Researcher Database

Kenji Oku
Hokkaido University Hospital Internal Medicine

Researcher Profile and Settings


  • Hokkaido University Hospital Internal Medicine

Job Title

  • Lecturer

Research funding number

  • 70544295

J-Global ID

Research Activities

Published Papers

  • 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 0003-4967 2018/12 [Refereed][Not invited]
    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.
  • Oku K, Atsumi T
    Modern rheumatology 28 (5) 758 - 765 1439-7595 2018/09 [Refereed][Not invited]
  • 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 1478-6354 2018/04/17 [Refereed][Not invited]
    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.
  • 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 0049-3848 2018/04 [Refereed][Not invited]
    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.
  • 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 2151-464X 2018/04 [Refereed][Not invited]
    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.
  • 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 1439-7595 2018/01 [Refereed][Not invited]
  • Tanimura S, Fujieda Y, Kono M, Shibata Y, Hisada R, Sugawara E, Nakamura H, Ohmura K, Shimamura S, Mitani A, Shida H, Watanabe T, Kato M, Oku K, Bohgaki T, Amengual O, Yasuda S, Shimizu C, Atsumi T
    Modern rheumatology 28 (5) 1 - 7 1439-7595 2017/12 [Refereed][Not invited]
  • Oku K, Atsumi T, Akiyama Y, Amano H, Azuma N, Bohgaki T, Asanuma YF, Horita T, Hosoya T, Ichinose K, Kato M, Katsumata Y, Kawaguchi Y, Kawakami A, Koga T, Kohsaka H, Kondo Y, Kubo K, Kuwana M, Mimori A, Mimori T, Mimura T, Murakami K, Nakano K, Nakayamada S, Ogishima H, Ohmura K, Saito K, Sano H, Shibuya M, Takahashi Y, Takasaki Y, Takeuchi T, Tamura N, Tanaka Y, Tsuboi H, Tsunoda S, Yukawa N, Yamakawa N, Yamamoto K, Sumida T
    Modern rheumatology 28 (4) 1 - 7 1439-7595 2017/11 [Refereed][Not invited]
  • 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) 1 - 9 1439-7595 2017/11 [Refereed][Not invited]
  • 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 1439-7595 2017/10 [Refereed][Not invited]
  • 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  0025-7974 2017/10 [Refereed][Not invited]
    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.
  • Kenji Oku, Olga Amengual, Shinsuke Yasuda, Tatsuya Atsumi
    CURRENT RHEUMATOLOGY REPORTS 19 (8) 51  1523-3774 2017/08 [Refereed][Not invited]
    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.
  • Kenji Oku
    Japanese Journal of Clinical Immunology 40 (6) 435 - 441 1349-7413 2017 [Refereed][Not invited]
    Antiphospholipid syndrome (APS) is a clinical disorder characterized by thrombosis and/or pregnancy morbidity in the persistence of the pathogenic autoantibodies, the antiphospholipid antibodies (aPL). Recurernt thrombosis is often observed in patients with APS which requires persistent prophylaxis. However, an uniform prophylactic treatment for APS patients is inadequate and stratification of the thrombotic risks is important as aPL are prevalently observed in other various diseases or elderly population. It is previously known that the multiple positivity or high titre of aPL correlate to the thrombotic events. To progress the stratification of the thrombotic risks and to quantitatively analyze them, antiphospholipid score (aPL-S) and the Global Anti-Phospholipid Syndrome Score (GAPSS) were defined as the scoring-systems. Both of these scoring-systems 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) were put into scoring system. They 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 phosphatidylserine dependent antiprothrombin antibodies (aPS/PT).
  • 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 1439-7595 2017 [Refereed][Not invited]
    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.
  • 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 1439-7595 2017 [Refereed][Not invited]
    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.
  • Eri Sugawara, Masaru Kato, Ryo Hisada, Kenji Oku, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
    INTERNAL MEDICINE 56 (4) 445 - 448 0918-2918 2017 [Refereed][Not invited]
    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.
  • Ohe M, Shida H, Horita T, Ito K, Sugiura M, Hattori A, Oku K
    Drug discoveries & therapeutics 11 (4) 218 - 222 1881-7831 2017 [Refereed][Not invited]
  • Ohe M, Shida H, Horita T, Oku K
    Drug discoveries & therapeutics 11 (4) 223 - 225 1881-7831 2017 [Refereed][Not invited]
  • 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 1568-9972 2016/10 [Refereed][Not invited]
    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.
  • 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 0049-3848 2016/10 [Refereed][Not invited]
    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,/).
  • 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 1568-9972 2016/08 [Refereed][Not invited]
    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.
  • 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 1462-0324 2016/08 [Refereed][Not invited]
    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.
  • 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 1462-0324 2016/06 [Refereed][Not invited]
    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.
  • Takehiro Yamada, Nobuhisa Ishiguro, Kenji Oku, Issei Higuchi, Ikuma Nakagawa, Atsushi Noguchi, Shinsuke Yasuda, Tatsuya Fukumoto, Sumio Iwasaki, Kouji Akizawa, Ayako Furugen, Hiroaki Yamaguchi, Ken Iseki
