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Master

Affiliation (Master)

  • Faculty of Medicine　Internal Medicine　Internal Medicine

Affiliation (Master)

  • Faculty of Medicine　Internal Medicine　Internal Medicine

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Degree

  • MD, PhD

Profile and Settings

  • Name (Japanese)

    Amengual

  • Name (Kana)

    Olga

  • Name

    201301025266182930

通称等の別名

    Amengual Pliego Maria Olga

Alternate Names

Achievement

Research Interests

  • Rheumatoid arthritis   Antiphospholipid syndrome   Systemic lupus erythematosus   Nutrition, Diet   Antiphospholipid antibodies   anti beta 2glycoprotein I antibodies   Antiprothrombin antibodies   Phosphatidylserine dependent antiprothrombin antibodies   Thrombosis   Tissue factor   Gout   English Medical Education   International communication   Medical Education   

Research Areas

  • Life sciences / Allergies and connective tissue disease / Autoimmune diseases
  • Humanities & social sciences / Education - general / Medical Education
  • Life sciences / Nutrition and health science / Rheumatology, Autoimmunity and Nutrition

Research Experience

  • 2020/03 - Today Hokkaido University Department of Rheumatology, Endocrinology and Nephrology, Associate Professor/Lecturer MD, PhD
  • 2012/04 - 2020/02 Hokkaido University Department of Rheumatology, Endrocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo of Medicine Assistant Professor MD, PhD
  • 2009/04 - 2012/03 Hokkaido University, Graduate School of Medicine, Department of Medicine II RPD-Postdoctoral Fellowship (Japan Society for the promotion of the Science and Ministry of Education, Science, Culture, Sports and Technology)
  • 2005/09 - 2009/03 Post-doctoral Researcher, Hokkaido University, Graduate School of Medicine, Department of Medicine II
  • 2003/09 - 2005/08 Hokkaido University, Graduate School of Medicine, Department of Medicine II JSPS ( Japan Society for the promotion of the Science )Postdoctoral Fellowship
  • 2002/06 - 2003/08 Hokkaido University Graduate School of Medicine Post-doctoral researcher
  • 2002/01 - 2002/03 Hokkadio University Graduate School of Medicine, Medicine II Short-term postdoctoral fellowship
  • 1995 - 1997/06 Lupus Research Unit, St Thomas's Hospital, London UK (Grant panish Social Security Health Research Fund, FIS) Pre doctoral-Fellowship

Education

  • 2012/09 - 2012/11  Association for Medical Education in Europe  Essential Skills in Medical Education
  • 1995/09 - 1999/10  Autonomous University of Madrid, Spain  PhD Degree
  • 1991/01 - 1994/12  Hospital Ramon y Cajal, University of Alcalá of Henares, Madrid, Spain.  Department of Rheumatology  Training programme for medical interns (MIR) in the specialty of rheumatology.
  • 1983/09 - 1989/06  Autonomous University of Madrid, Spain  MD Degree

Committee Memberships

  • 2020/04 - Today   ASSOCIATION OF SPANISH RESEARCHERS IN JAPAN (ACE Japon)   Executive Vice-President
  • 2020/04 -2022/03   ASSOCIATION OF SPANISH RESEARCHERS IN JAPAN (ACE Japon)   Board or Director- Secretariat
  • 2013/04 -2013/09   Hokkaido University Hospital   Committee Member of the Working Group for the Promotion of the Internationalization

Awards

  • 2019/10 Support Office for Females Researchers Front office for Human Resource Education and Development Global Networking Award 2019
     Global Networking Award 2019 
    受賞者: Olga Amengual
  • 1999/05 Faculty of Medicine, Autonoma University, Madrid, Spain Award to the best PhD of the year
     Best PhD Award 
    受賞者: Olga Amengual

Published Papers

  • Maria Tada, Yuki Kudo, Michihito Kono, Masatoshi Kanda, Shuhei Takeyama, Kodai Sakiyama, Hotaka Ishizu, Tomohiro Shimizu, Tsutomu Endo, Ryo Hisada, Yuichiro Fujieda, Masaru Kato, Olga Amengual, Norimasa Iwasaki, Tatsuya Atsumi
    Clinical immunology (Orlando, Fla.) 264 110255 - 110255 2024/05/18 
    Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.
  • Haruka Moriya, Masaru Kato, Ryo Hisada, Keita Ninagawa, Maria Tada, Kodai Sakiyama, Mitsutaka Yasuda, Michihito Kono, Yuichiro Fujieda, Olga Amengual, Yasuka Kikuchi, Ichizo Tsujino, Takahiro Sato, Tatsuya Atsumi
    Rheumatology (Oxford, England) 2023/09/15 
    OBJECTIVE: Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relation between clinical signs of PVOD and severing of pulmonary vasculopathy in SSc. METHODS: This study comprised 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities (mPAP > 20 mmHg, PVR > 2 W.U. or PAWP > 15 mmHg). The chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0-1 group and the 2-3 group, according to the number of chest CT signs for PVOD, including 1) mediastinal lymph node enlargement, 2) thickened interlobular septal wall, and 3) ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function, and serum biomarkers were compared between the two groups. RESULTS: Mediastinal lymph node enlargement, thickened interlobular septal wall, and ground glass opacity were observed in 11 (21%), 32 (62%), and 11 (21%) patients, respectively. The 2-3 group (n = 15) had higher mPAP (p= 0.02) while lower DLco/VA (p= 0.02) compared with the 0-1 group (n = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide, and Krebs von den Lunge-6 were not different between the two groups. CONCLUSION: The CT signs for PVOD had positive correlation with mPAP but negative correlation with DLco in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein.
  • 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 1462-0324 2023/06/12 [Refereed]
     
    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 < 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.
  • 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 0023-6837 2023/06 [Refereed]
  • Yu Zuo, Sherwin Navaz, Alex Tsodikov, Katarina Kmetova, Lyndsay Kluge, Amala Ambati, Claire K. Hoy, Srilakshmi Yalavarthi, Danieli de Andrade, Maria G. Tektonidou, Savino Sciascia, Vittorio Pengo, Guillermo Ruiz‐Irastorza, H. Michael Belmont, Maria Gerosa, Paul R. Fortin, Guilherme Ramires de Jesus, D. Ware Branch, Laura Andreoli, Esther Rodriguez‐Almaraz, Michelle Petri, Ricard Cervera, Rohan Willis, David R. Karp, Quan‐Zhen Li, Hannah Cohen, Maria Laura Bertolaccini, Doruk Erkan, Jason S. Knight
    Arthritis & Rheumatology 75 (8) 1407 - 1414 2326-5191 2023/05/18 [Refereed]
     
    Objective This study aimed to elucidate the presence, antigen specificities, and potential clinical associations of anti–neutrophil extracellular trap (anti‐NET) antibodies in a multinational cohort of antiphospholipid (aPL) antibody–positive patients who did not have lupus. Methods Anti‐NET IgG/IgM levels were measured in serum samples from 389 aPL‐positive patients; 308 patients met the classification criteria for antiphospholipid syndrome. Multivariate logistic regression with best variable model selection was used to determine clinical associations. For a subset of the patients (n = 214), we profiled autoantibodies using an autoantigen microarray platform. Results We found elevated levels of anti‐NET IgG and/or IgM in 45% of the aPL‐positive patients. High anti‐NET antibody levels are associated with more circulating myeloperoxidase (MPO)–DNA complexes, which are a biomarker of NETs. When considering clinical manifestations, positive anti‐NET IgG was associated with lesions affecting the white matter of the brain, even after adjusting for demographic variables and aPL profiles. Anti‐NET IgM tracked with complement consumption after controlling for aPL profiles; furthermore, patient serum samples containing high levels of anti‐NET IgM efficiently deposited complement C3d on NETs. As determined by autoantigen microarray, positive testing for anti‐NET IgG was significantly associated with several autoantibodies, including those recognizing citrullinated histones, heparan sulfate proteoglycan, laminin, MPO–DNA complexes, and nucleosomes. Anti‐NET IgM positivity was associated with autoantibodies targeting single‐stranded DNA, double‐stranded DNA, and proliferating cell nuclear antigen. Conclusion These data reveal high levels of anti‐NET antibodies in 45% of aPL‐positive patients, where they potentially activate the complement cascade. While anti‐NET IgM may especially recognize DNA in NETs, anti‐NET IgG species appear to be more likely to target NET‐associated protein antigens.
  • H Moriya, Y Fujieda, O Amengual, T Kanbayashi, T Atsumi
    Scandinavian Journal of Rheumatology 52 (4) 444 - 446 0300-9742 2023/04/12
  • Cecilia B. Chighizola, Francesca Pregnolato, Danieli Andrade, Maria Tektonidou, Vittorio Pengo, Guillermo Ruiz‐Irastorza, H. Michael Belmont, Maria Gerosa, Paul Fortin, D. Ware Branch, Laura Andreoli, Michelle A. Petri, Ricard Cervera, Jason S. Knight, Rohan Willis, Maria Efthymiou, Hannah Cohen, Doruk Erkan, Maria Laura Bertolaccini
    Arthritis & Rheumatology 75 (6) 984 - 995 2326-5191 2023/04/02 [Refereed]
     
    Objective The present study was undertaken to longitudinally evaluate titers of antibodies against β2‐glycoprotein I (anti‐β2GPI) and domain 1 (anti‐D1), to identify predictors of variations in anti‐β2GPI and anti‐D1 titers, and to clarify whether antibody titer fluctuations predict thrombosis in a large international cohort of patients who were persistently positive for antiphospholipid antibodies (aPL) in the APS ACTION Registry. Methods Patients with available blood samples from at least 4 time points (at baseline [year 1] and at years 2–4 of follow‐up) were included. Detection of anti‐β2GPI and anti‐D1 IgG antibodies was performed using chemiluminescence (BIO‐FLASH; INOVA Diagnostics). Results Among 230 patients in the study cohort, anti‐D1 and anti‐β2GPI titers decreased significantly over time (P < 0.0001 and P = 0.010, respectively). After adjustment for age, sex, and number of positive aPL tests, we found that the fluctuations in anti‐D1 and anti‐β2GPI titer levels were associated with treatment with hydroxychloroquine (HCQ) at each time point. Treatment with HCQ, but not immunosuppressive agents, was associated with 1.3‐fold and 1.4‐fold decreases in anti‐D1 and anti‐β2GPI titers, respectively. Incident vascular events were associated with 1.9‐fold and 2.1‐fold increases in anti‐D1 and anti‐β2GPI titers, respectively. Anti‐D1 and anti‐β2GPI titers at the time of thrombosis were lower compared to titers at other time points. A 1.6‐fold decrease in anti‐D1 titers and a 2‐fold decrease in anti‐β2GPI titers conferred odds ratios for incident thrombosis of 6.0 (95% confidence interval [95% CI] 0.62–59.3) and 9.4 (95% CI 1.1–80.2), respectively. Conclusion Treatment with HCQ and incident vascular events in aPL‐positive patients predicted significant anti‐D1 and anti‐β2GPI titer fluctuations over time. Both anti‐D1 and anti‐β2GPI titers decreased around the time of thrombosis, with potential clinical relevance.
  • 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) 2023/02/27 [Refereed]
     
    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.
  • 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 2022/12 [Refereed]
     
    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.
  • 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 2022/09/13 [Refereed]
     
    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.
  • 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 2022/07/11 [Refereed]
     
    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.
  • Pregnancy outcomes in antiphospholipid antibody positive patients: prospective results from the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ('Registry').
    Erton ZB, Sevim E, de Jesús GR, Cervera R, Ji L, Pengo V, Ugarte A, Andrade D, Andreoli L, Atsumi T, Fortin PR, Gerosa M, Zuo Y, Petri M, Sciascia S, Tektonidou MG, Aguirre-Zamorano MA, Branch DW, Erkan D, APS ACTION
    Lupus Sci Med. 9 (1) e000633  2022/06 [Refereed]
  • 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 2022/04/06 [Refereed]
     
    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.
  • 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 55 151994 - 151994 2022/03/15 [Refereed]
     
    BACKGROUND: Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI). PATIENTS AND METHODS: Structural and resting-state functional MRI data were acquired from patients with IA, patients with osteoarthritis (OA) and heathy controls (HCs). Two datasets were adopted to derive (51 IA, 56 OA, and 17 HCs) and validate (31 IA) the observations. 33 IA patients in the derivation dataset and all the patients in validation dataset required biological treatment and were clinically evaluated before and after therapy. Via whole-brain pair-wise FC analyses, we analyzed IA-specific FC measures relevant to therapeutic response to biologics. RESULTS: The value of FC between left insular cortex (IC) and anterior cingulate cortex (ACC) was significantly low in IA patients compared with OA patients and HCs. We demonstrated that the FC between left anterior long insular gyrus as a subdivision of IC and ACC was significantly associated with therapeutic response to biologics regarding the improvement of patients' global assessment (PGA) in both derivation and validation datasets. CONCLUSION: Disease-specific resting-state FC provides a means to assess the therapeutic improvement of PGA and would be a clinical decision-making tool with predictability for treatment response in both RA and SpA.
  • 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 2021/11/03 [Refereed]
     
    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.
  • Gkrouzman E, Sevim E, Finik J, Andrade D, Pengo V, Sciascia S, Tektonidou MG, Ugarte A, Chighizola CB, Belmont HM, Lopez-Pedrera C, Ji L, Fortin P, Efthymiou M, de Jesus GR, Branch DW, Nalli C, Petri M, Rodriguez E, Cervera R, Knight JS, Atsumi T, Willis R, Bertolaccini ML, Cohen H, Rand J, Erkan D, APS ACTION
    J Rheumatol 48 (4) 541 - 547 1499-2752 2021/04 [Refereed]
     
    Objective. The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time. Methods. A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-β2 glycoprotein-I (anti–β2-GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis. Results. Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate (P = 0.906) and multivariable analysis (P = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10–0.64, P = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53–7.13, P = 0.002) the odds of an unstable aPL profile over time. Conclusion. Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories.
  • Yuichiro Fujieda, Olga Amengual
    European journal of rheumatology 2020/11/19 [Refereed]
     
    Antiphospholipid syndrome (APS) is a systemic disorder clinically characterized by widespread thrombosis and obstetric complications associated with the persistent presence of antiphospholipid antibodies (aPLs). The persistent presence of aPLs represents a thrombotic risk in APS, which can be stratified according to the aPL profile. Thrombosis occurs in both arteries and veins. Notably, arterial thromboses have a higher recurrence compared with venous thromboses and a tendency for recurrence in the same vascular (arterial) site. Secondary prevention of arterial thrombosis requires more intensive treatment than prevention of venous thrombosis. Data from randomized clinical trials indicated that factor Xa inhibitors should not be recommended for APS. Recurrent thromboses in patients with APS treated with factor Xa inhibitors were mainly arterial, with a high rate of stroke. Dual antiplatelet therapy may have some benefit for preventing the recurrence of arterial thrombosis in patients with APS. This review article describes pathogenic mechanisms, clinical features, risk assessment, and management of arterial thrombosis in patients with APS. Particularly, we discuss how secondary prophylaxis may be a useful approach to reduce the occurrence of arterial thrombosis.
  • Olga Amengual, Tatsuya Atsumi
    Rheumatology international 2020/11/17 [Refereed][Invited]
     
