusion. Our findings suggest that the association between cigarette smoking and SLE could be differentiated by the TNFRSF1B rs 1061622 T allele among female Japanese subjects. This preliminary exploratory result should be confirmed in it larger study. (First Release August 15 2009: J Rheumatol 2009;36:2195-203; doi: 10.3899/jrheum.090181)
• [Management of antiphospholipid syndrome].

  Atsumi T

  [Rinsho ketsueki] The Japanese journal of clinical hematology 50 10 1427 - 1433 10 2009年10月 [査読有り][通常論文]
  
• 全身性エリテマトーデスおよび抗リン脂質抗体症候群患者におけるTNFSF4多型の解析

  中川 久子, 堀田 哲也, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本臨床免疫学会会誌 32 5 410 - 410 (一社)日本臨床免疫学会 2009年10月
• Nicked beta 2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property

  Hisako Nakagawa, Shinsuke Yasuda, Eiji Matsuura, Kazuko Kobayashi, Masahiro Ieko, Hiroshi Kataoka, Tetsuya Horita, Tatsuya Atsumi, Takao Koike

  BLOOD 114 12 2553 - 2559 2009年09月 [査読有り][通常論文]
   

  Angiostatin was first discovered as a plasminogen fragment with antitumor/antiangiogenic property. One of the angiostatin isoforms, that is, angiostatin 4.5 (AS4.5), consisting of plasminogen kringle 1 to 4 and a most part of kringle 5, is produced by autoproteolysis and present in human plasma. beta 2-glycoprotein I (beta 2GPI) is proteolytically cleaved by plasmin in its domain V (nicked beta 2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked beta 2GPI as well as in intact beta 2GPI at higher concentrations. In the present study, we found significant binding of nicked beta 2GPI to AS4.5 (K(D) = 3.27 x 10(6) M(-1)). Via this binding, nicked beta 2GPI attenuates the antiangiogenic functions of AS4.5 in the proliferation of arterial/venous endothelial cells, in the extracellular matrix invasion and the tube formation of venous endothelial cells, and in vivo angiogenesis. In contrast, intact beta 2GPI does not bind to AS4.5 or inhibit its antiangiogenic activity. Thus, nicked beta 2GPI exerts dual effects on angiogenesis, that is, nicked beta 2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked beta 2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked beta 2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus. (Blood. 2009; 114: 2553-2559)
• Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis

  Ryuji Koike, Masayoshi Harigai, Tatsuya Atsumi, Koichi Amano, Shinichi Kawai, Kazuyoshi Saito, Tomoyuki Saito, Masahiro Yamamura, Tsukasa Matsubara, Nobuyuki Miyasaka

  MODERN RHEUMATOLOGY 19 4 351 - 357 2009年08月 [査読有り][通常論文]
   

  The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance.
• The Effects of Phosphatidylserine-Dependent Antiprothrombin Antibody on Thrombin Generation

  Yoshie Sakai, Tatsuya Atsumi, Masahiro Ieko, Olga Amengual, Shin Furukawa, Akira Furusaki, Miyuki Bohgaki, Hiroshi Kataoka, Tetsuya Horita, Shinsuke Yasuda, Takao Koike

  ARTHRITIS AND RHEUMATISM 60 8 2457 - 2467 2009年08月 [査読有り][通常論文]
   

