95 results on '"George Bertsias"'
Search Results
2. Microglia activation in the presence of intact blood–brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus
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Dionysis Nikolopoulos, Theodora Manolakou, Alexia Polissidis, Anastasia Filia, George Bertsias, Yassemi Koutmani, and Dimitrios T Boumpas
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
IntroductionInflammatory mediators are detected in the cerebrospinal fluid of systemic lupus erythematosus patients with central nervous system involvement (NPSLE), yet the underlying cellular and molecular mechanisms leading to neuropsychiatric disease remain elusive.MethodsWe performed a comprehensive phenotyping of NZB/W-F1 lupus-prone mice including tests for depression, anxiety and cognition. Immunofluorescence, flow cytometry, RNA-sequencing, qPCR, cytokine quantification and blood–brain barrier (BBB) permeability assays were applied in hippocampal tissue obtained in both prenephritic (3-month-old) and nephritic (6-month-old) lupus mice and matched control strains. Healthy adult hippocampal neural stem cells (hiNSCs) were exposedex vivoto exogenous inflammatory cytokines to assess their effects on proliferation and apoptosis.ResultsAt the prenephritic stage, BBB is intact yet mice exhibit hippocampus-related behavioural deficits recapitulating the human diffuse neuropsychiatric disease. This phenotype is accounted by disrupted hippocampal neurogenesis with hiNSCs exhibiting increased proliferation combined with decreased differentiation and increased apoptosis in combination with microglia activation and increased secretion of proinflammatory cytokines and chemokines. Among these cytokines, IL-6 and IL-18 directly induce apoptosis of adult hiNSCs ex vivo. During the nephritic stage, BBB becomes disrupted which facilitates immune components of peripheral blood, particularly B-cells, to penetrate into the hippocampus further augmenting inflammation with locally increased levels of IL-6, IL-12, IL-18 and IL-23. Of note, an interferon gene signature was observed only at nephritic-stage.ConclusionAn intact BBB with microglial activation disrupting the formation of new neurons within the hippocampus represent early events in NPSLE. Disturbances of the BBB and interferon signature are evident later in the course of the disease.
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- 2023
3. 2022 EULAR points to consider for the measurement, reporting and application of IFN-I pathway activation assays in clinical research and practice
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Javier Rodríguez-Carrio, Agata Burska, Philip G Conaghan, Willem A Dik, Robert Biesen, Maija-Leena Eloranta, Giulio Cavalli, Marianne Visser, Dimitrios T Boumpas, George Bertsias, Marie Wahren-Herlenius, Jan Rehwinkel, Marie-Louise Frémond, Mary K Crow, Lars Rönnblom, Marjan A Versnel, Edward M Vital, and Immunology
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundType I interferons (IFN-Is) play a role in a broad range of rheumatic and musculoskeletal diseases (RMDs), and compelling evidence suggests that their measurement could have clinical value, although testing has not progressed into clinical settings.ObjectiveTo develop evidence-based points to consider (PtC) for the measurement and reporting of IFN-I assays in clinical research and to determine their potential clinical utility.MethodsEULAR standardised operating procedures were followed. A task force including rheumatologists, immunologists, translational scientists and a patient partner was formed. Two systematic reviews were conducted to address methodological and clinical questions. PtC were formulated based on the retrieved evidence and expert opinion. Level of evidence and agreement was determined.ResultsTwo overarching principles and 11 PtC were defined. The first set (PtC 1–4) concerned terminology, assay characteristics and reporting practices to enable more consistent reporting and facilitate translation and collaborations. The second set (PtC 5–11) addressed clinical applications for diagnosis and outcome assessments, including disease activity, prognosis and prediction of treatment response. The mean level of agreement was generally high, mainly in the first PtC set and for clinical applications in systemic lupus erythematosus. Harmonisation of assay methodology and clinical validation were key points for the research agenda.ConclusionsIFN-I assays have a high potential for implementation in the clinical management of RMDs. Uptake of these PtC will facilitate the progress of IFN-I assays into clinical practice and may be also of interest beyond rheumatology.