    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.
  • Ogata Y, Fujieda Y, Sugawara M, Sato T, Ohnishi N, Kono Michihito, Kato M, Oku K, Amengual O, Atsumi T
    22th Asia Pacific League of Associations for Rheumatology Congress, Kyoto, Japan 60 (3) 1331 - 1337 2020/10 [Refereed]
     
    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.
  • Wen Shi Lee, Masaru Kato, Eri Sugawara, Michihiro Kono, Yuki Kudo, Michihito Kono, Yuichiro Fujieda, Toshiyuki Bohgaki, Olga Amengual, Kenji Oku, Shinsuke Yasuda, Tomohiro Onodera, Norimasa Iwasaki, Tatsuya Atsumi
    Arthritis & rheumatology (Hoboken, N.J.) 72 (9) 1493 - 1504 2020/09 
    OBJECTIVE: Optineurin (OPTN) is an autophagy adaptor/receptor that acts as an intrinsic negative regulator of osteoclast differentiation. RANKL expressed by rheumatoid arthritis synovial fibroblasts (RASFs) is primarily responsible for the development of bone erosions in patients with RA. The aim of the present study was to explore the role of OPTN in the pathogenesis of joint destruction in RA. METHODS: RASFs were left untreated or incubated with tumor necrosis factor (TNF) or interferon-γ (IFNγ), and expression of OPTN by RASFs was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Expression of RANKL and osteoprotegerin (OPG) was evaluated in cultures of OPTN-reduced RASFs with or without TNF or IFNγ treatment. OPTN-reduced RASFs were cocultured with monocytes and stained for tartrate-resistant acid phosphatase (TRAP). IκBα, NF-κB1, and RelA protein levels were measured to evaluate NF-κB signaling. Expression of messenger RNA (mRNA) for matrix metalloproteinase 3 (MMP3), interleukin-6 (IL6), GATA binding protein 3 (GATA3), carbohydrate sulfotransferase 15 (CHST15), hyaluronan synthase 1 (HAS1), and GATA1 was analyzed by RT-qPCR. RESULTS: In RASFs incubated with TNF or IFNγ, OPTN expression was up-regulated and RANKL expression was increased, and these effects were further pronounced in OPTN-reduced RASFs (all P < 0.05 versus controls). OPG mRNA levels remained unchanged. Monocytes cocultured with OPTN-reduced RASFs differentiated to a greater extent into TRAP+ multinucleated cells compared to monocytes cocultured with control RASFs (P < 0.05). IκBα degradation and nuclear NF-κB1 expression following TNF treatment were both prolonged in OPTN-reduced RASFs (each P < 0.05 versus controls). MMP3 mRNA levels were up-regulated, while GATA3, CHST15, and HAS1 mRNA levels were down-regulated in OPTN-reduced RASFs (each P < 0.05 versus controls). CONCLUSION: OPTN plays a protective role in RA when it is up-regulated in RASFs in the presence of proinflammatory cytokines. Absence of OPTN might worsen RA by generating a joint-destructive state, as indicated by evidence of increased RANKL expression on RASFs and subsequent osteoclast differentiation.
  • 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 2020/09 [Refereed]
     
    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.
  • Kohei Karino, Michihiro Kono, Michihito Kono, Keita Sakamoto, Yuichiro Fujieda, Masaru Kato, Olga Amengual, Kenji Oku, Shinsuke Yasuda, Tatsuya Atsumi
    Rheumatology (Oxford, England) 59 (7) 1734 - 1742 1462-0324 2020/07/01 [Refereed][Not invited]
     
    OBJECTIVE: Rapidly progressive interstitial lung disease (RPILD) is a major cause of death in patients with DM. Although clinically amyopathic DM (CADM) represents risk for RPILD, the incidence rate of RPILD in patients with CADM varies widely. Whole-body (WB) MRI can reveal involvement of systemic muscle and myofascia. The objective of this study was to explore the risk factors for RPILD in patients with DM using WB-MRI. METHODS: This retrospective study comprised 41 patients with DM who underwent WB-MRI before the initiation of treatment in our hospital. Muscular and myofascial signals were scored on 42 muscular groups. The myofascia/muscle ratio was calculated and used to define the relevance of myofascia-dominant involvement. RPILD was defined as worsening of dyspnoea, hypoxaemia and radiographic ILD/fibrosis within 3 months from the onset of respiratory symptoms. RESULTS: Among the 41 patients, 17 had CADM and 30 had ILD, including 10 patients with RPILD. All patients including those with CADM showed abnormal signal intensity in both muscle and myofascia (median score: 15 and 23, respectively). Muscle signal scores positively correlated with the serum creatine kinase level (r = 0.714; P< 0.001). Patients with RPILD showed a significantly higher myofascia/muscle ratio than those without RPILD (1.929 vs 1.200; P= 0.027). Logistic regression analysis identified higher myofascia/muscle ratio as independent risk factors for developing RPILD. CONCLUSION: Myofascia-dominant involvement was defined and appreciated in patients with DM using WB-MRI. This may be one of the risk factors for RPILD.
  • 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 38 (4) 581 - 588 2020/07 [Refereed][Not invited]
     
    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.
  • Eri Sugawara, Masaru Kato, Yuki Kudo, Wenshi Lee, Ryo Hisada, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Shinsuke Yasuda, Tomohiro Onodera, Shigetsugu Hatakeyama, Tatsuya Atsumi
    Autophagy 16 (5) 946 - 955 1554-8627 2020/05 [Refereed][Not invited]
     
    We aimed to investigate the involvement of macroautophagy/autophagy in autoimmunity in rheumatoid arthritis (RA) through citrullination of VIM (vimentin) and its interaction with MHC class II in synovial fibroblasts (SFs). The cell surface expression of MHC class II and B7 costimulatory molecules on SFs was analyzed by flow cytometry after treatment with IFNG/IFN-γ (interferon gamma). Intracellular citrullinated autoantigens in SFs were analyzed by immunoblotting using serum from anti-citrullinated peptide antibodies (ACPA)-positive patient as a primary antibody. SFs were incubated in serum-free medium or treated with proteasome inhibitor MG132 to induce autophagy. An autophagy inhibitor 3-methyladenin (3-MA) was used. Intracellular citrullinated VIM (cVIM) was evaluated by immunoblotting and immunocytochemistry. The interaction between MHC class II and cVIM was evaluated with co-immunoprecipitation and proximity ligation assay (PLA). We demonstrated that MHC class II, CD274/B7-H1 and PDCD1LG2/B7-DC were expressed on SFs following treatment with IFNG whereas CD276/B7-H3 was detected on SFs regardless of the presence of IFNG. ACPA-positive sera recognized a 54 kDa protein in SFs. By immunoprecipitation, the 54 kDa protein recognized by RA sera was revealed to be cVIM. Following induction of autophagy, intracellular cVIM was increased in SFs but the effect was canceled by 3-MA. The interaction between MHC class II and cVIM was demonstrated by co-immunoprecipitation. Furthermore, PLA revealed the significant increase of MHC class II-cVIM interaction following induction of autophagy. Our findings suggest that SFs may contribute to the autoimmunity in RA through citrullination of VIM and its interaction with MHC class II promoted by autophagy.Abbreviations: 3-MA: 3-methyladenine; ACPA: anti-citrullinated peptide antibodies; anti-CCP: anti-cyclic citrullinated peptide antibody; cVIM: citrullinated VIM; BECN1: beclin1; DAPI: 4',6-diamidino-2-phenylindole; FBS: fetal bovine serum; HLA: human leukocyte antigen; IFNG/IFN-γ: interferon gamma; IL6: interleukin 6; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence index; MHC: major histocompatibility complex; OA: osteoarthritis; PADI: peptidyl arginine deiminase; PepA: pepstatin A; PBS: phosphate-buffered saline; PtdIns3K: phosphatidylinositol 3-kinase; RA: rheumatoid arthritis; SFs: synovial fibroblasts; siRNA: small interfering RNA; VIM: vimentin.
  • Recommendations of the Spanish Rheumatology Society for Primary Antiphospholipid Syndrome. Part II: Obstetric Antiphospholipid Syndrome and Special Situations.
    Cáliz Cáliz R, Díaz Del Campo, Fontecha P, Galindo Izquierdo M, López Longo FJ, Martínez Zamora MÁ, Santamaria Ortiz A, Amengual Pliego O, Cuadrado Lozano MJ, Delgado Beltrán MP, Ortells LC, Pérez ECC, Rego GD, Corral SG, Varela CF, López MM, Nishishinya B, Navarro MN, Testa CP, Pérez HS, Silva-Fernández L, Taboada VMM
    Reumatol Clin (Engl Ed) 16 (2) 133 - 148 2020/03 [Refereed][Invited]
  • Recommendations of the Spanish Rheumatology Society for Primary Antiphospholipid Syndrome. Part I: Diagnosis, Evaluation and Treatment.
    Cáliz Cáliz R, Díaz Del Campo, Fontecha P, Galindo Izquierdo M, López Longo FJ, Martínez Zamora MÁ, Santamaria Ortiz A, Amengual Pliego O, Cuadrado Lozano MJ, Delgado Beltrán MP, Ortells LC, Pérez ECC, Rego GD, Corral SG, Varela CF, López MM, Nishishinya B, Navarro MN, Testa CP, Pérez HS, Silva-Fernández L, Taboada VMM
    Reumatol Clin (Engl Ed) 16 (2) 71 - 86 2020/03 [Refereed][Invited]
  • Wen Shi Lee, Olga Amengual
    Immunological medicine 43 (1) 16 - 35 2020/03 [Refereed][Not invited]
     
    Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which affects the majority of organs and systems. Traditional therapies do not lead to complete remission of disease but only relieve symptoms and inflammation. B cells are the most important effector cell types in the pathogenesis of SLE. Therefore, therapies targeting B cells and their related cytokines are a very important milestone for SLE treatment. Several biologics that modulate B cells, either depleting B cells or blocking B cell functions, have been developed and evaluated in clinical trials. Belimumab, a fully humanized monoclonal antibody that specifically binds B cells activating factor (BAFF), was the first of these agents approved for SLE treatment. In this review, we explore the currently available evidence in B cell targeted therapies in SLE including agents that target B cell surface antigens (CD19, CD20, CD22), B cell survival factors (BAFF and a proliferation-inducing ligand, APRIL), cytokines (interleukin-1 and type 1 interferons) and co-stimulatory molecules (CD40 ligand). We highlighted the mechanisms of action and the individual characteristics of these biologics, and present an update on the clinical trials that have evaluated their efficacy and safety. Finally, we describe some of the emerging and promising therapies for SLE treatment.
  • 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 0049-0172 2019/12 [Refereed]
     
    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.
  • Sato T, Nakamura H, Fujieda Y, Ohnishi N Abe N, Kono M, Kato M, Oku K, Bohgaki T, Amengual O, T, Yasuda S, Atsumi T
    Lupus 63rd 2019/10 [Refereed][Not invited]
  • Ryo Hisada, Masaru Kato, Eri Sugawara, Masatoshi Kanda, Yuichiro Fujieda, Kenji Oku, Toshiyuki Bohgaki, Olga Amengual, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
    Journal of thrombosis and haemostasis : JTH 17 (7) 1134 - 1143 1538-7933 2019/07 [Refereed][Not invited]
     
    Essentials The mechanism of antiphospholipid antibodies (aPL) production remains unclear. We investigated lymphocyte subset, single nucleotide polymorphisms (SNP), and aPL-producing cells. The increase of circulating plasmablasts was associated with type I interferon upregulation. Our novel ex vivo assay revealed circulating plasmablasts as a major source of aPL. SUMMARY: Background/objective Antiphospholipid antibodies (aPL) are pathogenic autoantibodies in antiphospholipid syndrome (APS). This study aimed to clarify the mechanism of aPL production. Methods T cell and B cell subsets were evaluated in peripheral blood mononuclear cells (PBMCs) of 26 primary APS (PAPS), 19 systemic lupus erythematosus-associated APS (SLE/APS) patients and 10 healthy controls. The SLE-related or APS-related single nucleotide polymorphisms (SNP) were analyzed in those patients. Interferon (IFN) score was calculated based on the mRNA expression of Ly6e, Mx1, IFIT1, and IFIT3 in PBMCs. The PBMCs obtained from APS patients were cultured ex vivo following depletion of CD20 positive or negative B cells and the culture supernatants were applied to aPL measurements. Results In PAPS and SLE/APS patients, Th2, Th17, and plasmablasts were increased while regulatory T, memory B, and regulatory B cells were decreased compared to healthy controls. Genetic analysis revealed that the increase of plasmablasts was more pronounced in patients carrying a risk allele of toll like receptor (TLR) 7 SNP rs3853839. The IFN score was significantly higher in the risk allele carriers. Ex vivo experiments showed that aPL were present in the culture supernatant of PBMCs lacking CD20+CD19+ subset, but not in that of cells lacking CD20-CD19+ subset. Conclusions Our data indicate an important role of plasmablasts in the production of aPL. Furthermore, the increase of plasmablasts was associated with TLR 7 and type I IFN, suggesting a common pathophysiology in SLE and APS. Targeting plasmablasts might be a novel immunological therapeutic approach in the treatment of APS.
  • 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 1462-0324 2019/06 [Refereed][Not invited]
     
    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.
  • Kazumasa Ohmura, Kenji Oku, Tamao Kitaori, Olga Amengual, Ryo Hisada, Masatoshi Kanda, Yuka Shimizu, Yuichiro Fujieda, Masaru Kato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Mayumi Sugiura-Ogasawara, Tatsuya Atsumi
    Clinical immunology (Orlando, Fla.) 203 37 - 44 1521-6616 2019/06 [Refereed][Not invited]
     
    Recurrent pregnancy loss (RPL) is often considered idiopathic, however excessive complement activation has been observed in pregnancy related manifestations. Anti-C1q antibodies (anti-C1q) are associated with the activation of complement pathway in lupus patients, while it remains unclear in RPL. Firstly, we showed that both the prevalence and titre of anti-C1q were significantly higher in unexplained RPL than in healthy parous individuals. Secondly, we established the murine model of anti-C1q induced pregnancy loss using a monoclonal anti-mouse C1q antibody, JL-1. In mice treated with JL-1, high ratio of pregnancy loss and fetal growth restriction were frequently observed and complement activation occurred. C5a receptor (C5aR) blockade cancelled these pathogenic changes in mice treated with JL-1. In conclusion, our study reveals an association between the prevalence of anti-C1q and RPL. Additionally, our murine model has indicated that anti-C1q can induce reproductive failure, which might be ameliorated by therapy targeting the C5-C5aR axis.
  • Nobuya Abe, Yuichiro Fujieda, Olga Amengual, Tatsuya Atsumi
    BMJ (Clinical research ed.) 365 l1344  0959-8138 2019/04/17 [Refereed][Not invited]
  • 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 1462-0324 2019/04 [Refereed][Not invited]
     
    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.
  • 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 (一社)日本リウマチ学会 63回 539 - 539 2019/03
  • 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 1439-7595 2018/12 [Refereed][Not invited]
  • Y. Fujieda, O. Amengual, T. Atsumi
    Lupus 27 (13) 2012 - 2013 1477-0962 2018/11/01
  • Pathogenesis of Antiphospholipid syndrome:and update
    Fujieda Y, Amengual O, Atsumi T
    Lupus 2018/10 [Refereed][Invited]
  • 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 1439-7595 2018/09 [Refereed][Not invited]
     