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 38 (9) 1430 - 1433 0918-6158 2015/09 [Refereed][Not invited]
    A 56-year-old woman with systemic lupus erythematosus had bacteremia due to multidrug-resistant Pseudomonas aeruginosa (MDRP). She was initially treated with imipenem cilastatin, tobramycin, and aztreonam; however, MDRP was still detected intermittently in her plasma. Multidrug-susceptibility tests demonstrated that MDRP was susceptible only to colistin. Therefore, in addition to these antibiotics, the administration of intravenous colistin methanesulfonate, a prodrug formula of colistin, was started at a daily dose of 2.5 mg/kg (as colistin base activity). The initial dose setting was based on the patient's renal function (baseline creatinine clearance=32.7mL/min). After initiating colistin, the patient's C-reactive protein levels gradually decreased. Blood cultures showed no evidence of MDRP on days 8, 14, and 22 after colistin initiation. However, the patient's renal function went from bad to worse owing to septic shock induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. A few days later, the trough plasma levels of colistin were 7.88 mg/L, which appeared to be higher than expected. After decreasing the colistin dose, the patient's renal function gradually improved. On the final day of colistin treatment, the plasma levels decreased to 0.60 mg/L. MDRP could not be detected in blood culture after colistin treatment. Therefore, we successfully treated a case of bloodstream infection due to MDRP by therapeutic drug monitoring (TDM) of colistin. It is suggested that the monitoring of blood colistin levels by liquid chromatography-tandem mass spectrometry can contribute to safer, more effective antimicrobial therapy of MDRP because TDM facilitates quick decisions on dose adjustments.
  • 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 1462-0324 2015/08 [Refereed][Not invited]
  • 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 1439-7595 2015/03 [Refereed][Not invited]
    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.
  • 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 2326-5191 2015/02 [Refereed][Not invited]
    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.
  • Yuichiro Fujieda, Haruki Shida, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
    Japanese Journal of Clinical Immunology 37 (5) 430 - 436 1349-7413 2015/01/06 [Refereed][Not invited]
    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.
  • Hiroshi Kataoka, Shinsuke Yasuda, Shinji Fukaya, Kenji Oku, Tetsuya Horita, Tatsuya Atsumi, Takao Koike
    MODERN RHEUMATOLOGY 25 (1) 90 - 95 1439-7595 2015/01 [Refereed][Not invited]
    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.
  • 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 1462-0324 2015/01 [Refereed][Not invited]
    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.
  • 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 0911-4300 2015 [Refereed][Not invited]
  • 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 0911-4300 2015 [Refereed][Not invited]
  • 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 0172-8172 2014/09 [Refereed][Not invited]
    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.
  • [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 0047-1852 2014/07 [Refereed][Not invited]
  • Masashi Ohe, Kenji Oku, Michihito Kono, Toshiyuki Bohgaki
    KOREAN JOURNAL OF INTERNAL MEDICINE 29 (2) 259 - 261 1226-3303 2014/03 [Refereed][Not invited]
  • Olga Amengual, Tatsuya Atsumi, Kenji Oku, Eriko Suzuki, Tetsuya Horita, Shinsuke Yasuda, Takao Koike
    Modern Rheumatology 23 (1) 81 - 88 1439-7595 2013/01 [Refereed][Not invited]
    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.
  • Kenji Oku, Olga Amengual, Tatsuya Atsumi
    EUROPEAN JOURNAL OF CLINICAL INVESTIGATION 42 (10) 1126 - 1135 0014-2972 2012/10 [Refereed][Not invited]
    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.
  • 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 0004-3591 2012/02 [Refereed][Not invited]
    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.
  • 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 1439-7595 2011/06 [Refereed][Not invited]
    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.
  • 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 0315-162X 2010/08 [Refereed][Not invited]
    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)
  • Kenji Oku, Tatsuya Atsumi, Olga Amengual, Takao Koike
    SEMINARS IN THROMBOSIS AND HEMOSTASIS 34 (4) 335 - 339 0094-6176 2008/06 [Refereed][Not invited]
    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.
  • Takeuchi J, Tashiro J, Nakagaki O, Yoshida M, Kamoshima H, Oku K, Yoshioka N
    Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics 1 45 (1) 95 - 99 0300-9173 2008/01 [Refereed][Not invited]

Educational Activities

Teaching Experience

  • 医学総論
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Master's Thesis Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • Basic Principles of Medicine
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • Principles of Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • Dissertation Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology
  • Dissertation Research in Clinical Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 免疫、代謝・内分泌、腎 Rheumatology, Endocrinology, Nephrology

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