  Objective. Antibodies to prothrombin (APTs) and to beta(2)-glycoprotein I are the major autoantibodies responsible for lupus anticoagulant (LAC) activity. APTs comprise antibodies against prothrombin alone as well as antibodies against phosphatidylserine/prothrombin complex (anti-PS/PT), the latter being highly associated with the anti phospholipid syndrome (APS). The effect of anti-PS/PT on thrombin generation has not been elucidated, and the paradoxical effect of LAC (an anticoagulant in vitro, but a procoagulant in vivo) remains an enigma. The purpose of this study was to investigate the effects of anti-PS/PT on thrombin generation and to examine the LAC paradox. Methods. We evaluated 36 anti-PS/PT-positive APS patients and 127 healthy subjects. Markers of in vivo thrombin/fibrin generation, including prothrombin fragment F(1+2), thrombin-antithrombin III complex, soluble fibrin monomer, D-dimer, and fibrin degradation products, were measured. Mouse monoclonal anti-PS/PT antibody 231D was established, and its effects on in vitro thrombin generation were investigated by chromogenic assay. Results. Significantly elevated levels of markers thrombin/fibrin generation were observed in anti-PS/PT-positive patients, regardless of the presence or absence of anticardiolipin antibodies, as compared with healthy subjects. In the presence of low concentrations of human activated factor V (FVa), monoclonal antibody 231D increased thrombin generation in a dose-dependent manner. In contrast, when high concentrations of FVa were added, monoclonal antibody 231D decreased thrombin generation. Under a constant concentration of FVa a high concentration of human FXa enhanced the effect of 231D. Conclusion. The presence of anti-PS/PT greatly correlated with increased thrombin generation in APS patients. The in vitro effects of monoclonal antibody 231D on thrombin generation are "biaxial" according to the FVa/FXa balance. These data may serve as a clue to understanding the LAC paradox and the thrombogenic properties of anti-PS/PT.
• STAT4 single nucleotide polymorphism, rs7574865 G/T, as a risk for antiphospholipid syndrome.

  Horita T, Atsumi T, Yoshida N, Nakagawa H, Kataoka H, Yasuda S, Koike T

  Annals of the rheumatic diseases 68 8 1366 - 1367 8 2009年08月 [査読有り][通常論文]
  
• Immunological Reconstitution after Autologous Hematopoietic Stem Cell Transplantation in Patients with Systemic Sclerosis: Relationship Between Clinical Benefits and Intensity of Immunosuppression

  Toshiyuki Bohgaki, Tatsuya Atsumi, Miyuki Bohgaki, Akira Furusaki, Makoto Kondo, Kazuko C. Sato-Matsumura, Riichiro Abe, Hiroshi Kataoka, Tetsuya Horita, Shinsuke Yasuda, Yoshiharu Amasaki, Mitsufumi Nishio, Ken-Ichi Sawada, Hiroshi Shimizu, Takao Koike

  JOURNAL OF RHEUMATOLOGY 36 6 1240 - 1248 2009年06月 [査読有り][通常論文]
   

  Objective. To analyze the relationship between clinical benefits and immunological changes in patients with systemic sclerosis (SSc) treated with autologous hematopoietic stern cell transplantation (HSCT). Methods. Ten patients with SSc were treated with high-dose cyclophosphamide followed by highly purified CD34+ cells (n = 5) or unpurified grafts (n = 5). Two groups of patients were retrospectively constituted based on their clinical response (good responders, 11 = 7; and poor responders, n = 3). As well as clinical findings, immunological reconstitution through autologous HSCT was assessed by fluorescence-activated cell sorter analysis, quantification of signal joint T cell receptor rearrangement excision circles (sjTREC), reflecting the thymic function, and foxp3 a key gene of regulatory T cells, mRNA levels. Results. Patients' clinical and immunological findings were similar between good and poor responders, or CD34-purified and Unpurified groups at inclusion. The sjTREC values were significantly suppressed at 3 months after autologous HSCT in good responders compared with poor responders (p = 0.0152). Reconstitution of CD4+CD45RO- naive T cells was delayed in good responders compared with poor responders. The phenotype of other lymphocytes, cytokine production in T cells, and foxp3 gene expression levels after autologous HSCT did not correlate with clinical response in good or poor responders. Clinical and immunological findings after autologous HSCT were similar between CD34-purified and Unpurified groups. Conclusion. Our results suggest that immunosuppression intensity, sufficient to induce transient suppression of thymic function, is attributable to the feasible clinical response in patients with SSc treated with autologous HSCT Appropriate monitoring of sjTREC values may predict clinical benefits in transplanted SSc patients after autologous HSCT. (First Release May 15 2009; J Rheumatol 2009;36:1240-8; doi: 10.3899/jrheum.081025)
• Complement activation in patients with primary antiphospholipid syndrome.