    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.
  • Women and Science
    García-Martín F, Rosich M, de Vega S, San Gabriel A, Amengual O
    Journal of Science and Humanities Areces Foundation 19 111 - 121 2018/07 [Invited]
  • Olga Amengual, Tatsuya Atsumi
    Modern Rheumatology 28 (3) 409 - 416 1439-7609 2018/05/04 [Refereed][Invited]
     
    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.
  • 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.
  • T. Watanabe, K. Oku, O. Amengual, R. Hisada, K. Ohmura, I. Nakagawa, H. Shida, T. Bohgaki, T. Horita, S. Yasuda, T. Atsumi
    Lupus 27 (2) 225 - 234 1477-0962 2018/02/01 [Refereed][Not invited]
     
    The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial (n = 6) and venous (n = 9) thrombosis (median follow-up period 69 months). Cox’s proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01–0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.
  • 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 1538-7933 2017/09 [Refereed][Not invited]
     
    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.
  • 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.
  • H. Nakamura, O. Amengual, T. Horita, M. Kato, K. Oku, T. Bohgaki, S. Yasuda, T. Atsumi
    LUPUS 26 (7) 783 - 784 0961-2033 2017/06 [Refereed][Not invited]
  • 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 (一社)日本リウマチ学会 61回 460 - 460 2017/03 [Refereed][Not invited]
  • 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 0961-2033 2017/03 [Refereed][Not invited]
     
    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.
  • 菅原 恵理, 加藤 将, 久田 諒, 藤枝 雄一郎, 奥 健志, 坊垣 暁之, アメングアル オルガ, 渥美 達也
    日本臨床免疫学会会誌 日本臨床免疫学会 40 (4) 302b - 302b 2017 

    【目的】関節リウマチ（Rheumatoid arthritis: RA）の滑膜線維芽細胞（Fibroblast like synoviocytes: FLS）におけるオートファジーとビメンチンのシトルリン化の関連を明らかにする．【方法】6名のRAの患者血清の抗シトルリン化ビメンチン抗体価をELISA法で測定した．ヒト滑膜組織から分離したFLSをプロテアソーム阻害薬のMG132および無血清培地による飢餓状態で刺激しオートファジーを誘導した．オートファジーおよび細胞内のシトルリン化ビメンチンを抗LC3抗体，抗シトルリン抗体，抗ビメンチン抗体，抗β-アクチン抗体，抗シトルリン化ビメンチン抗体陽性患者血清を一次抗体として用いたウエスタンブロット法で評価した．【結果】抗シトルリン抗体，抗ビメンチン抗体，抗シトルリン化ビメンチン抗体陽性患者血清は54 kDaのタンパクを認識し，FLS内のビメンチンのシトルリン化が示唆された．24時間の10 μMのMG132刺激および，2-3時間の飢餓状態でLC3-IIおよびシトルリン化蛋白が有意に増加したが，ビメンチンの蛋白量は増加せず，オートファジー誘導によりビメンチンのシトルリン化の亢進が示唆された．【結論】オートファジーはFLSにおけるビメンチンのシトルリン化を促進し，RAの病態形成に関与している可能性がある．

  • 久田 諒, 加藤 将, 菅原 恵理, 藤枝 雄一郎, 奥 健志, 坊垣 暁之, Amengual Olga, 保田 晋助, 渥美 達也
    日本臨床免疫学会会誌 日本臨床免疫学会 40 (4) 302c - 302c 0911-4300 2017 

    【背景/目的】抗リン脂質抗体症候群（APS）において抗リン脂質抗体（aPL）は病原性を有する自己抗体とされるが，その産生機序については不明な点が多い．今回，APS患者における末梢血リンパ球サブセットを行い，更に末梢血単核球細胞（PBMC）をex vivoの系で刺激しaPL産生能をもつ細胞の同定を試みるアプローチを行った．【方法】原発性抗リン脂質抗体症候群（PAPS）患者，全身性エリテマトーデス続発性抗リン脂質抗体症候群（SLE/APS）患者，健常者の3群について，リンパ球サブセット解析を行い比較した．次にCD20 microbeadsを用いてCD20陽性細胞を除去したAPS患者のPBMCを刺激・培養し，培養上清中のaPLをELISA法及びcell-based assayにより測定した．【結果】PAPS群18名，SLE/APS群8名，健常者群8名についてサブセット解析を行った．Pre-switched memory B cell（p = 0.030），post-switched memory B cell（p = 0.032）はPAPS群で健常者群と比べ有意に減少していた．また，一部のAPS患者のPBMC培養上清からaPL-IgG（ELISA），aPL-IgM（cell-based assay）が検出され，CD20陽性細胞を除去したPBMCの培養上清中からもaPL-IgG，aPL-IgMが検出された．【結論】PAPS患者においてpre-switched memory B cellとpost-switched memory B cellの減少が見られた．また，aPL産生にCD20陰性B細胞が寄与している可能性が示唆された．

  • Effectiveness of a Medical English Course on Communication Abilities of Graduate Medical Students
    Amengual O, Oku K, Murakami M, Anwar D, Jego EH, Bohgaki, Horitat, Atsumi T
    Medical Science Educator Journal 2017 [Refereed][Not invited]
  • Eric Hajime Jego, Olga Amengual
    MODERN RHEUMATOLOGY 27 (6) 1101 - 1105 1439-7595 2017 [Refereed][Not invited]
     
    In light of the present revolution happening in medical education in Japan as medical schools implement new curricula to conform to global standards, there is a growing demand for more internationalization and higher quality practical medical English education. In response, many institutions including governmental organizations, universities and academic associations are moving ahead with new initiatives to adapt to these changing demands. This paper reviews the current trends and innovations in medical English education in Japan. This paper also describes one initiative by the Japan College of Rheumatology (JCR) known as the JCR International School held yearly in Karuizawa. By examining recent trends and innovations in medical English education in Japan, the most relevant and applicable can be elucidated to illuminate a path forward for improved medical English education within the JCR.
  • 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.
  • 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, T. Atsumi
    LUPUS 25 (12) 1288 - 1298 0961-2033 2016/10 [Not refereed][Not invited]
     
    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 2GPI-dependent anticardiolipin antibody (aCL/2GPI) on monocytes. Methods Human serum incubated with FLAG-2GPI 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 2GPI), was revealed as a 2GPI-binding molecule in the immunoprecipitation assay. TF mRNA was markedly induced by oxidized LDL/2GPI complexes with either WBCAL-1 (monoclonal aCL/2GPI) 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 2GPI binding serum molecule by LC-MS search. Oxidized LDL/aCL/2GPI complexes significantly induced TF expressions on monocytes. These data suggest that complexes of oxidized LDL and aCL/2GPI may have a crucial role in the pathophysiology of APS.
  • 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][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,/).
  • 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.
  • Kenji Oku, Olga Amengual, Hiroyuki Nakamura, Ryo Hisada, Kazumasa Oomura, Masaru Mato, Toshiyuki Bohgaki, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
    JOURNAL OF REPRODUCTIVE IMMUNOLOGY 112 129 - 130 0165-0378 2015/11 [Refereed][Not invited]
  • Murakami M, Olga A, Iguchi K, Otaki J
    [Hokkaido igaku zasshi] The Hokkaido journal of medical science 90 (2) 99 - 104 0367-6102 2015/11 [Refereed][Not invited]
     
    In the past, we made several efforts making curriculum changes to Medical English Practice, however, these changes did not improve motivation effectively. We have completely modified the curriculum in 2012, and performed a questionnaire survey to 112 sophomore medical students. In the final exam, students answered a questionnaire assessing all classes of the course by scoring 3 points (no change required), 2 points (minor change required), and 1 point (major change required or discontinue). In addition, students could write free comments about potential contents they would like to add to the curriculum. Each class was assessed as more than or equal to 2.5 points on average (range: 2.50-2.96). Potential contents students want to add are: 1. Speaking (45 students [55%]), 2. Listening (30 students [37%]), 3. Reading (6 students [7%]), 4. Writing (1 student [1%]). The most frequent suggestion was to include group discussions in speaking (27 students [33%]), followed by listening on topics of healthcare systems (11 students [13%]). Many students suggested to include conversation classes in small groups, or classes in which international students introduce the structure of healthcare systems of their home countries to the curriculum. Increasing the participation of international faculty, staff and students in the Medical English Practice might contribute to the improvement of medical students' motivation.
  • O. Amengual, D. Fujita, E. Ota, L. Carmona, K. Oku, M. Sugiura-Ogasawara, A. Murashima, T. Atsumi
    LUPUS 24 (11) 1135 - 1142 0961-2033 2015/10 [Refereed][Not invited]
     
    Objective: Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. Methods: Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I 2 statistic. All analyses were conducted using Review Manager 5.3. Results: Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63-7.33), respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. Conclusion: This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy.
  • 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]
  • K. Oku, O. Amengual, T. Bohgaki, T. Horita, S. Yasuda, T. Atsumi
    LUPUS 24 (7) 774 - 775 0961-2033 2015/06 [Refereed][Invited]
  • 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.
  • T. Kurita, S. Yasuda, O. Amengual, T. Atsumi
    LUPUS 24 (1) 3 - 9 0961-2033 2015/01 [Refereed][Not invited]
     
    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.
  • 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]
  • 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, Amengual O, Hisada R, Oomura K, Nakagawa N, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T
    Japanese Journal of Clinical Immunology 38 (3) 157 - 163 0911-4300 2015 [Refereed][Not invited]
  • 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 (一社)日本臨床免疫学会 37 (5) 430 - 436 0911-4300 2014/10 
    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)
  • 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 2326-5191 2014/10 [Refereed][Not invited]
  • K. Oku, O. Amengual, T. Atsumi
    LUPUS 23 (12) 1269 - 1272 0961-2033 2014/10 [Refereed][Not invited]
     
    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.
  • 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 2326-5191 2014/10 [Refereed][Not invited]
  • 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 2326-5191 2014/10 [Refereed][Not invited]
  • 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 2326-5191 2014/10 [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.
  • 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 1568-9972 2014/09 [Refereed][Not invited]
     
    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.
  • Kenji Oku, Olga Amengual, Polona Zigon, Tetsuya Horita, Shinsuke Yasuda, Tatsuya Atsumi
    RHEUMATOLOGY 52 (10) 1775 - 1784 1462-0324 2013/10 [Refereed][Not invited]
     
    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.
  • Oku Kenji, Amengual Olga, Nakagawa Ikuma, Watanabe Toshiyuki, Kanetsuka Yusaku, Bohgaki Toshiyuki, Horita Tetsuya, Yasuda Shinsuke, Atsumi Tatsuya
    ARTHRITIS AND RHEUMATISM 65 S7 - S8 0004-3591 2013/10 [Refereed][Not invited]
  • 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  0004-3591 2013/10 [Refereed][Not invited]
  • M. Kato, T. Atsumi, K. Oku, O. Amengual, H. Nakagawa, Y. Fujieda, K. Otomo, T. Horita, S. Yasuda, T. Koike
    Lupus 22 (8) 761 - 771 0961-2033 2013/07 [Refereed][Not invited]
     
    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 in vitro. Taken together, in a susceptible background CD36 scavenger receptor function may be involved in the thrombotic pathophysiology in patients with APS. © The Author(s), 2013. Reprints and permissions.
  • 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.
  • Y. Fujieda, T. Atsumi, O. Amengual, T. Odani, K. Otomo, M. Kato, K. Oku, Y. Kon, T. Horita, S. Yasuda, T. Koike
    LUPUS 21 (14) 1506 - 1514 0961-2033 2012/12 [Refereed][Not invited]
     
    Objective: To study the clinical and immunological manifestations of antiphospholipid syndrome (APS) in the Japanese population by a single-centre registration. Methods: In this retrospective cohort study, 141 consecutive patients with APS, fulfilling the Sydney revised Sapporo criteria for definite APS, who visited 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 9-79 years). Seventy patients (49.6%) had primary APS, and 71 (50.4%) had systemic lupus erythematosus. The prevalence of thrombosis was 85.8 per cent, arterial thrombosis was found in 93 patients (66.0%) and venous thrombosis was found in 46 patients (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-beta 2 glycoprotein 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 was substantiated in Japanese patients with APS. Lupus (2012) 21, 1506-1514.
  • 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.
  • 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  0004-3591 2012/10 [Refereed][Not invited]
  • 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  0004-3591 2012/10 [Refereed][Not invited]
  • 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.
  • 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  0004-3591 2011/10 [Refereed][Not invited]
  • Olga Amengual, Tatsuya Atsumi, Takao Koike
    CURRENT VASCULAR PHARMACOLOGY 9 (5) 606 - 618 1570-1611 2011/09 [Refereed][Not invited]
     
    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.
  • 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｣.
    Atsumi T, Amengual O
    分子リウマチ治療 4 (4) 16 - 20 2011 [Refereed][Not invited]
  • 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
    Lupus 20 (2) 191 - 205 0961-2033 2011/01/01 [Refereed][Not invited]
     
    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).
  • 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)
  • Hideto Yamada, Tatsuya Atsumi, Olga Amengual, Takao Koike, Itsuko Furuta, Kaori Ohta, Gen Kobashi
    JOURNAL OF REPRODUCTIVE IMMUNOLOGY 84 (1) 95 - 99 0165-0378 2010/01 [Refereed][Not invited]
     
    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.
  • 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 0004-3591 2009/08 [Refereed][Not invited]
     
    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.
  • K. Oku, T. Atsumi, M. Bohgaki, O. Amengual, H. Kataoka, T. Horita, S. Yasuda, T. Koike
    ANNALS OF THE RHEUMATIC DISEASES 68 (6) 1030 - 1035 0003-4967 2009/06 [Refereed][Not invited]
     
    Objective: To investigate the significance of complement activation in patients with primary antiphospholipid syndrome (APS). Methods: Thirty-six patients with primary APS, 42 control patients with non-systemic lupus erythematosus (SLE) connective tissue diseases, and 36 healthy volunteers were analysed retrospectively. Serum complement levels (C3, C4, CH(50)) and anaphylatoxins (C3a, C4a, C5a) were examined in all subjects, and serum complement regulatory factors (factor H and factor I) were measured in patients with primary APS. Plasma anticoagulant activity was determined in a mixing test using the activated partial thromboplastin time. Results: Serum complement levels were significantly lower in patients with primary APS than in patients with non-SLE connective tissue diseases ( mean (SD) C3: 81.07 (17.86) vs 109.80 (22.76) mg/dl, p<0.001; C4: 13.04 (8.49) vs 21.70 (6.96) mg/dl, p<0.001; CH(50): 31.32 (8.76) vs 41.40 (7.70) U/ml, p<0.001) or healthy volunteers. Only two healthy subjects with low serum C4 levels showed hypocomplementaemia, whereas most patients with primary APS showed raised serum C3a and C4a. No subjects showed raised C5a. Patients with primary APS with low serum C3 or C4 had significantly higher levels of C3a or C4a than healthy controls. No patients had low serum complement regulatory factors. Among patients with primary APS, hypocomplementaemia was significantly more common in those with high anticoagulant activity than in those with low or normal activity. Conclusion: Hypocomplementaemia is common in patients with primary APS, reflecting complement activation and consumption, and was correlated with anticoagulant activity, suggesting that antiphospholipid antibodies may activate monocytes and macrophages via anaphylatoxins produced in complement activation.
  • 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 日本臨床分子医学会 46回 77 - 77 2009/04
  • 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 (一社)日本血栓止血学会 20 (2) 230 - 230 0915-7441 2009/04
  • 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 0004-3591 2008/09 [Refereed][Not invited]
  • 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.
  • 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 (一社)日本リウマチ学会 52回・17回 311 - 311 2008/04
  • Y. Kon, T. Atsumi, H. Hagiwara, A. Furusaki, H. Kataoka, T. Horita, S. Yasuda, O. Amengual, K. Takao
    CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 26 (1) 129 - 132 0392-856X 2008/01 [Refereed][Not invited]
     
    Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular thrombosis. TMA has been reported in patients with antiphospholipid antibodies and/or antiphospholipid syndrome but its pathogenesis is not clarified. We present two patients with TMA associated with IgG phosphatidylserine dependent antiprothrombin antibodies (aPS/P7). Case 1: A 44-year-old Japanese female with systemic lupus erythematosus (SLE) and positive lupus anticoagulant (LA) was started on ticlopidine after having stroke. Four weeks later she developed MA. IgG/MIA anticardiolipin antibodies (aCL) were negative, but strong positive IgG aPS/PT were detected. Case 2: A 32-year-old Russian female with SLE was admitted because of hypertension, renal insufficiency and proteinuria at 14 weeks of pregnancy. She developed TMA after surgical abortion. IgG aPS/PT and LA were strongly positive but IgG/MIA aCL were negative. Neither case had von Willebrand factor cleaving protease (ADAMTS-13), suggesting that TMA in those patients was associated with thrombophilia rather than insufficient ADAMTS-13. Both patients were successfully treated with a series of plasma exchange.
  • Olga Amengual, Tatsuya Atsumi, Yukiko Komano, Hiroshi Kataoka, Tetsuya Horita, Shinsuke Yasuda, Takao Koike
    ARTHRITIS AND RHEUMATISM 56 (8) 2803 - 2805 0004-3591 2007/08 [Refereed][Not invited]
  • Takao Koike, Miyuki Bohgaki, Olga Amengual, Tatsuya Atsumi
    JOURNAL OF AUTOIMMUNITY 28 (2-3) 129 - 133 0896-8411 2007/03 [Refereed][Not invited]
     
    Antiphospholipid antibodies (aPL) are an heterogeneous group of circulating immunoglobulins arising in a wide range of infectious and autoimmune diseases. Since the early 80 s, the interest on anticardiolipin antibodies (aCL) has exponentially increased due to their association with thrombosis. The antiphospholipid syndrome (APS) was defined as a clinical disorder characterized by thrombosis and pregnancy morbidity associated to the persistent presence of aCL and/or lupus anticoagulant (LA). Thrombosis is the major manifestation in patients with aPL, but the spectrum of symptoms and signs associated with aPL has considerably broadened, and other manifestations such as thrombocytopenia, nonthrombotic neurological syndromes, psychiatric manifestations, livedo reticularis, skin ulcers, haemolytic anemia, pulmonary hypertension, cardiac valve abnormality and atherosclerosis have also been related to the presence of those antibodies. Numerous mechanisms have been proposed to explain the thrombotic tendency of patients with aPL, but the pathogenesis seems to be multifactorial. (C) 2007 Elsevier Ltd. All rights reserved.
  • Olga Amengual, Tatsuya Atsumi, Takao Koike
    APLAR Journal of Rheumatology 9 (4) 377 - 386 0219-0494 2006/12 [Refereed][Invited]
     
    Antiphospholipid antibodies (aPL) (anticardiolipin antibodies and lupus anticoagulant) are associated with thrombosis and pregnancy morbidity, the antiphospholipid syndrome (APS). Despite the clear association between aPL and those manifestations, the precise underlying disease mechanisms remain unclear. APL may affect the normal procoagulant and anticoagulant reactions occurring on cell membranes, and also may interact with certain cells, altering the expression and secretion of procoagulant substances. In this article, we review the immunological characteristics of anticardiolipin antibodies and their potential effects on the coagulation and fibrinolytic systems implicated in the development of thrombotic complications in patients with APS. © 2006 Asia Pacific League of Associations for Rheumatology.
  • Amengual Olga, Atsumi Tatsuya, Kataoka Hiroshi, Horita Tetsuya, Yasuda Shinsuke, Koike Takao
    ARTHRITIS AND RHEUMATISM 54 (9) S560  0004-3591 2006/09 [Refereed][Not invited]
  • S. Furukawa, S. Yasuda, O. Amengual, T. Horita, T. Atsumi, T. Koike
    ANNALS OF THE RHEUMATIC DISEASES 65 (8) 1118 - 1120 0003-4967 2006/08 [Refereed][Not invited]
  • T Atsumi, O Amengual, S Yasuda, E Matsuura, T Koike
    AUTOIMMUNITY 38 (5) 377 - 381 0891-6934 2005/08 [Refereed][Not invited]
     
    beta 2-Glycoprotein I (beta 2GPI), a phospholipid-binding protein, is one of the major target antigens for antiphospholipid antibodies (aPL) found in patients with antiphospholipid syndrome (APS). Thrombophilic disorders in APS patients are strongly associated with aPL, and their pathogenic properties depend on the presence of beta 2GPI. Procoagulant cell stimulation by aPL, via beta 2GPI, is one of the most plausible mechanisms of thrombosis in APS, and p38 mitogen activated protein kinase (MAPK) pathway plays a crucial role in such activation. beta 2GPI is proteolytically cleaved in domain V by activated factor X or plasmin, leading to the generation of the nicked form of beta 2GPI. Recently, increasing attention is focused on the role of nicked-beta 2GPI as a regulator of extrinsic fibrinolysis pathway.
  • Atsumi T, Amengual O, Yasuda S, Koike T
    20th Congress of the International Society on Thrombosis and Haemostasis, Sydney, Australia 114 (5-6) 533 - 538 0049-3848 2005/08 [Refereed][Not invited]
     
    According to the preliminary classification criteria of the antiphospholipid syndrome (APS) (Sapporo Criteria), beta(2)-glycoprotein I (beta(2)GPI)-dependent anticardiolipin antibodies (aCL) and Lupus anticoagulant (LA) are the only laboratory tests considered as criteria for the classification of the 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. We assessed the sensitivity and specificity of aPS/PT for the diagnosis of APS in our population of patients with a variety of autoimmune disorders and investigated whether aPS/PT could be used as diagnostic test in patients suspected of having APS. The study population comprised 219 patients with autoimmune diseases including 82 patients with APS and 137 without APS (55 systemic lupus erythematosus, 32 rheumatoid arthritis, 10 primary Sjogren's syndrome, 8 scleroderma, 5 Behcet's disease and 27 other rheumatic diseases). IgG/M aPS/PT were measured by ELISA using phosphatidylserine-prothrombin complex as antigen immobilized on ELISA plates in the presence of CaCl2. IgG/M aCL were measured by standard methods and LA was detected by clotting assays. aPS/PT, aCL and LA were more frequently found in patients with APS (47, 46 and 69, respectively) than in those without APS (11, 19 and 29, respectively) (OR 95% [CI]; 15.4 [7.2-32.7], 7.9 [4.1-15.2, 19.8 [9.6-40.6], respectively]. The sensitivity of each assay for the diagnosis of APS was 57%, 56% and 86% with a specificity of 92%, 86% and 79%, respectively. aPS/PT and aCL have similar diagnostic value for APS, therefore, we propose that aPS/PT should be further explored, not only for research purposes, but also as a candidate of one of the laboratory criteria for the classification of the APS. (c) 2004 Published by Elsevier Ltd.
  • T Atsumi, S Furukawa, O Amengual, T Koike
    LUPUS 14 (7) 499 - 504 0961-2033 2005 [Refereed][Not invited]
     
    The pathogenesis of thrombocytopenia in patients with antiphospholipid syndrome (APS) is heterogeneous. Patients with antiphospholipid antibodies (aPL) and thrombocytopenia in the absence of clinical manifestations of APS will be diagnosed and treated as idiopathic thrombocytopenic purpura. However, the presence of aPL places those individuals at particular risk for developing both bleeding and thrombotic complications. Therefore, we propose the inclusion of such patients in the subgroup 'aPL-associated thrombocytopenia'. More attention should be devoted to this subgroup of patients to elucidate the role of aPL in the development of thrombocytopenia and to facilitate the adequate monitoring of its potential thrombotic risk.
  • ML Sanchez, K Katsumata, T Atsumi, FI Romero, ML Bertolaccini, A Funke, O Amengual, E Kondeatis, RW Vaughan, A Cox, GRV Hughes, MA Khamashta
    ANNALS OF THE RHEUMATIC DISEASES 63 (12) 1645 - 1648 0003-4967 2004/12 [Refereed][Not invited]
     
    Objective: To investigate whether variation in the HLA-DM gene is important in producing a group of pathogenic autoantibodies-antiphospholipid antibodies (aPL)-on the basis that HLA class II restricted antigen presentation is involved in the production of aPL. Methods: HLA-DMA and DMB polymorphisms were genotyped by polymerase chain reaction combined with restriction enzyme digestion in 51 white patients with primary antiphospholipid syndrome (APS), 82 with systemic lupus erythematosus (SLE) ( 42 with APS and 40 without APS), and 109 healthy white controls. The association with the aPL profile was examined. Results: The distribution of DMA alleles in APS patients and in patients with APS associated with SLE was significantly different from that in controls by 4x2 chi(2) test with 3 degrees of freedom (p = 0.035 and 0.011, respectively), but it was not different between SLE patients without APS and controls. The allelic distribution of DMA was also different between patients with IgG class anticardiolipin antibody or those with lupus anticoagulant (LA) and controls (p = 0.012 and 0.007, respectively) and between patients with and without LA among SLE patients ( p = 0.035). All these differences included the increase in DMA*0102 in the former groups. Conclusions: The results suggest that HLA-DMA*0102 or its linked gene(s) form one of the genetic risks for the production of aPL.
  • M Bohgaki, T Atsumi, Y Yamashita, S Yasuda, Y Sakai, A Furusaki, T Bohgaki, O Amengual, Y Amasaki, T Koike
    INTERNATIONAL IMMUNOLOGY 16 (11) 1633 - 1641 0953-8178 2004/11 [Refereed][Not invited]
     
    The anti-phospholipid syndrome (APS) is characterized by thrombosis and the presence of anti-phospholipid antibodies (aPL). Tissue factor (TF), the major initiator of the coagulation system, is induced on monocytes by aPL in vitro, explaining, in part, the pathophysiology in this syndrome. However, little is known regarding the nature of the aPL-induced signal transduction pathways leading to TF expression. In this study, we investigated aPL-inducible genes in PBMC using cDNA array system and real-time PCR. Our results indicated that the mitogen-activated protein kinase (MAPK) pathway was related to TF expression when PBMCs were treated, in the presence of beta(2)Glycoprotein I (beta(2)GPI), with human monoclonal anti-beta(2)GPI antibodies [beta(2)GPI-dependent anti-cardiolipin antibodies (aCL/beta(2)GPI)]. Western blotting studies using monocyte cell line (RAW264.7) demonstrated that p38 MAPK protein was phosphorylated with nuclear factor kappaB (NF-kappaB) activation by monoclonal aCL/beta(2)GPI treatment, and that SB203580, a specific p38 MAPK inhibitor, decreased the aCL/beta(2)GPI-induced TF mRNA expression. The p38 MAPK phosphorylation, NF-kappaB translocation and TF mRNA expression triggered by aCL/beta(2)GPI were abolished in the absence of beta(2)GPI. These results demonstrated that the p38 MAPK signaling pathway plays an important role in aPL-induced TF expression on monocytes and suggest that the p38 MAPK may be a possible therapeutic target to modify a pro-thrombotic state in patients with APS.
  • O Amengual, T Atsumi, T Koike
    CLINICAL IMMUNOLOGY 112 (2) 144 - 149 1521-6616 2004/08 [Refereed][Not invited]
     
    The preliminary classification criteria for definite anti phospholipid syndrome (APS) include the presence of anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA) as laboratory criteria. However, antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies comprising also antibodies against phospholipid-binding proteins or their complexes with phospholipids. Prothrombin is one of the antigen recognized by aPL. In the last decade, there has been increasing interest in antibodies against prothrombin alone and those against phosphatidylserine-prothrombin complex. The latter, phosphatidylserine-dependent antiprothrombin antibodies (aPT), have been closely associated with APS and LA. In this paper, we review the properties of anti prothrombin antibodies. (C) 2004 Elsevier Inc. All rights reserved.
  • H Das, T Atsumi, Y Fukushima, H Shibuya, K Ito, Y Yamada, Y Amasaki, K Ichikawa, O Amengual, T Koike
    CLINICAL RHEUMATOLOGY 23 (3) 218 - 222 0770-3198 2004/06 [Refereed][Not invited]
     
    Our objective in this study was to explore the diagnostic value of antiagalactosyl IgG antibodies in rheumatoid arthritis (RA). The study comprised 266 Japanese patients with systemic autoimmune diseases, including 60 with RA. Human agalactosyl IgG was prepared enzymatically, and the serum levels of antiagalactosyl IgG antibodies were determined using a lectin enzyme immunoassay. Serum IgG and IgM rheumatoid factors (RF) were measured using laser nephelometry for IgM (LN-RF) and an enzyme-linked immunosorbent assay for IgG (IgG-RF). Antiagalactosyl IgG antibodies were significantly more common in patients with RA than in those without (78% vs. 18%, odds ratio (OR) 16.51, 95% confidence interval (CI) 8.12-33.58, p<0.0001). Patients with RA also had a higher frequency of LN-RF than those without RA (75% vs. 28%, OR 7.81, 95% CI 3.91-15.58, p< 0.001). The specificity of antiagalactosyl IgG antibodies for RA was significantly higher than that of LN-RF (82% vs. 72%, p<0.0011). There was a significant correlation between titers of antiagalactosyl IgG antibodies and C-reactive protein levels. Antiagalactosyl IgG antibodies are more specific markers for RA than conventional LN-RF, and may provide useful information for the diagnosis of RA.
  • S Yasuda, T Atsumi, M Ieko, E Matsuura, K Kobayashi, J Inagaki, H Kato, H Tanaka, M Yamakado, M Akino, H Saitou, Y Amasaki, S Jodo, O Amengual, T Koike
    BLOOD 103 (10) 3766 - 3772 0006-4971 2004/05 [Refereed][Not invited]
     
    beta(2)-Glycoprotein I (beta(2)-GPI) is proteolytically cleaved by plasmin in domain V (nicked beta(2)-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked P2-GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked P2-GPI against total beta(2)-GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked beta(2)-GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked beta(2)-GPI binds to Glu-plasminogen with K-D Of 0.37 x 10(-6) M, presumably mediated by the interaction between the fifth domain of nicked beta2-GPI and the fifth kringle domain of Glu-plasminogen. Nicked beta(2-)GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact beta2-GPI lacks these properties. These data suggest that beta(2)-GPI/plasmin-nicked beta(2)-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop. (C) 2004 by The American Society of Hematology.
  • O Amengual, T Atsumi, MA Khamashta
    RHEUMATOLOGY 42 (9) 1029 - 1031 1462-0324 2003/09 [Refereed][Not invited]
  • K Oku, T Atsumi, S Furukawa, T Horita, Y Sakai, S Jodo, Y Amasaki, K Ichikawa, O Amengual, T Koike
    RHEUMATOLOGY 42 (6) 773 - 777 1462-0324 2003/06 [Refereed][Not invited]
     