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- 2023
4. Type I interferon pathway assays in studies of rheumatic and musculoskeletal diseases
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Agata Burska, Javier Rodríguez-Carrio, Robert Biesen, Willem A Dik, Maija-Leena Eloranta, Giulio Cavalli, Marianne Visser, Dimitrios T Boumpas, George Bertsias, Marie Wahren-Herlenius, Jan Rehwinkel, Marie-Louise Frémond, Mary K Crow, Lars Ronnblom, PG Conaghan, Marjan Versnel, Ed Vital, and Immunology
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Inflammation ,Reumatologi och inflammation ,Rheumatology ,Lupus Erythematosus ,Arthritis ,Rheumatoid ,Immunology ,Systemic ,Immunology and Allergy ,Cytokines ,Rheumatology and Autoimmunity - Abstract
ObjectivesTo systematically review the literature for assay methods that aim to evaluate type I interferon (IFN-I) pathway activation and to harmonise-related terminology.MethodsThree databases were searched for reports of IFN-I and rheumatic musculoskeletal diseases. Information about the performance metrics of assays measuring IFN-I and measures of truth were extracted and summarised. A EULAR task force panel assessed feasibility and developed consensus terminology.ResultsOf 10 037 abstracts, 276 fulfilled eligibility criteria for data extraction. Some reported more than one technique to measure IFN-I pathway activation. Hence, 276 papers generated data on 412 methods. IFN-I pathway activation was measured using: qPCR (n=121), immunoassays (n=101), microarray (n=69), reporter cell assay (n=38), DNA methylation (n=14), flow cytometry (n=14), cytopathic effect assay (n=11), RNA sequencing (n=9), plaque reduction assay (n=8), Nanostring (n=5), bisulphite sequencing (n=3). Principles of each assay are summarised for content validity. Concurrent validity (correlation with other IFN assays) was presented for n=150/412 assays. Reliability data were variable and provided for 13 assays. Gene expression and immunoassays were considered most feasible. Consensus terminology to define different aspects of IFN-I research and practice was produced.ConclusionsDiverse methods have been reported as IFN-I assays and these differ in what elements or aspects of IFN-I pathway activation they measure and how. No ‘gold standard’ represents the entirety of the IFN pathway, some may not be specific for IFN-I. Data on reliability or comparing assays were limited, and feasibility is a challenge for many assays. Consensus terminology should improve consistency of reporting.
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- 2023
5. Treat to target in Behcet's disease
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George E. Fragoulis, George Bertsias, Bahram Bodaghi, Ahmet Gul, Jan van Laar, Gonca Mumcu, David Saadoun, Ilknur Tugal-Tutkun, Gulen Hatemi, Petros P. Sfikakis, Fragoulis G. E. , Bertsias G., Bodaghi B., Gul A., van Laar J., Mumcu G., Saadoun D., Tugal-Tutkun I., Hatemi G., Sfikakis P. P., Immunology, and Internal Medicine
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Immunology ,Immunology and Allergy ,Disease activity ,Behcet's disease ,Treat-to-target - Abstract
During the last decades the efficacy of biologic agents, mainly of anti-TNFs, in controlling the activity of serious manifestations of Behcet's Disease (BD) has been established. On the other hand, the clinical heterogeneity of BD has precluded the validation of a widely-accepted composite index for disease assessment and for target disease-state definitions, such as low disease activity and remission, and the testing of their implementation in clinical practice. Therefore, in contrast to other systemic rheumatic diseases, a treat-to-target strategy has not yet been developed in BD. There are several challenges towards this approach, including standardization of outcome measures for assessing the disease activity in each-affected organ and construction of a composite disease activity index. The challenges for the development of a treat-to-target strategy and possible solutions are discussed in this position paper, which stemmed from a round table discussion that took place in the 19th International Conference on BD.