  Oku K, Atsumi T, Bohgaki M, Amengual O, Kataoka H, Horita T, Yasuda S, Koike T

  Annals of the rheumatic diseases 68 1030 - 1035 6 2009年06月 [査読有り][通常論文]
  
• ホスファチジルセリン依存性抗プロトロンビン抗体による向血栓細胞における組織因子発現機序

  奥 健志, 渥美 達也, Amengual Olga, 宮本 江里子, 藤枝 雄一郎, 大友 耕太郎, 加藤 将, 橋本 陶子, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本臨床分子医学会学術総会プログラム・抄録集 46回 77 - 77 日本臨床分子医学会 2009年04月
• 自己免疫疾患における血栓症発症リスクとしての「抗リン脂質抗体スコア【aPL-S】」の意義

  大友 耕太郎, 渥美 達也, 加藤 将, 奥 健志, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本血栓止血学会誌 20 2 229 - 229 (一社)日本血栓止血学会 2009年04月
• 原発性抗リン脂質抗体症候群における低補体血症の意義

  奥 健志, 渥美 達也, オルガ・アメングアル, 藤枝 雄一郎, 大友 耕太郎, 加藤 将, 橋本 陶子, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本血栓止血学会誌 20 2 230 - 230 (一社)日本血栓止血学会 2009年04月
• 抗リン脂質抗体症候群 「抗リン脂質抗体スコア(aPL-S)」と血栓発症リスクの検討

  大友 耕太郎, 渥美 達也, 加藤 将, 小谷 俊雄, 藤枝 雄一郎, 橋本 陶子, 深谷 進司, 奥 健志, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 198 - 198 (一社)日本リウマチ学会 2009年03月
• 抗リン脂質抗体症候群 Angiostatin 4.5(plasminogen Kringle 1-4.5)を介したnicked β2GPIの血管新生に与える影響

  中川 久子, 保田 晋助, 松浦 栄次, 小林 和子, 家子 正裕, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 199 - 199 (一社)日本リウマチ学会 2009年03月
• 抗リン脂質抗体症候群 抗リン脂質抗体症候群患者における全身性エリテマトーデスの疾患感受性遺伝子の多型解析

  堀田 哲也, 中川 久子, 藤枝 雄一郎, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 199 - 199 (一社)日本リウマチ学会 2009年03月
• 血管炎 当科における血管炎症候群に対するシクロホスファミドパルス間欠静注療法(IVCY)の検討

  大友 耕太郎, 堀田 哲也, 加藤 将, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 210 - 210 (一社)日本リウマチ学会 2009年03月
• SLEの病因・病態 全身性エリテマトーデスおよび抗リン脂質抗体症候群におけるBANK1とBLKの一塩基多型の関連

  中川 久子, 藤枝 雄一郎, 堀田 哲也, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 212 - 212 (一社)日本リウマチ学会 2009年03月
• 強皮症 強皮症患者の間質性肺病変に対する自家末梢血幹細胞移植(aPBSCT)の有効性

  小谷 俊雄, 保田 晋助, 吉田 修也, 藤枝 雄一郎, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 235 - 235 (一社)日本リウマチ学会 2009年03月
• 強皮症 強皮症患者の制御性T細胞における転写因子AML-1の発現低下

  片岡 浩, 保田 晋助, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 235 - 235 (一社)日本リウマチ学会 2009年03月
• リウマチ性疾患の検査 血小板由来マイクロパーティクルと膠原病

  加藤 将, 渥美 達也, 藤枝 雄一郎, 大友 耕太郎, 橋本 陶子, 奥 健志, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 273 - 273 (一社)日本リウマチ学会 2009年03月
• 関節リウマチ患者における肺病変の検討

  藤枝 雄一郎, 渥美 達也, 加藤 将, 大友 耕太郎, 橋本 陶子, 奥 健志, 古崎 章, 片岡 浩, 堀田 哲也, 保田 晋助, 南須原 康行, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 314 - 314 (一社)日本リウマチ学会 2009年03月
• 心筋線維化に伴う急速な心機能の低下により死亡した強皮症の一症例

  小谷 俊雄, 堀田 哲也, 橋本 陶子, 保田 晋助, 藤枝 雄一郎, 片岡 浩, 渥美 達也, 小池 隆夫, 田中 伸哉

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 383 - 383 (一社)日本リウマチ学会 2009年03月
• RA患者における手関節造影MRIを用いた炎症性滑膜定量による生物学的製剤の効果判定