    Objective. To assess the significance of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) abnormalities in patients with systemic lupus erythematosus (SLE). Methods. Forty-four patients with SLE were retrospectively analysed. Patients were classified into three groups [1 and 2: patients with central nervous system (CNS) manifestations before and after starting high-dose steroid therapy, respectively; 3: patients without CNS manifestations. MRI was performed in all 44 patients and SPECT in 31. Results. Abnormal findings in MRI were found in 19 patients. MRI abnormalities were significantly more frequent in patients with CNS manifestations than in those without [71 vs 17%, odds ratio (OR) 11.9, confidence interval (CI) 2.8-49.9, P=0.0003]. After the initiation of steroid therapy, patients with CNS manifestations also had an increased frequency of abnormal MRI. No correlation was found between SPECT findings and CNS manifestations. However, patients with CNS manifestations after starting steroids showed a markedly increased frequency of abnormal MRI and SPECT compared with those without CNS manifestations (80 vs 7%; OR 56, CI 4.4-719, P=0.0003). The positive predictive value of abnormality in both techniques in developing CNS manifestations after starting steroids was 89%. Conclusion. MRI findings correlated with CNS manifestations in SLE. Where there is a high suspicion of CNS involvement, the combination of MRI and SPECT may be useful in predicting CNS manifestations after starting steroid therapy.
  • O Amengual, T Atsumi, T Koike
    ARTHRITIS AND RHEUMATISM 48 (4) 886 - 895 0004-3591 2003/04 [Refereed][Not invited]
  • Actualización en el Sindrome Antifosfolipido
    Amengual Olga
    Inmunologia 21 159 - 163 2002 [Refereed][Invited]
  • R Caliz, T Atsumi, E Kondeatis, O Amengual, MA Khamashta, RW Vaughan, JS Lanchbury, GRV Hughes
    RHEUMATOLOGY 40 (1) 31 - 36 1462-0324 2001/01 [Refereed][Not invited]
     
    Objectives. We investigated the association between HLA class II haplotypes and antiphospholipid syndrome (APS). Methods. HLA DRB1, DQB1 and DQA1 genotypes were determined by the polymerase chain reaction using sequence-specific primers in 83 Caucasoid British patients with APS. The genotype frequencies were compared between subgroups of patients acid 177 healthy controls. Results. DPB1*0604/5/6/7/9-DQA1*0102-DRB1*1302 and DQB1*0303-DQA1*0201-DRB1*0701 haplotypes showed significantly positive correlations with APS [P = 0.0087 and P = 0.0012, respectively]. The association of the former was enhanced in primary APS patients with anti-beta2-glycoprotein I antibodies (anti-beta 2GPI) [odds ratio 6.2, 95% confidence interval (2.2-17.6). P = 0.0014, corrected P = 0.042]. Conclusions. These alleles and haplotypes might affect anti-beta 2GPI production and APS development in different and heterogeneous fashion.
  • NM Lewis, K Katsumata, T Atsumi, ML Sanchez, FI Romero, ML Bertolaccini, A Funke, O Amengual, MA Khamashta, GRV Hughes
    ARTHRITIS AND RHEUMATISM 43 (7) 1655 - 1656 0004-3591 2000/07 [Refereed][Not invited]
  • A Elbeialy, K Strassburger-Lorna, T Atsumi, ML Bertolaccini, O Amengual, M Hanafi, MA Khamashta, GRV Hughes
    CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 18 (4) 492 - + 0392-856X 2000/07 [Refereed][Not invited]
     
    Objectives Previous studies showed that antiphospholipid antibodies (aPL) are frequent in the sera of leprosy patients and are most probably directed against body tissue cardiolipins. Some groups have demonstrated differences between the binding specificity of "autoimmune-aPL" and "non-autoimmune-aPL". It is widely accepted that a plasma protein beta 2-Glycoprotein I (beta 2-GPI), is required for the binding of autoimmune anticardiolipin antibodies (aCL) to cardiolipin. However, some reports suggested heterogeneity of leprosy aCL with respect to their beta 2-Glycoprotein I (beta 2GPI) dependency, although no thromboembolic complications have been reported. This study was designed to assess the specificity of aPL by investigating the prevalence of aCL, anti-phosphatidylserine (aPS), anti-phosphatidylinositol (aPI), anti-beta 2GPI and antiprothrombin (aPT) antibodies, and evaluate their clinical significance in a group of patients with lepromatous leprosy. Patients and methods 35 lepromatous leprosy patients were selected randomly from an Egyptian leprosarium as a study group. 35 normal household contact controls were selected matching the study group for both sex and age. aCL, aPS, aPI, aPT, anti-beta 2GPI and beta 2-dependent aCL antibodies were investigated by ELISA in all patients and controls. Results aCL antibodies were more frequent in leprosy patients than in controls [13/35 (37%) vs. 3/35 (9%), respectively, p = 0.02] and significantly correlated with Raynaud's phenomenon, skin modules, chronic skin ulcers and urticarial skin rash. No association was found with hypopigmentation, hyperpigmentation and saddle nose. None of the patients presented aPS nor aPI. Only 1 subject from the control group presented aPI along with aCL. aPT were present in 2/35 (5.7%) and anti-beta 2GPI in 1/35 (2.9%) leprotic patients. None of the individuals from the control group presented aPT nor anti-beta 2GPI. Conclusions An association was found between the presence of aCL and certain dermatological manifestations of leprosy, such as Raynaud's phenomenon, skin nodules, chronic skin ulcers and urticarial skin rash. As in other infectious diseases, there was a lack of beta 2GPI-dependency and an absence of thrombotic complications.
  • ML Bertolaccini, T Atsumi, AR Caliz, O Amengual, MA Khamashta, GRV Hughes, T Koike
    ARTHRITIS AND RHEUMATISM 43 (3) 683 - 688 0004-3591 2000/03 [Refereed][Not invited]
     
    Objective. To investigate the associations between HLA class II genes and antiphosphatidylserine/prothrombin antibodies (aPS/PT) in a group of British caucasoid patients with antiphospholipid antibodies (aPL), Methods. This study included 82 patients with aPL, IgG aPS/PT were detected in sera using enzyme-linked immunosorbent assays. HLA-DQB1, DQA1, and DRB1 genotypes were determined by polymerase chain reaction using sequence-specific primers. All results were compared with 177 matched healthy control subjects. Results. IgG aPS/PT were present in 41 of 82 patients (50%), The frequencies of DQB1*0301/4, DQB1*0604/5/6/7/9, and DRB1*1302 alleles were increased in patients with aPS/PT compared with controls. To minimize the interference of the association between anti-beta(2)-glycoprotein I (anti-beta(2)GPI) and HLA, patients with anti-beta(2)GPI were excluded from further analyses, and only HLA-DQB1*0301/4 remained significant compared with controls (odds ratio [OR] 2.75, 95% confidence interval [95% CI] 1.2-6.5, P < 0.03), In the haplotype analysis, HLA-DQB1*0301/4;DQA1*0301/2;DRB1*04 was significantly increased in patients with IgG aPS/PT compared with controls (OR 4.75, 95% CI 1.72-13.10, P = 0.0063), Conclusion, The HLA-DQB1*0301/4;DQA1*0301/2;DRB1*04 haplotype and its components may influence the production of aPS/PT in the antiphospholipid syndrome, which partly explains the correlation between the lupus anticoagulant and DQB1*03.
  • Comment on the article Apolipoprotein (a) deposition in atherosclerotic coronary arteries of a patient with systemic lupus erythematosus by Asanuma et al.
    Atsumi T, Amengual O, Khamashta MA, Romero FI, Hughes GRV
    Arthritis Rheum . 43 2142  2000 [Refereed][Not invited]
  • Oxidized lipoproteins and the antiphospholipid syndrome.
    Amengual, O, Atsumi T, Khamashta MA
    Seminars Clinical Immunol 1 21 - 27 2000 [Refereed][Not invited]
  • FI Romero, T Atsumi, FJ Tinahones, JM Gomez-Zumaquero, O Amengual, MA Khamashta, GRV Hughes
    ARTHRITIS AND RHEUMATISM 42 (12) 2606 - 2611 0004-3591 1999/12 [Refereed][Not invited]
     
    Objective. To demonstrate the existence of antibodies that react against malondialdehyde (MDA)modified lipoprotein(a) (MDA-Lp[a]), a molecule that exhibits behavioral similarities to MDA-modified low-density lipoprotein (MDA-LDL), and to assess the possible relationship of these antibodies (anti-MDA-Lp[a]) to anti-MDA-LDL antibodies (anti-MDA-LDL) in the antiphospholipid syndrome (APS), Methods. We studied 104 patients with APS (61 with primary APS and 43 with APS secondary to systemic lupus erythematosus) and 106 healthy controls. Anti-MDA-Lp(a) were measured by enzyme-linked immunosorbent assay (ELISA) using MDA-Lp(a) as antigen, Plasma levels of Lp(a) were determined, Anti-MDA-LDL, anticardiolipin antibodies (aCL), and anti-beta(2)-glycoprotein I antibodies (anti-beta(2)GPI) were also measured by ELISA, Inhibition assays were performed to determine the presence of crossreactivity between anti-MDA-Lp(a) and anti-MDA-LDL, Results. Anti-MDA-Lp(a) were detected in 38 of 104 patients (37%) but in only 6 of 106 controls (6%) (chi(2) = 28, P < 0.0001), Levels of anti-MDA-Lp(a) were also higher in patients than in controls (P < 0.0001). Titers of these antibodies did not correlate with plasma levels of Lp(a), The presence of anti-MDA-Lp(a) was significantly associated with that of anti-MDA-LDL (chi(2) = 22.09, P < 0.0001). There was a strong correlation between the titers of anti-MDA-Lp(a) and anti-MDA-LDL (r = 0.59, P < 0.0001), and inhibition assays showed significant cross-reactivity between the 2 populations of antibodies, Anticardiolipin antibodies and anti-beta(2)GPI were present in sera from 67 patients (64%) and 48 patients (46%), respectively, No correlation was found between the titer of anti-MDA-Lp(a) and titers of either aCL or anti-beta(2)GPI, Conclusion, We report for the first time the existence of autoantibodies against MDA-Lp(a), The presence of antibodies reacting not only against MDA-LDL but also against MDA-Lp(a) supports the hypothesis of a role for oxidative phenomena in the pathogenesis of APS and atherosclerosis.
  • T Atsumi, A Tsutsumi, O Amengual, MA Khamashta, GRV Hughes, Y Miyoshi, K Ichikawa, T Koike
    RHEUMATOLOGY 38 (8) 721 - 723 1462-0324 1999/08 [Refereed][Not invited]
     
    Objectives. beta 2-Glycoprotein I (beta 2GPI) exon 7 polymorphism leads to a valine-leucine amino acid exchange at position 247 in domain 5 of beta 2GPI, between the phospholipid binding site and the cryptic site of the epitopes for anti-beta 2CPI antibodies. Therefore, position 247 polymorphism may affect the conformational change of beta 2GPI and the exposure of the epitopes for anticardiolipin antibodies (aCL) (= anti-beta 2GPI antibodies). In this study we analysed the genetic polymorphism of beta 2GPI in a British cohort of well-defined antiphospholipid syndrome (APS) patients. Methods. This study comprised 88 Caucasoid patients with APS [57 with primary APS and 31 with APS secondary to systemic lupus erythematosus (SLE)]. Polymorphism assignment was determined by polymerase chain reaction followed by allele-specific restriction enzyme digestion (PCR-RFLP). The presence of anti-beta 2GPI antibodies was detected by ELISA utilizing irradiated ELISA plates. Results and conclusions. Anti-beta 2CPI antibodies were present in 28 of 57 primary APS patients (49%) and in 19 of 31 secondary APS patients (61%). The allele containing valine(247) was significantly more frequent in primary APS patients with anti-beta 2GPT antibodies than in controls (OR = 2.51, 95% CI 1.03-6.13, P = 0.0396) or in primary APS patients without anti-beta 2GPI antibodies (OR = 2.92, 95% CI 1.16-7.39, Y = 0.0204). This tendency was not found in the secondary APS group. In conclusion, the beta 2GPT polymorphism, valine/leucine(247), is correlated with anti-beta 2GPI antibody production in patients with primary APS, and valine247 may be important in the formation of beta 2GPI antigenicity.
  • JL Pablos, RA Caliz, PE Carreira, T Atsumi, L Serrano, O Amengual, B Santiago, MA Khamashta, GRV Hughes, JJ Gomez-Reino
    JOURNAL OF RHEUMATOLOGY 26 (3) 588 - 590 0315-162X 1999/03 [Refereed][Not invited]
     
    Objective. Antiphospholipid antibodies (aPL) are thrombophilic risk markers in patients with systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). The risk factors for recurrent venous or arterial thrombosis and indications for longterm anticoagulation therapy are debated. We hypothesized that carrying a second thrombophilic defect, factor V Leiden mutation, would increase the risk for thrombosis in patients with aPL. Methods. Seventy-five patients with primary APS and 83 with SLE and aPL with or without thrombosis followed at 2 university hospitals were studied. Factor V mutation rate was analyzed in patients and in 200 healthy blood donors by polymerase chain reaction analysis. Results. The prevalence of factor V Leiden mutation in patients with SLE and aPL or primary APS was similar to controls. Patients with deep vein thrombosis or arterial thrombosis did not have a significantly increased rate of factor V mutation compared to controls or to patients with aPL without thrombosis. Conclusion, Factor V Leiden mutation is not significantly associated with vein thrombosis in patients with aPL. However, due to the sample size we cannot rule out synergy between both factor V Leiden and aPL. A trend toward increased risk for thrombosis was detected in patients with the mutation and this should be analyzed in a larger study.
  • SS Sanfilippo, MA Khamashta, T Atsumi, O Amengual, ML Bertolaccini, D D'Cruz, N Amft, GT Swana, GRV Hughes
    JOURNAL OF RHEUMATOLOGY 25 (11) 2131 - 2134 0315-162X 1998/11 [Refereed][Not invited]
     
    Objective, To clarify risk factors for the development of clinical features of antiphospholipid syndrome (APS) in patients with anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE). Methods, We studied 65 SLE patients, all with positive IgG and/or IgM aCL. Patients were divided into 2 groups; I: 29 SLE patients with features of APS (SLE/APS) and II: 36 aCL positive SLE patients without any feature of APS (SLE/aCL). Serum samples were collected from our serum bank. Anti-beta(2)-glycoprotein I (anti-beta(2)-GPI) were tested by ELISA using irradiated plates in the absence of cardiolipin. Anti-dsDNA antibodies were tested by standard Farr assay. Results. There were no major differences between SLE clinical manifestations in both groups. However, the frequency of IgG anti-beta(2)-GPI was markedly increased in SLE/APS (18/29, 62%) than in SLE/aCL (4/36, 11%) (chi-squared 18.6, p = 0.0001). The levels of anti-dsDNA antibodies in the same samples were slightly lower in SLE/APS. Conclusion. Our data suggest that increased levels of IgG anti-beta(2)-GPI may be a specific feature of SLE/APS patients rather than reflecting a polyclonal B cell activation.
  • ML Bertolaccini, B Roch, O Amengual, T Atsumi, MA Khamashta, GRV Hughes
    BRITISH JOURNAL OF RHEUMATOLOGY 37 (11) 1229 - 1232 0263-7103 1998/11 [Refereed][Not invited]
     