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- 2023
6. Association between type I interferon pathway activation and clinical outcomes in rheumatic and musculoskeletal diseases : a systematic literature review informing EULAR points to consider
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Javier Rodríguez-Carrio, Agata Burska, P G Conaghan, Willem A Dik, Robert Biesen, Maija-Leena Eloranta, Giulio Cavalli, Marianne Visser, Dimitrios T Boumpas, George Bertsias, Marie Wahren-Herlenius, Jan Rehwinkel, Marie-Louise Frémond, Mary K Crow, Lars Ronnblom, Ed Vital, Marjan Versnel, and Immunology
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Reumatologi och inflammation ,Rheumatology ,arthritis ,rheumatoid ,Immunology ,autoimmunity ,immune system diseases ,Immunology and Allergy ,systemic ,cytokines ,lupus erythematosus ,Rheumatology and Autoimmunity - Abstract
EULAR [SCI019]; UK National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre, Rodríguez-Carrio J, Burska A, Conaghan PG, Dik WA, Biesen R, Eloranta ML, Cavalli G, Visser M, Boumpas DT, Bertsias G, Wahren-Herlenius M, Rehwinkel J, Frémond ML, Crow MK, Ronnblom L, Vital E, Versnel M
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- 2023
7. EULAR study group on 'MHC-I-opathy'
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Jonas JW Kuiper, Jörg C Prinz, Efstratios Stratikos, Piotr Kuśnierczyk, Akiko Arakawa, Sebastian Springer, Dillon Mintoff, Ivan Padjen, Russka Shumnalieva, Seçil Vural, Ina Kötter, Marleen G van de Sande, Ayşe Boyvat, Joke H de Boer, George Bertsias, Niek de Vries, Charlotte LM Krieckaert, Inês Leal, Nataša Vidovič Valentinčič, Ilknur Tugal-Tutkun, Hanane el Khaldi Ahanach, Félicie Costantino, Simon Glatigny, Danijela Mrazovac Zimak, Fabian Lötscher, Floor G Kerstens, Marija Bakula, Elsa Viera Sousa, Peter Böhm, Kees Bosman, Tony J Kenna, Simon J Powis, Maxime Breban, Ahmet Gul, John Bowes, Rik JU Lories, Johannes Nowatzky, Gerrit Jan Wolbink, Dennis G McGonagle, Franktien Turkstra, and Repositório da Universidade de Lisboa
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Ankylosing ,Arthritis ,Behcet Syndrome ,Arthritis, Psoriatic ,Immunology ,610 Medicine & health ,Psoriatic ,General Biochemistry, Genetics and Molecular Biology ,Rheumatology ,Immune System Diseases ,Immunology and Allergy ,Spondylitis, Ankylosing ,610 Medizin und Gesundheit ,Spondylitis - Abstract
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
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- 2023
8. Gender Equity in Academic Rheumatology, Current Status and Potential for Improvement: A Cross-Sectional Study to Inform an EULAR Task Force
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Pavel V Ovseiko, Laure Gossec, Laura Andreoli, Uta Kiltz, Leonieke van Mens, Neelam Hassan, Marike van der Leeden, Heidi J Siddle, Alessia Alunno, Iain B McInnes, Nemanja S Damjanov, Florence Apparailly, Caroline Ospelt, Irene E van der Horst-Bruinsma, Elena Nikiphorou, Katie L Druce, Zoltán Szekanecz, Alexandre Sepriano, Tadej Avcin, George Bertsias, Georg Schett, Anne-Maree Keenan, Linda H Pololi, Laura C Coates, University of Oxford, Service de Rhumatologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Brescia, Ruhr University Bochum (RUB), Department of Clinical Immunology and Rheumatology [Academic Medical Center, Amsterdam], University of Amsterdam [Amsterdam] (UvA), North Bristol NHS Trust [Bristol, UK], University of Bristol [Bristol], Amsterdam UMC - Amsterdam University Medical Center, University of Leeds, University of L'Aquila [Italy] (UNIVAQ), University of Glasgow, University of Belgrade [Belgrade], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University hospital of Zurich [Zurich], VU University Medical Center [Amsterdam], King‘s College London, University of Manchester [Manchester], University of Debrecen Egyetem [Debrecen], Leiden University Medical Center (LUMC), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), University of Crete [Heraklion] (UOC), Universitätsklinikum Erlangen [Erlangen], NIHR - Leeds Musculoskeletal Biomedical Research Unit (LMBRU), National Institute for Health Research (NIHR), Brandeis University, Gestionnaire, Hal Sorbonne Université, Rehabilitation medicine, AMS - Ageing & Vitality, AMS - Musculoskeletal Health, APH - Aging & Later Life, APH - Health Behaviors & Chronic Diseases, APH - Societal Participation & Health, Rheumatology, AII - Inflammatory diseases, and AMS - Tissue Function & Regeneration
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Gender Equity ,Male ,[SDV]Life Sciences [q-bio] ,Immunology ,health services research ,Europe ,[SDV] Life Sciences [q-bio] ,Cross-Sectional Studies ,Rheumatology ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,Immunology and Allergy ,Humans ,Female ,epidemiology ,ddc:610 ,Rheumatologists ,qualitative research - Abstract
ObjectivesEvidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology.MethodsThis cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by χ2 test and t-test.ResultsData from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work–life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement.ConclusionsThere are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.