  神島 保, 堀田 哲也, 大友 耕太郎, 藤枝 雄一郎, 片岡 浩, 保田 晋助, 加藤 将, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 397 - 397 (一社)日本リウマチ学会 2009年03月
• 膠原病診療におけるプロカルシトニン測定の意義

  加藤 将, 片岡 浩, 藤枝 雄一郎, 大友 耕太郎, 橋本 陶子, 奥 健志, 堀田 哲也, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 453 - 453 (一社)日本リウマチ学会 2009年03月
• 関節リウマチRA患者におけるRas guanyl nucleotide-releasing protein(RasGRP4)発現の検討

  橋本 陶子, 保田 晋助, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 475 - 475 (一社)日本リウマチ学会 2009年03月
• Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and adverse pregnancy outcomes

  Hideto Yamada, Tatsuya Atsumi, Gen Kobashi, Chikako Ota, Emi H. Kato, Noriko Tsuruga, Kaori Ohta, Shinsuke Yasuda, Takao Koike, Hisanori Minakami

  JOURNAL OF REPRODUCTIVE IMMUNOLOGY 79 2 188 - 195 2009年01月 [査読有り][通常論文]
   

  Antiphospholipid antibody (aPL) is associated with thromboembolism. There is scant evidence of a relationship between the aPL profile and serious adverse pregnancy outcome. The aim of this study was to assess whether aPL measurements during early pregnancy were useful in predicting a serious adverse pregnancy outcome. In this prospective study, we measured aPLs, including lupus anticoagulant (LA), IgG, IgM, IgA anticardiolipin antibody (aCL), IgG, IgM phosphatidylserine-dependent antiprothrombin antibody, and IgG kininogen-dependent antiphosphatidylethanolamine antibody (aPE) during the first trimester in a consecutive series of 1155 women. The 99th percentile cut-off values in each aPL were determined using samples from 105 women who did not exhibit any pregnancy morbidity. We assessed the predictive risk of a serious adverse pregnancy outcome adjusted for confounding factors. We found that IgG aCL was asssociated with developing pregnancy-induced hypertension (PIH) (odds ratio 11.4, 95% CI 2.7-48); IgG aPE with PIH (8.3, 2.4-29), severe PIH (20.4, 4.5-91), and premature delivery (PD) (12.7, 3.1-50); and LA with PD (11.0, 2.8-44) and low birth weight (8.0, 2.1-31). The combinations of IgG aPE plus IgG aCL (17.5, 4.7-66.7) or IgG aPE plus LA (22.2, 5.4-909) measurements predicted severe PIH with 30.8% sensitivity and 99.2% specificity. We conclude that aPL measurements during early pregnancy may be useful in predicting adverse pregnancy outcome. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
• Clinical features of haemophagocytic syndrome in patients with systemic autoimmune diseases: analysis of 30 cases.

  Fukaya S, Yasuda S, Hashimoto T, Oku K, Kataoka H, Horita T, Atsumi T, Koike T

  Rheumatology (Oxford, England) 47 1686 - 1691 11 2008年11月 [査読有り][通常論文]
  
• ホスファチジルセリン依存性抗プロトロンビン抗体による血管内皮細胞活性化

  奥 健志, 渥美 達也, 宮本 江里子, 大友 耕太郎, 加藤 将, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本血栓止血学会誌 19 5 720 - 720 (一社)日本血栓止血学会 2008年10月
• 抗リン脂質抗体症候群 : 20年の歩み

  小池 隆夫, 堀田 哲也, 保田 晋介, 渥美 達也

  日本内科学会雑誌 97 9 2009 - 2017 The Japanese Society of Internal Medicine 2008年09月10日
• STAT4 polymorphisms are associated with not only systemic lupus erythematosus, but also antiphospholipid syndrome

  Horita Tetsuya, Yoshida Nobuya, Nakagawa Hisako, Kataoka Hiroshi, Yasuda Shinsuke, Atsumi Tatsuya, Koike Takao

  ARTHRITIS AND RHEUMATISM 58 9 S175 - S176 2008年09月 [査読有り][通常論文]
  
• The phosphatidylserine-dependent monoclonal antiprothrombin antibody with lupus anticoagulant activity induces tissue factor and adhesion molecules expression on endothelial cells: Possible implication of p38 mitogen-activate protein kinase (MAPK) pathway