    The family of antiphospholipid antibodies (aPL) includes a heterogeneous population of autoantibodies whose specificity is directed against not only phospholipids, but their complex with plasma proteins. Anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) tests are widely performed to screen the aPL family which is associated with thrombotic complications in patients with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). The clinical significance of other aPL tests, including antibodies against phosphatidylserine (aPS), phosphatidylinositol (aPI), phosphatidic acid (aPA), phosphatidyl choline (aPC) and phosphatidylethanolamine (aPE), has not been established. The purpose of this study was to evaluate whether multiple aPL tests have enhanced diagnostic value for APS. We tested IgG/M/A aPS, aPI, aPA, aPC and aPE by ELISA using 10% bovine serum as blocking and sample diluent in 26 SLE patients with clinical manifestations of APS, but negative for both aCL and LA (Group 1). The results were compared with 32 SLE patients without any features of APS (Group 2) and 24 SLE patients with APS (aCL and/or LA positive) (Group 3). In Group 1, 1/26 (4%) was positive for IgA aPE, less frequent than in other groups, and none of the patients had any other aPL. In Group 2, 1/32 (3%) was positive for aPS, two (6%) for aPI, one (3%) for aPA and four (12.5%) for aPE. None was positive for aPC. In the third group, 13/24 (54%) were positive for aPS, 11 (46%) for aPI, 15 (63%) for aPA, four (17%) for aPC and seven (29%) for aPE. Since aPE was found in some patients, we extended the study, including 207 SLE patients, and tested aPE. IgG/M/A aPE was found in six (3%), 10 (5%) and 21 (10%), respectively, but no association was found between aPE and any clinical features of APS. This study suggests that screening by multiple aPL tests does not increase the diagnostic yield in APS.
  • FI Romero, O Amengual, T Atsumi, MA Khamashta, FJ Tinahones, GRV Hughes
    BRITISH JOURNAL OF RHEUMATOLOGY 37 (8) 883 - 888 0263-7103 1998/08 [Refereed][Not invited]
     
    The prevalence and clinical significance of antibodies against beta(2)-glycoprotein I (anti-beta(2)GPI) and antibodies against oxidized low-density lipoprotein (anti-ox-LDL) were evaluated as potential indicators of arterial disease in patients with systemic lupus erythematosus (SLE) and SLE with secondary antiphospholipid syndrome (APS). IgG anti-beta(2)GPI and IgG anti-ox-LDL were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples from 118 patients with SLE, including 40 with secondary APS. IgG anti-beta(2)GPI were positive in 17% (20/118) of SLE patients. The presence and titres of IgG anti-beta(2)GPI were strongly associated with a history of arterial thrombosis. Haemolytic anaemia was also significantly associated with the presence of IgG anti-beta(2)GPI. The prevalence of IgG anti-ox-LDL was 53% (63/118), but there was no association with arterial thrombosis. No correlation between the values of anti-ox-LDL and those of anti-beta(2)GPI was found. These results suggest that IgG anti-beta(2)GPI could be a marker for arterial thrombosis in SLE patients, while IgG anti-ox-LDL were not associated with arterial disease in this group of lupus patients.
  • O Amengual, T Atsumi, MA Khamashta, ML Bertolaccini, GRV Hughes
    ARTHRITIS AND RHEUMATISM 41 (8) 1513 - 1514 0004-3591 1998/08 [Refereed][Not invited]
  • ML Bertolaccini, T Atsumi, BJ Hunt, O Amengual, MA Khamashta, GRV Hughes
    THROMBOSIS AND HAEMOSTASIS 80 (1) 202 - 203 0340-6245 1998/07 [Refereed][Not invited]
  • ML Bertolaccini, T Atsumi, MA Khamashta, O Amengual, GRV Hughes
    JOURNAL OF RHEUMATOLOGY 25 (6) 1104 - 1108 0315-162X 1998/06 [Refereed][Not invited]
     
    Objective. Prothrombin (factor II) is one of the phospholipid binding proteins with a procoagulant property. Some publications have shown the presence of autoantibodies against prothrombin (aPT) in patients with antiphospholipid antibodies (aPL). We assessed the clinical significance of aPT in thrombotic events in patients with systemic lupus erythematosus (SLE). Methods. IgG and IgM aPT were tested by ELISA in 207 patients with SLE, Results. Fifty-eight patients (28%) had positive aPT (> mean + 3 SD of 100 controls). Twenty-eight (14%) had IgG alone, 21 (10%) IgM alone, and 9 (4%) had both IgG and IgM, Patients with aPT had a history of thrombosis more frequently than those without aPT [31/58 (53%) vs 47/149 (32%), chi-squared = 7.6, p = 0.006]. No correlation was found between the presence of aPT and clinical features of SLE. Conclusion. aPT are frequently found in patients with SLE, and are a potential marker for thrombosis.
  • T Atsumi, MA Khamashta, O Amengual, S Donohoe, Mackie, I, K Ichikawa, T Koike, GRV Hughes
    CLINICAL AND EXPERIMENTAL IMMUNOLOGY 112 (2) 325 - 333 0009-9104 1998/05 [Refereed][Not invited]
     
    It is known that antiphospholipid antibodies (aPL) hamper the anticoagulant activity of the protein C system, but the mechanism is still obscure. In this study, we demonstrate that anticardiolipin antibodies (not anti-protein C autoantibodies) can bind protein C via beta(2)-GPI, which bears their binding epitope, in a fashion dependent on negatively charged phospholipids. We studied the binding of IgG from aPL to protein C in the presence of beta(2)-GPI by ELISA (anti-'protein C' antibody ELISA), and compared their binding with those obtained in the absence of beta(2)-GPI. In the anti-'protein C' antibody ELISA system, 47% of 78 aPL(+) patients had a positive titre in the presence of cardiolipin (CL) and beta(2)-GPI, but binding was not found in the absence of beta(2)-GPI. Highly significant correlations were found between the titre of anti-'protein C' antibody in the presence of beta(2)-GPI and that of anti-beta(2)-GPI antibody (r=0.802, P = 0.0001). We further analysed the interaction between protein C, phospholipids, beta(2)-GPI and human aCL MoAbs established from patients with antiphospholipid syndrome. In a first set of experiments, the binding of beta(2)-GPI to protein C and its phospholipid dependency were investigated. beta(2)-GPI bound to protein C in the presence of CL or phosphatidylserine, but not in the presence of phosphatidylcholine or phosphatidylethanolamine. In a second group of experiments, the binding of three human monoclonal aCL recognizing the cryptic epitope of beta(2)-GPI (virtually anti-beta(2)-GPI antibodies) was evaluated in the presence of cardiolipin and beta(2)-GPI. All three human monoclonal aCL bound to protein C in the presence of CL and beta(2)-GPI, whereas they did not in the absence of either beta(2)-GPI or CL. These data suggest that protein C could be a target of aCL by making a complex with CL and beta(2)-GPI, leading to protein C dysfunction.
  • T Atsumi, MA Khamashta, RS Haworth, G Brooks, O Amengual, K Ichikawa, T Koike, GRV Hughes
    ARTHRITIS AND RHEUMATISM 41 (5) 800 - 807 0004-3591 1998/05 [Refereed][Not invited]
     
    Objective. To explore a possible correlation between endothelin 1 (ET-1), the most potent endothelium-derived contracting factor that modulates vascular smooth muscle tone, and arterial disease in patients with the antiphospholipid syndrome (APS), Methods. Plasma levels of ET-1 were measured in APS patients with (n = 16) and without (n = 11) arterial thrombosis and in non-APS patients with arterial thrombosis (n = 9), In addition, steady-state prepro-ET-l messenger RNA (mRNA) levels were determined in endothelial cells treated with a range of human monoclonal anticardiolipin antibodies (aCL) (as anti-beta(2)-glycoprotein I antibodies) by semiquantitative P-32-dCTP-labeled reverse transcription-polymerase chain reaction. Results. Compared with healthy controls, markedly increased plasma levels of ET-1 were found in APS patients with arterial thrombosis (2.00 +/- 0.87 versus 0.96 +/- 0.37 pg/ml; P = 0.0001) but not in other groups. Three human monoclonal aCL induced prepro-ET-l mRNA levels significantly more than did control monoclonal antibody lacking aCL activity, Conclusion. Plasma ET-1 levels correlated significantly with a history of arterial thrombosis in patients with APS. Prepro-ET-l mRNA was induced by human monoclonal aCL in the in vitro experimental system. The induction of ET-1 by antiphospholipid antibodies might contribute to increased arterial tone, leading to vasospasm and, ultimately, to arterial occlusion.
  • T Atsumi, R Caliz, O Amengual, MA Khamashta, GRV Hughes
    THROMBOSIS AND HAEMOSTASIS 79 (5) 924 - 927 0340-6245 1998/05 [Refereed][Not invited]
     
    A role for Fc gamma receptor in the pathophysiology of thrombosis in APS has been hypothesized. The polymorphism of this receptor, Fc gamma RIIA H/R131, is associated with the binding affinity for human IgG(2) (i.e. Fc gamma RIIA-H131 isoform has a higher affinity than Fc gamma RIIA-R131). Since anti-beta(2) glycoprotein I antibodies (anti beta(2)GPI), which play a major pathogenic role in APS, show IgG(2) dominant distribution, we investigated the prevalence of receptor isoforms in patients with antiphospholipid antibodies (aPL) by a PCR-RFLP method. We studied 100 Caucasian patients with aPL. (57 primary APS, 32 secondary APS to SLE and II other diseases with aPL) and 41 healthy controls. H131/H131, H131/R131 and R131/R131 genotypes were found in 21 (21%), 50 (50%) and 19 (29%) in the patient group, and 9 (22%). 23 (56%) and 9 (22%) in control group, respectively. Thus there was no statistically significant difference in the prevalence of each genotype in these groups. None of the clinical manifestations of primary APS (arterial/venous thrombosis, recurrent pregnancy loss and thrombocytopenia) was significantly correlated with any Fc gamma RIIA genotype. In conclusion, Fc gamma RIIA polymorphism did not correlate with the manifestations of APS, and Fc gamma IIA genotype is not a genetic marker of APS.
  • O Amengual, T Atsumi, MA Khamashta, GRV Hughes
    THROMBOSIS AND HAEMOSTASIS 79 (2) 276 - 281 0340-6245 1998/02 [Refereed][Not invited]
     
    The antiphospholipid syndrome (APS) is characterised by both arterial and venous thrombosis, recurrent pregnancy loss and thrombocytopaenia in association with antiphospholipid antibodies (aPL). To explore further the pathogenesis of thrombosis in APS, we evaluated the behaviour of tissue factor (TF) pathway in patients with APS. Plasma antigen levels of soluble TF and tissue factor pathway inhibitor (TFPI), a physiological regulator of TF dependent coagulation activation, were measured in 57 APS patients (36 primary and 21 secondary to systemic lupus erythematosus). Significantly elevated levels of both TF and TFPI were found in AP-S patients compared with 25 healthy controls (279 +/- 15 vs. 217 +/- 17 pg/ml, p = 0.01; 56.24 +/- 2.00 vs. 47.92 +/- 2.22 ng/ml, p = 0.01, respectively), suggesting in vivo upregulation of TF pathway in patients with APS. By flow-cytometry, monocytes from a healthy donor displayed higher TF antigen expression when incubated in the presence of APS plasmas than in control plasmas (24.23 +/- 3.11 vs. 12.78 +/- 1.57%, p = 0.002). Peripheral blood mononuclear cells (PBMC) also expressed more procoagulant activity (PCA) when incubated in the presence of APS plasmas than in control plasmas (1.80 +/- 0.12 vs. 1.35 +/- 0.054, p = 0.001) implying that TF up-regulation in APS was reproducible in vitro. Human monoclonal anticardiolipin antibodies induced PCA on PBMC and also TF mRNA on both PBMC and human umbilical vein endothelial cells shown by reverse-transcription polymerase chain reaction. These data strongly suggest that the TF pathway is implicated in the pathogenesis of aPL related thrombosis.
  • T Atsumi, MA Khamashta, C Andujar, MJ Leandro, O Amengual, PRJ Ames, GRV Hughes
    JOURNAL OF RHEUMATOLOGY 25 (1) 69 - 73 0315-162X 1998/01 [Refereed][Not invited]
     
    Objective. To assess the significance of lipoprotein(a) [Lp(a)], a risk factor for atherothrombosis, and its relationship with fibrinolysis in a cohort of patients with antiphospholipid syndrome (APS). Methods. Plasma levels of Lp(a) were measured in 68 patients with APS (42 primary, 26 secondary to systemic lupus erythematosus), Results. Elevated plasma levels of Lp(a) were found in patients with APS compared to 22 healthy controls (p = 0.0001). The significance persisted after comparing Lp(a) levels in 3 APS subgroups (arterial thrombosis, n = 37; venous thrombosis, n = 31; recurrent miscarriages, n = 24) with those of controls (p < 0.0001). Patients with APS with maximal elevation of Lp(a) showed a lower fibrinolytic activity (lower D-dimer and higher plasminogen activator inhibitor) than patients whose Lp(a) was within a normal range. Conclusion. These findings suggest that Lp(a) may represent a marker of APS and that Lp(a) has a negative effect on the fibrinolytic system that might contribute to the thrombotic tendency of APS.
  • Mendonça LLF, Amengual O, Atsumi T, Khamashta MA, Hughes GRV
    JOURNAL OF RHEUMATOLOGY 25 (1) 189 - 190 0315-162X 1998/01 [Refereed][Not invited]
  • Amengual O, Atsumi T, Khamashta MA, Hughes GR
    Annals of the Academy of Medicine, Singapore 1 27 61 - 66 0304-4602 1998/01 [Refereed][Not invited]
  • MA Khamashta, O Amengual, T Atsumi
    BRITISH JOURNAL OF RHEUMATOLOGY 36 (11) 1235 - 1235 0263-7103 1997/11 [Refereed][Not invited]
  • O Amengual, T Atsumi, MA Khamashta, F Tinahones, GRV Hughes
    BRITISH JOURNAL OF RHEUMATOLOGY 36 (9) 964 - 968 0263-7103 1997/09 [Refereed][Not invited]
     
    The prevalence and clinical significance of anti-oxidized low-density lipoprotein antibodies (anti-ox-LDL) were evaluated in patients with the antiphospholipid syndrome (APS). Anti-ox-LDL were measured in the sera of 107 patients with APS (64 primary APS, 43 secondary to systemic lupus erythematosus) by enzyme-linked immunosorbent assay (ELISA) utilizing malondialdehyde (MDA)-modified LDL as antigen. In the same patients, anticardiolipin antibodies (aCL) and anti-beta 2-glycoprotein I antibodies (anti-beta 2GPI) were also measured. A positive titre of anti-ox-LDL was detected in 22% of patients, but only in 6% of control subjects (chi(2) = 12, P = 0.0005). Levels of anti-ox-LDL were higher in patients with arterial thrombosis (n = 58) than in those without (n = 49) (P = 0.0001). Anti-ox-LDL levels correlated weakly with those of aCL (r = 0.196, P = 0.043), but not with those of anti-beta 2GPI (r = 0.076). Our findings suggest that elevated levels of anti-sx-LDL may represent another potential marker of APS, particularly of patients prone to arterial thrombosis.
  • Lipids and atherosclerosis in systemic lupus erythematosus
    Ames PRJ, Amengual O, Atsumi T, Khamashta MA
    Lipidos Research 1 17 - 19 1997 [Refereed][Invited]
  • Significado clínico de los anticuerpos antifosfolípido
    Amengual O, Cuadrado MJ, Khamashta MA
    Jano 3 58 - 60 1997 [Refereed][Invited]
  • T Atsumi, MA Khamashta, O Amengual, GRV Hughes
    THROMBOSIS AND HAEMOSTASIS 77 (1) 222 - 223 0340-6245 1997/01 [Refereed][Not invited]
  • O Amengual, T Atsumi, MA Khamashta, T Koike, GRV Hughes
    BRITISH JOURNAL OF RHEUMATOLOGY 35 (12) 1239 - 1243 0263-7103 1996/12 [Refereed][Not invited]
     
    The clinical significance of anti-beta 2 glycoprotein I (beta 2-GPI) antibodies was evaluated in patients with antiphospholipid syndrome (APS), primary and secondary to systemic lupus erythematosus (SLE): Anti-beta 2-GPI were tested in 120 patients (39 primary APS, 32 APS with SLE and 49 SLE without APS) by ELISA utilizing irradiated plates in the absence of cardiolipin. Anticardiolipin antibodies (aCL) and antiphosphatidylserine antibodies were also measured in the same patients using standardized assays. Anti-beta 2-GPI titres correlated strongly to those of aCL (r = 0.816, P = 0.0001), and to those of antiphosphatidylserine antibodies (r = 0.841, P = 0.0001). Anti-beta 2-GPI were detected in 53.5% of APS patients (38/71), but only in 4.1% of SLE patients without APS (2/49). In the latter group, 24.5% (12/49) of patients had a positive titre of aCL. The anti-beta 2-GPI assay showed higher specificity for APS than the aCL in APS (96 as 75%, respectively, chi(2) = 6.75, P = 0.00094). Our findings suggest that the assay of anti-beta 2-GPI may improve the specificity for APS.
  • O Amengual, T Atsumi, MA Khamashta, GRV Hughes
    ANNALES DE MEDECINE INTERNE 147 15 - 17 0003-410X 1996/09 [Refereed][Not invited]
     
    Antiphospholipid antibodies are a heterogeneous group of autoantibodies with clinical importance because of their strong association with thrombotic events. Recent evidence have shown that antiphospholipid antibodies are not directed against phospholipids, as has previously been thought, but are a part of a large family of autoantibodies against phospholipid-binding plasma proteins. So far, one of the most common and best characterized antigenic target is beta(2)-glycoprotein I (beta(2)-GPI), which plays an important role in the binding of anticardiolipin antibodies (aCLA) to cardiolipin. The detection of anti-beta(2)-GPI antibodies by using a simple and rapid ELISA may facilitate the recognition of <<pathogenic>> aCL in antiphospholipid syndrome.
  • Anticuerpos antifosfolípido
    Cuadrado MJ, Amengual O, Khamashta MA
    Rev Esp Reumatol 23 389 - 395 1996 [Refereed][Invited]

MISC

Books etc

  • Pathogenesis of antiphospholipid syndrome. In Systemic lupus erythematosus, basic, applied and clinical aspects.
    Olga Amengual, Tatssuya Atsumi (ContributorEdited by George C Tsokos. Chapter 56)
    Academic Press 2020
  • Women and Science. (In Spanish)
    García-Martín F, Rosich M, de Vega S, San Gabriel A, Amengual O (Contributor)
    Journal of Science and Humanities Fundación Areces. 2018/07
  • Clinical and Prognostic Significance of Non-criteria Antiphospholipid Antibody Tests. In Antiphospholipid Syndrome: Current Research Highlights and Clinical Insights.
    Bertolaccin ML, Amengual O, Artim-Eser B, Atsumi T, de Groot PG, de Laat, B, Devreese K, Giles I, Meroni PL, Borghi MO, Rahman A, Rand J, Regnault V, Kumar R, Tincani A, Wahl D, Willis R, Zuily S, Sanna G (ContributorEdited by Doruk Erkan and Dr. Michael Lockshin.)
    Springer International Publishing 2017
  • Disease and Risk Measurement Criteria in APS. Antiphospholipid score. In Antiphospholipid Syndrome: Current Research Highlights and Clinical Insights.
    Amigo MC, Oku K, Sciascia S, Goycoechea-Robles MV, Zuily S, Amengual O, Roccatello D, Otomo K, Atsumi T, Bertolaccini ML, Wahl D (ContributorEdited by Doruk Erkan and Dr. Michael Lockshin.)
    Publisher Springer International Publishing 2017
  • Laboratory Markers with clinical significance in the antiphospholipid Syndrome.In: Cervera R, Khamashta MA, editors Antiphospholipid Syndrome in Systemic Autoimmune Diseases
    Amengual O, Bertolaccini ML, Atsumi T (Others)
    Elsevier 2016
  • Pathogenesis of antiphospholipid syndrome. In: George C Tsokos, editor.Systemic lupus erythematosus, basic, applied and clinical aspects
    Olga Amengual, Tatsuya Atsumi 
    Academic Press 2016
  • Task Force Report on “Non-criteria” Antiphospholipid Antibodies test. In: Erkan D and Pierangeli SS, Editors. Antiphospholipid Syndrome: Insights and Highlights from the 13th International Congress on Antiphospholipid Antibodies.
    Bertolaccini L, Amengual O, Atsumi T, Binder W, Kutteh WH, Laat B, Forastiero R, Kutteh W, Lambert M, Matsubayashi H, Murthy V, Petri M, Rand J, Sanmarco M, Tebo A, Pierangeli S (Others)
    Springer 2012
  • Antiphospholipid syndrome pathogenesis.In: Lahita RG, editor. Systemic Lupus Erythematosus, 5th edition.
    Atsumi T, Amengual O, Koike T 
    San Diego: Academic Press 2010
  • Ethiopathology of the antiphospholipid syndrome.In: Tanaka K and Davie EW editors. Recent Advances in Thrombosis and Haemostasis
    Atsumi T, Amengual O, Koike T (In: Tanaka K and Davie EW editors. Recent Advances in Thrombosis and Haemostasis)
    Springer Japan KK 2008
  • Antiphospholipid antibodies and the antiphospholipid syndrome.In: New Innmunology Research Developments
    Amengual O, Atsumi T, Koike T (In: New Innmunology Research Developments)
    Nova Publishers, Inc 2008
  • Genetics of antiphospholipid syndrome.In: Khamashta MA editor. Hughes Syndrome: Antiphospholipid syndrome, 2nd edition
    Atsumi T, Amengual O (In: Khamashta MA editor. Hughes Syndrome: Antiphospholipid syndrome, 2nd edition)
    London Springer-Verlag , 2006
  • Antiphospholipid syndrome and atherosclerosis. In: Atherosclerosis and Autoimmunity. Y Shoenfeld, D Harats and G. Wick editors,
    Amengual O, Atsumi T, Khamashta MA, Hughes GRV 
    Elseviere Science B.V 2001
  • "Endotheliology” in antiphospholipid antibodies. In: Atherosclerosis and Autoimmunity. Y Shoenfeld , D Harats and G. Wick editors.
    Atsumi T, Amengual O, Khamashta MA 
    Elseviere Science B.V. 2001
  • Antiprothombin antibodies. In: Khamashta MA editor. Hughes Syndrome
    Bertolaccini ML, Amengual O, Atsumi T 
    London Springer; 2000
  • Los anticoagulantes y antiagregantes plaquetarios. In: Manual de inflamación
    Cuadrado MJ, Amengual O 
    Medical & Marketing Communications SL. Madrid 1999