  Oku Kenji, Atsumi Tatsuya, Amengual Olga, Miyamoto Eriko, Otomo Kotaro, Kato Masaru, Kataoka Hiroshi, Horita Tetsuya, Yasuda Shinsuke, Koike Takao

  ARTHRITIS AND RHEUMATISM 58 9 S404 - S405 2008年09月 [査読有り][通常論文]
  
• Alternative splicing of RasGRP1 in lupus patients: Frequency, clinical features and cytokine production

  Yasuda Shinsuke, Stevens Richard L, Terada Tomoko, Hashimoto Toko, Kataoka Hiroshi, Horita Tetsuya, Atsumi Tatsuya, Koike Takao

  ARTHRITIS AND RHEUMATISM 58 9 S817 - S818 2008年09月 [査読有り][通常論文]
  
• The comparison of efficacy and safety between etanercept (ETN) plus methotrexate (MTX) combination therapy and ETN monotherapy in MTX-refractory Japanese patients with rheumatoid arthritis: 52-week clinical results from the JESMR study

  Kameda Hideto, Ueki Yukitaka, Saito Kazuyoshi, Nagaoka Shouhei, Hidaka Toshihiko, Atsumi Tatsuya, Tsukano Michishi, Kasama Tsuyoshi, Shiozawa Shunichi, Tanaka Yoshiya, Takeuchi Tsutomu

  ARTHRITIS AND RHEUMATISM 58 9 S531  2008年09月 [査読有り][通常論文]
  
• 免疫疾患におけるTh17とTregの役割 強皮症患者調節性T細胞における転写因子AML-1の発現低下

  片岡 浩, 堀田 哲也, 保田 晋助, 渥美 達也, 小池 隆夫

  日本臨床免疫学会会誌 31 4 276 - 276 (一社)日本臨床免疫学会 2008年08月
• 強皮症患者調節性T細胞における転写因子AML-1の発現低下

  片岡 浩, 堀田 哲也, 保田 晋助, 渥美 達也, 小池 隆夫

  日本臨床免疫学会会誌 31 4 296 - 296 (一社)日本臨床免疫学会 2008年08月
• 関節リウマチにおける肺合併症の検討

  藤枝 雄一郎, 渥美 達也, 古崎 章, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫, 南須原 康行, 小野寺 祐也

  日本臨床免疫学会会誌 31 4 309 - 309 (一社)日本臨床免疫学会 2008年08月
• 関節リウマチ患者の末梢血単核球におけるRas guanyl nucleotide-releasing protein(RasGRP4)発現異常の検討

  橋本 陶子, 保田 晋助, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本臨床免疫学会会誌 31 4 319 - 319 (一社)日本臨床免疫学会 2008年08月
• Antiprothrombin antibody testing: Detection and clinical utility

  Kenji Oku, Tatsuya Atsumi, Olga Amengual, Takao Koike

  SEMINARS IN THROMBOSIS AND HEMOSTASIS 34 4 335 - 339 2008年06月 [査読有り][通常論文]
   

  Anticardiolipin antibody (aCL), anti-beta 2 glycoprotein I antibodies, and lupus anticoagulant (LA) are the only laboratory tests considered within the revised criteria for the classification of the antiphospholipid syndrome (APS). Recently, antibodies against phosphatidylserine-prothrombin complex (aPS/PT) have been detected, and these antibodies, rather than antibodies against prothrombin alone, are closely associated with APS and LA. The sensitivity and specificity of aPS/PT for the diagnosis of APS were assessed in a population of patients with a variety of autoimmune disorders. aCL and aPS/PT have similar diagnostic value for APS, therefore aPS/PT should be further explored, not only for research purposes but also as a candidate for one of the laboratory criteria for the classification of the APS.
• 抗リン脂質抗体症候群の診断

  渥美 達也

  日本血栓止血学会誌 = The Journal of Japanese Society on Thrombosis and Hemostasis 19 3 329 - 332 The Japanese Society on Thrombosis and Hemostasis 2008年06月01日 

  Point
  （1）抗リン脂質抗体症候群は血栓症または妊娠合併症を臨床症状とする．
  （2）診断にはβ2-グリコプロテインI依存性抗カルジオリピン抗体あるいはループスアンチコアグラントの存在を証明することが必要．
  （3）抗β2-グリコプロテインI抗体，ホスファチジルセリン依存性抗プロトロンビン抗体も診断に有用な検査である．
  （4）抗リン脂質抗体症候群以外にも抗リン脂質抗体と関連する臨床症状があり，最近それらは抗リン脂質抗体関連疾患群として提唱された．
• 全身性エリテマトーデスの病態解明 SLE患者におけるRasGRP1発現の異常

  保田 晋助, Richard Stevens, 寺田 智子, 堀田 哲也, 片岡 浩, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 161 - 161 (一社)日本リウマチ学会 2008年04月
• 日本人全身性エリテマトーデス(SLE)および抗リン脂質抗体症候群(APS)患者におけるSTAT4の遺伝子多型の解析

  吉田 修也, 堀田 哲也, 中川 久子, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 240 - 240 (一社)日本リウマチ学会 2008年04月
• 全身性エリテマトーデスにおけるcomplement receptor 2の遺伝子多型の解析

  堀田 哲也, 中川 久子, 吉田 修也, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 240 - 240 (一社)日本リウマチ学会 2008年04月
• 抗リン脂質抗体症候群(APS)の診断における「抗リン脂質抗体スコア」の有用性

  大友 耕太郎, 渥美 達也, 加藤 将, 吉田 修也, 奥 健志, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 241 - 241 (一社)日本リウマチ学会 2008年04月
• Tyrosine Kinase 2およびInterferon Regulatory Factor5の一塩基多型と抗リン脂質抗体症候群の関連

  中川 久子, 堀田 哲也, 吉田 修也, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 241 - 241 (一社)日本リウマチ学会 2008年04月
• 血管炎症候群に対するシクロホスファミドパルス療法(IVCY)の有用性の検討(続報)

  大友 耕太郎, 堀田 哲也, 吉田 修也, 加藤 将, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 262 - 262 (一社)日本リウマチ学会 2008年04月
• 強皮症の病態生理におけるTregとnon-Tregとのバランス

  片岡 浩, 堀田 哲也, 保田 晋助, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 274 - 274 (一社)日本リウマチ学会 2008年04月
• 強皮症患者の間質性肺炎に対する自家末梢血幹細胞移植(aPBSCT)の効果に関する検討

  吉田 修也, 保田 晋助, 藤枝 雄一郎, 古崎 章, 近藤 真, 坊垣 暁之, 片岡 浩, 堀田 哲也, 西尾 充史, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 275 - 275 (一社)日本リウマチ学会 2008年04月
• 膠原病に合併した血球貪食症候群 30例の臨床像の解析

  深谷 進司, 保田 晋助, 藤枝 雄一郎, 笠原 郁美, 加藤 将, 大友 耕太郎, 吉田 修也, 橋本 陶子, 片岡 浩, 堀田 哲也, 渥美 達也, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 278 - 278 (一社)日本リウマチ学会 2008年04月
• 関節リウマチ患者における肺合併症の検討

  藤枝 雄一郎, 古崎 章, 堀田 哲也, 笠原 郁美, 吉田 修也, 加藤 将, 大友 耕太郎, 片岡 浩, 保田 晋助, 渥美 達也, 小池 隆夫, 南須原 康行

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 302 - 302 (一社)日本リウマチ学会 2008年04月
• 抗リン脂質抗体症候群(APS)患者単球におけるPhospholipid Scramblase1(PLSCR1)の発現

  宮本 江里子, 渥美 達也, オルガ・アメングアル, 奥 健志, 大友 耕太郎, 加藤 将, 片岡 浩, 堀田 哲也, 保田 晋助, 小池 隆夫

  日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 311 - 311 (一社)日本リウマチ学会 2008年04月
• 関節リウマチ患者におけるRas guanyl nucleotide-releasing protein(RasGRP4)発現異常の検討

  橋本 陶子, 保田 晋助, 寺田 智子, 片岡 浩, 堀田 哲也, 渥美 達也, Stevens Richard L., 小池 隆夫

  日本リウマチ学会総