Presentations

  • 魚の摂取量が関節リウマチ患者の分子標的治療に与える影響に関する研究
    垂水 政人, アメングアルオルガ, 藤枝雄一郎, 安田允孝, 小住由依, 竹山脩平, 吉村大, 久田諒, 河野 通仁, 加藤 将, 渥美 達也
    日本臨床リウマチ学会, 札幌  2022/10
  • Advances in the management of Rheumatoid Arthritis  [Invited]
    Olga Amengual
    School of Pharmaceutical Sciences, Fukuoka, Japan.  2022/06
  • Intake of fish rich in n-3 polyunsaturated fatty acids is associated with good response to treatment in rheumatoid arthritis patients receiving targeted therapies
    Tarumi M, Amengual O, Fujieda Y, Navidad Fuentes M, Tsuchida N, Yasuda M, Nishino K, Kosumi Y, Takeyama S, Yoshimura M, Ninagawa K, Aso K, Kono M, Kato M, Cáliz Cáliz R, Atsumi T
    The Annual European Congress of Rheumatology (EULAR)  2022/06
  • Antiphospholipd Syndrome International Research Collaboration  [Invited]
    Olga Amengual
    The 16th symposium of the academic standardization committee of the Japanese society of thrombosis and hemostasis, Web  2022/02
  • Rheumatology and the Spectrum of rheumatic diseases  [Invited]
    School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan  2022/01
  • Advances in the treatment of Rheumatoid Arthritis  [Invited]
    Olga Amengual
    School of Pharmaceutical Sciences, Kyushu University, Fukuoka  2021/07
  • What is Rheumatology? Rheumatology in the healthcare system  [Invited]
    the School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan  2020/07
  • Prophylaxis for the prevention of obstetric complications in asymptomatic women with antiphospholipid antibodies.
    Amengual O, Fujita D, Otta E, Carmona L, Kenji O, Sugiura-Ogasawara M, Murashima A, Atsumi T
    The Annual European Congress of Rheumatology EULAR, Rome, Italy  2020/06
  • Measures to prevent COVID-19 infection  [Invited]
    Olga Amengual
    Webinar entitled “What we are learning about covid-19 combined experiences from Japan and Spain” organized by the Association of Spanish Researchers in Japan (ACE Japón)  2020/04
  • Effects of fish consumption on response to targeted therapies in Japanese and Spanish rheumatoid arthritis patients.
    Amengual O, Caliz R
    超異分野 meetup -Toward innovation beyond boundaries. Organized by Hokkaido Diversity Research Environment Promotion Network.  2020/03
  • Long-term effect of a medical English course on communication abilities of graduate medical students.
    Amengual O, Fujieda Y, Oku K, Atsumi T
    Asia Pacific Medical Education Conference (APMEC), Singapore  2020/01
  • Clinical significance of antiphospholipid antibodies and management of the antiphospholipid syndrome  [Invited]
    Olga Amengual
    Inter-hospital clinical session for hospitals in the region of Andalucía held at the Hospital Virgen de la Nieves,Granada. Spain  2020
  • What is Rheumatology? Importance in the health system  [Invited]
    Olga Amengual
    Sapporo English Medical Interpreters' (SEMI) Group  2019/12
  • International collaborative approach in the antiphospholipid syndrome
    Olga Amengual
    Second meeting of the Association of Spanish Researchers in Japan (ACE Japón), ). Okinawa OIST,  2019/11
  • IgG phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome.
    Amengual O, Sugiura-Ogasawara M, Oku K, Murashima A, Atsumi T
    44th Meeting of Japanese Society for Clinical Immunology, Tokyo  2019/09
  • Sapporo, the city of Antiphospholipid Syndrome
    Olga Amengual
    First meeting of the Association of Spanish Researchers in Japan ( ACE Japan). Tokyo, Japan  2018/11
  • Longitudinal evolution of IgM phosphatidylserine-dependent antiprothrombin antibody titers in patients with autoimmune diseases.
    Amengual O, Nakamura H, Oku K, Hisada R, Fujieda Y, Kato M, Bohgaki T, Yasuda S, Atsumi T
    The 10th Congress of the Asian-Pacific Society on Thrombosis and Hemostasis, Sapporo, Japan  2018/06
  • Clinical relevance of testing IgM phosphatidylserine dependent antiprothrombin antibodies.
    Amengual O, Nakamura H, Oku K, Hisada R, Fujieda Y, Kato M, Bohgaki T, Yasuda S, Atsumi T
    The 10th Congress of the Asian-Pacific Society on Thrombosis and Hemostasis, Sapporo, Japan  2018
  • Pain and stiffness in pelvic girdle, a case discussion.  [Invited]
    Olga Amengual
    リウマチ・膠原病診療のピットフォール. Sapporo, Japan  2017/09
  • IgG phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome.
    Amengual O, Sugiura-Ogasawara M, Oku K, Murashima A, Atsumi T
    44th Meeting of Japanese Society for Clinical Immunology, Tokyo, Japan  2017/09
  • Postgraduate Medical English education and recommendations for medical English education in the primary care
    Olga Amengual, Manabu Murakami, Toshiyuki Bohgaki , Kenji Oku, Tatsuya Atsumi.
    日本プライマリ・ケア連合学会北海道ブロック支部第4回地方会, 札幌  2016/07
  • Pre-Graduation Medical English Education for Undergraduates and Proposals for Medical English Education in Primary Care.
    Olga Amengual, Manabu Murakami, Toshiyuki Bohgaki, Kenji Oku, Tatsuya Atsumi
    日本プライマリ・ケア連合学会北海道ブロック支部第4回地方会  2016/07
  • Women Physicians in Europe: Career & Family Balance.  [Invited]
    Olga Amengual
    Hokkaido Medical Association Hokkaido. Sapporo, Japan  2016/02
  • Why Rheumatology is important in the health care system?  [Invited]
    Olga Amengual
    Takikawa City Hospital, Hokkaido Japan  2015/11
  • Impact of a medical English program in communication skills of graduate medical students.
    Olga Amengual, Murakami M, Jego EH, Bohgaki T, Oku K, Otaki J, Atsumi T
    The Annual Meeting of the Spanish Society for medical Education. Murcia, Spain  2015/10
  • Impact of a medical English course on communication skills of medical students.
    Amengual O, Murakami M, Jego EH, Bohgaki T, Oku K, Otaki J
    The 47th Annual Meeting of the Japan Society for medical Education. Niigata, Japan  2015/07
  • Prophylaxis for the prevention of obstetric complications in asymptomatic women with antiphospholipid antibodies
    Amengual O, Fujita D, Otta E, Carmona L, Kenji O, Sugiura-Ogasawara M, Murashima A, Atsumi T
    The Annual European Congress of Rheumatology EULAR, Rome, Italy  2015/06
  • Significance of IgG phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results from the initial and validation studies.
    Amengual O, Forastiero R, Sugiura-Ogasawara M, Oku K, Otomo K, Alves J, C. Favas C, Zigon P, Ambrozic A, Tomšic M, Ruiz-Irastorza G, Ruiz-Arruza I, Bertolaccini ML, Norman GL, Shums Z, Arai J
    The Annual European Congress of Rheumatology EULAR, Rome, Italy  2015/06
  • International Multi-centre study to evaluate the clinical significance of phosphatidylserine-dependent antiprothrombin antibodies o the diagnosis of antiphospholipid syndrome.
    Amengual O, Forastiero R, Sugiura-Ogasawara M, Oku K, Otomo K, Alves J, C. Favas C, Zigon P, Ambrozic A, Tomšic M, Ruiz-Irastorza G, Ruiz-Arruza I, Bertolaccini ML, Norman GL, Shums Z, Arai J, Atsumi T
    European League Against Rheumatism, EULAR, Paris, France  2014/06
  • What is a systematic review?  [Invited]
    Olga Amengual
    Ten Topics in Rheumatology  2012/09
  • A comparative analysis of the methods to detect phosphatidylserine-dependent antiprothrombin antibodies.  [Not invited]
    Olga Amengual
    6th Annual Congress of Asia Pacific Society on Thrombosis and Haemostasis, Bali, Indonesis  2010/10
  • A comparative analysis of the methods to detect phosphatidylserine-dependent antiprothrombin antibodies
    Amengual O, Atsumi T, Binder W, Arai J, Kato M, Otomo K, Fujieda Y, Horital T, Yasuda S, Takao K
    6th Annual Congress of Asia Pacific Society on Thrombosis and Haemostasis. Bali, Indonesia  2010/10
  • Up-regulated expression of Phospholipid Scramblase 1 in antiphospholipid syndrome: a novel pathogenic mechanism of thrombosis.  [Not invited]
    Amengual O, Atsumi T, Suzuki E, Oku K, Kato M, Otomo K, Fujieda Y, Kataoka H, Horita T, Yasuda S, Koike T
    7th International Congress on Autoimmunity Ljubljana, Slovenia  2010/05
  • Up-regulated expression of Phospholipid Scramblase 1 on monocytes in patients with antiphospholipid syndrome.
    Amengual O, Atsumi T, Suzuki E, Oku K, Hashimoto T, Kato M, Otomo K, Fujieda Y, Kataoka H, Horita T, Yasuda S, Koike T
    American College of Rheumatology 73rd Annual Scientific Meeting, Philadelphia, USA, October  2009/10
  • Aminophospholipid translocase (ATP10A) polymorphisms and the risk of thrombosis in patients with antiphospholipid antibodies.
    Amengual O, Atsumi T, Horita T, Kataoka H, Yasuda S, Koike T
    American College of Rheumatology 71th National Scientific Meeting, Boston MA, USA  2007/11
  • Beta2glycoprotein I-dependent anticardiolipin antibodies-induced tissue factor expression is enhanced by interferon alpha; a crucial role for lipid scramblase 1.
    Amengual O, Atsumi T, Kataoka H, Horita T, Yasuda S, Koike T
    American College of Rheumatology 70th National Scientific Meeting, Washington DC, USA  2006/11
  • The role of;lipid;scramblase;in the induction of;issue;factor mediated by bet;lycoprotein I-dependent anticardiolipin antibodies
    Amengual O, Atsumi T, Oku K, Kataoka H, Horita T, Yasuda S, Koike T
    5th International Congress of Autoimmunity, Sorrento, Italy  2006/11
  • Induction of Lipid Scramblase mRNA by Antiphosphospholip Antibodies: A New Possible Pathogenic Mechanism of Thrombosis in Patients with Antiphospholipid Syndrome.
    Amengual O, Atsumi T, Sakai Y, Tetsuya H, Shinsuke Y, Takao K
    American College of Rheumatology 69th National Scientific Meeting, San Diego, USA  2005/11
  • The value of IgM phosphatidylserine dependent antiprothrombin antibody determination for the diagnosis of antiphospholipid syndrome.
    Amengual O, Atsumi T, Kon Y, Sakai Y, Bohgaki M, Furukawa S, Yasuda S, Amasaki Y, Ieko M, Koike T
    11th International Congress on Antiphospholipid Antibodies. Sydney, Australia,  2004/11
  • Diagnostic value of matrix metalloproteinase 3 (MMP-3) in serum of patients with arthralgias.
    Amengual O, Atsumi T, Yasuda S, Amasaki Y, Koike T
    American College of Rheumatology 68th National Scientific Meeting, San Antonio, USA  2004/10
  • The determination of IgM phosphatidylserine dependent antiprothrombin antibodies is a useful tool for the evaluation of patients with lupus anticoagulant
    Amengual O, Atsumi T, Kon Y, Sakai Y, Furukawa S, Yasuda S, Jodo S, Amasaki Y, Koike T
    7th International Congress SLE and related conditions. New York, USA  2004/05
  • Diagnostic value of matrix metalloproteinase-3 (MMP-3) serum levels in rheumatoid arthritis (RA)
    Amengual O, Atsumi T, Jodo S, Amasaki Y, Koike T
    48th General Assembly and Scientific Meeting of Japan College of Rheumatology, Okayama, Japan  2004/04
  • The human platelet antigen 6Wb represents a risk factor for thrombosis in patients with systemic lupus erythematosus.
    Amengual O, Atsumi T, Komano Y, Jodo S, Amasaki Y, Ichikawa K, Koike T
    American College of Rheumatology 66th National Scientific Meeting. New Orleans, USA  2002/10
  • Glycoprotein IIIA polymorphism HPA6Wa/b and aPL are independent risks for thrombocytopenia in patients with SLE. 10th International Symposium on Antiphospholipid Antibodies
    Amengual O, Atsumi T, Komano Y, Jodo S, Amasaki Y, Ichikawa K, Koike T
    Taormina, Italy,  2002/09
  • Update in the antiphospholipid syndrome  [Invited]
    Olga Amengual
    Annual Meeting of the Spanish Society of Immunology  2002/06
  • Sindrome antifosfolipido  [Not invited]
    Olga Amengual
    Meeting of the Extremena Society of Rheumatology, Caceres, Spain  2000
  • IgG2 restriction of anti2 Glycoprotein I antibodies in patients with antiphospholipid syndrome.
    Amengual O, Atsumi T, Khamashta MA, Bertolaccini ML, Hughes GRV
    American College of Rheumatology 62nd National Scientific Meeting, San Diego, USA  1998/11
  • IgG2 restriction of anti2 Glycoprotein I antibodies in patients with antiphospholipid syndrome
    Amengual O, Atsumi T, Khamashta MA, Bertolaccini ML, Hughes GRV
    The 8th International Symposium on Antiphospholipid Antibodies, Sapporo Japan  1998/10
  • Thrombotic mechanisms in autoimmune diseases  [Not invited]
    Olga Amengual
    Ten Topics , Barcelona, Spain  1998/07
  • Restriction of anti-2 glycoprotein I antibodies to the IgG2 subclass in patients with antiphospholipid syndrome.
    Amengual O, Atsumi T, Khamashta MA, Bertolaccini ML, Hughes GRV
    Annual Meeting of the Spanish Society of Rheumatology, Cádiz, Spain  1998/05
  • Induction of tissue factor expression by antiphospholipid antibodies.
    Amengual O, Atsumi T, Khamashta MA, Hughes GRV
    American College of Rheumatology 61st National Scientific Meeting. Washington,USA,  1997/11
  • Up-regulation of tissue factor (TF) in patients with antiphospholipid syndrome (APS)
    Amengual, O, Atsumi T, Khamashta MA, Hughes GRV
    Annual General Meeting of the British Society for Rheumatology, Harrogate, UK  1997
  • Increased plasma levels of tissue factor in patients with antiphospholipid syndrome
    Amengual O, Atsumi T, Khamashta MA, Hughes GRV
    American College of Rheumatology 60th National Scientific Meeting. Orlando, USA  1996/10
  • Antibodies against oxidized low-density lipoprotein in 107 patients with antiphospholipid syndrome.
    Amengual O, Atsumi T, Khamashta MA, Tinahones F, Cuadrado MJ, Hughes GRV
    American College of Rheumatology 60th National Scientific Meeting. Orlando, USA  1996/10
  • Increased plasma levels of tissue factor in patients with antiphospholipid syndrome.
    Amengual O, Atsumi T, Khamashta MA, Hughes GRV
    7th International Symposium on Antiphospholipid Antibodies. New Orleans, Louisiana, USA  1996/10
  • Clinical significance of antiphospholpid antibody family  [Not invited]
    Olga Amengual
    Anual Meeting of the SORCOM, Madrid, Spain  1996/06
  • Beta 2-glycoprotein I antibody specificity in patients with the antiphospholipid syndrome.
    Amengual O, Atsumi T, Khamashta MA, Hughes GRV
    Annual General Meeting of the British Society for Rheumatology. Brighton, UK  1996
  • Beta 2-glycoprotein I antibody specificity in patients with the antiphospholipid syndrome
    Amengual O, Atsumi T, Khamashta MA, Hughes GRV
    Second Meeting of the European Haematology Association. Paris, France  1996
  • Thrombosis and antiphospholipid antibodies  [Not invited]
    Olga Amengual
    Multidisciplinary Simposium on systemic lupus eryhtematosus, Hospital Juan Ramón Jiménez, Huelva,Spain  1995/11
  • Specificity of ELISA for antibody to beta 2-glycoprotein I in patients with antiphospholipid syndrome.
    Amengual O, Atsumi T, Khamashta MA, Hughes GRV
    American College of Rheumatology 59th National Scientific Meeting. San Francisco, USA  1995/10
  • Cyclosporine therapy in autoimmune rheumatological diseases of childhood.
    Amengual O, Gamir ML, Román E, Navío T, Revenga M, Garmendia EE
    The Annual Meeting of the Spanish Society of Rheumatology, Sevilla, Spain  1994/05

Teaching Experience

  • Coordinator and Lecturer of English Medical ProgramCoordinator and Lecturer of English Medical Program Department of Rheumatology, Endocrinology and Neprology, Hokkaido University Gradutate School of Medicine)
  • Lecturer in the course "Expert English"Lecturer in the course "Expert English" School of Pharmaceutical Sciences, Fukuoka, Japan
  • Lecturer in the course "Expert English"Lecturer in the course "Expert English" School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
  • Lecturer in the Course Basic Clinical Medicine-I for Graduate StudentsLecturer in the Course Basic Clinical Medicine-I for Graduate Students Hokkaido University, Faculty of Medicine and Graduate School of Medicine
  • Lecturer in the course "Expert English"Lecturer in the course "Expert English" School of Pharmaceutical Sciences, Fukuoka, Japan.
  • Lecturer in the course "Pharmaceutical Biochemistry in English-I"Lecturer in the course "Pharmaceutical Biochemistry in English-I" School of Pharmaceutical Sciences, Fukuoka, Japan
  • Lecturer in the course Medical English for BeginnersLecturer in the course Medical English for Beginners Faculty of Communication, Hokkaido University 2018-2019
  • Lecture in the couse ¨Pharmaceutical English II¨Lecture in the couse ¨Pharmaceutical English II¨ Faculty of Pharmacology Hokkaido University 2016-2018
  • Lecturer in the course "Medical English" for undergraduate medical studentsLecturer in the course "Medical English" for undergraduate medical students Faculty of Medicine Hokkaido University 2013-2018
  • Lecturer in the Course Basic Clinical Medicine-I for Graduate StudentsLecturer in the Course Basic Clinical Medicine-I for Graduate Students Hokkaido University
  • Invited teacher in the course “Communicating your research”Invited teacher in the course “Communicating your research” Hokkaido University, Faculty of Science
  • Update Course in Rheumatology Junio 1999Update Course in Rheumatology Junio 1999 College of Physicians of Segovia, Spain
  • Preparatory course for Residents (MIR)Preparatory course for Residents (MIR) Hospital Ramón y Cajal. Madrid, Spain

Association Memberships

  • JAPAN ASSOCIATION FOR INTERNATIONAL HEALTH   Japan Society for Medical English Education   Japanese Society on Thrombosis and Hemostasis   Vice-President and Member of the Association of Spanish Scientist in Japan (ACE)   Japanese Society for Clinical Immunology   The Spanish Society of Rheumatology   JAPAN COLLEGE OF RHEUMATOLOGY   

Works

  • Consultant Rheumatologist at the Hospital General, Segovia, Spain
    Olga Amengual 1998/06 -2002/05
  • Consultant iRheumatologist , Valdelaguila, Clinic Segovia, Spain
    Olga Amengual 1997/07 -2002/05
  • Resident in Rheumatology at the Hospital Ramon y Cajal, Madrid Spain
    Olga Amengual 1991/01 -1994/12
  • General Practitionner ( part time) at Primary Care Unit Segovia, Spain
    Olga Amengual 1989/10 -1990/12

Research Projects

  • Effects of fish consumption on clinical response to targeted therapies in Japanese and Spanish patients with rheumatoid arthritis
    Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2020/04 -2023/03 
    Author : Amengual Olga, 渥美 達也
     
    During the first year, we researched food frequency questionnaires and, after consultation with nutritionists, the brief type self-administered diet history questionnaire (BDHQ) was selected and purchased. Japanese BDHQ was officially translated into Spanish. Another dietary questionnaire focusing on fish consumption was prepared and adapted to Spanish and Japanese population. We drafted the retrospective study protocol, patient's informed consent and data collection sheet in Japanese and Spanish. The documents were submitted to the Institutional Review Board of the two participating hospitals in Japan and Spain. By reviewing the medical records, patients with rheumatoid arthritis who were being treated with targeted therapies were identified.
  • English learning for science, Agriculture and Engineering ( ELSAE) at Hokkaido University
    Grant for Research on development of educational programs：By the President ‘s Office ( Hokkaido University)
    Date (from‐to) : 2015/04 -2016/03 
    Author : Olga Amengual
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/04 -2016/03 
    Author : Amengual Olga
     
    English is an important instrument for communication. Developing communicative competence in English is becoming a prominent part of educational programs at medical schools in Japan. The aim of this prospective study was to evaluate the effect of medical English courses (MEC) on medical students’communication skills. Graduate medical students joining the doctoral program were invited to participate. Self-confidence scores to perform communicative tasks in English were rated using visual analogue scales before and after the MEC (intervention groups), or before and after the follow-up period (control groups). Significant improvements in self-confidence scores to perform communicative tasks in English were observed following participation in MEC. In the control group, no improvements were observed in any of the evaluated tasks. In conclusion, MEC contributed to enhancing confidence for communication.
  • Organ specificity of thrombosis in antiphospholipid antibody syndrome
    Post-doctoral RPD-Fellowship from the Japan Society for the promotion of the Science (JSPS) and Ministry of Education, Science, Culture, Sports and Technology：JSPS-MEXT
    Date (from‐to) : 2009/04 -2012/03 
    Author : Olga Amengual
  • Asymmetric distribution of cell membrane phospholipids: correlation with the pathogenesis of antiphospholipid syndrome
    Post-doctoral Fellowship for foreign Scientist from the Japan Society for the promotion of the Science：JSPS
    Date (from‐to) : 2003/09 -2005/09 
    Author : Olga Amengual
  • Pre-doctoral Fellowship at St Thomas´ Hospital, London, UK
    Fondo de Investigaciones Sanitarias de la Seguridad Social：FIS, Spain
    Date (from‐to) : 1995/01 -1996/12 
    Author : Olga Amengual

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