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- 2022
9. Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus:the PISCOS study
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Matteo Piga, Elisabetta Chessa, Eric F Morand, Manuel F Ugarte-Gil, Maria Tektonidou, Ronald van Vollenhoven, Michelle Petri, Laurent Arnaud, Simone Appenzeller, Cynthia Aranow, Anca Askanase, Tadej Avcin, Sang-Cheol Bae, George Bertsias, Eloisa Bonfa, Ernesto Cairoli, Mario H Cardiel, Ricard Cervera, François Chasset, Carlo Chizzolini, Ann E Clarke, Fabrizio Conti, Nathalie Costedoat-Chalumeau, László Czirják, Andrea Doria, Thomas Dörner, Gerard Espinosa, Rebecca Fischer-Betz, Mercedes Garcìa, Dafna D Gladman, Luis A González, Iva Gunnarsson, Laniyati Hamijoyo, John G Hanly, Sarfaraz A Hasni, Frédéric A Houssiau, Murat Inanç, Luís S Inês, David Isenberg, Soren Jacobsen, Yeong-Jian Jan Wu, Yuko Kaneko, Yasuhiro Katsumata, Chak S Lau, Alexandra C Legge, Karoline Lerang, Maarten Limper, Worawit Louthrenoo, Shue-Fen Luo, António Marinho, Loreto Massardo, Alexis Mathian, Marta Mosca, Mandana Nikpour, José M Pego-Reigosa, Christine A Peschken, Bernardo A Pons-Estel, Guillermo J Pons-Estel, Anisur Rahman, Simona Rednic, Camillo Ribi, Guillermo Ruiz-Irastorza, Emilia I Sato, Amit Saxena, Matthias Schneider, Gian Domenico Sebastiani, Vibeke Strand, Elisabet Svenungsson, Yoshiya Tanaka, Zoubida Tazi Mezalek, Michael L Tee, Angela Tincani, Zahi Touma, Anne Troldborg, Carlos Vasconcelos, Évelyne Vinet, Edward M Vital, Alexandre E Voskuyl, Anne Voss, Daniel Wallace, Michael Ward, and Leonid D Zamora
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DISEASE-ACTIVITY STATE ,Rheumatology ,ACTIVITY INDEX ,Immunology ,CAUCASIAN PATIENTS ,SLE ,Immunology and Allergy ,FLARE ,IMPACT TRACKER ,REMISSION ,DOUBLE-STRANDED DNA ,MONOCENTRIC COHORT ,ASSESSMENT PGA - Abstract
The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0–3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from “no disease activity” (0) to the “most severe disease activity” (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.
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- 2022
10. Treatment of neuropsychiatric systemic lupus erythematosus: clinical challenges and future perspectives
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Dionysis Nikolopoulos, George Bertsias, and Antonis Fanouriakis
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030203 arthritis & rheumatology ,0301 basic medicine ,Cerebral hypoperfusion ,business.industry ,Lupus Vasculitis, Central Nervous System ,Immunology ,Autoantibody ,Neuroimaging ,03 medical and health sciences ,Neuropsychiatric systemic lupus erythematosus ,030104 developmental biology ,0302 clinical medicine ,Seizures ,immune system diseases ,Neuronal damage ,parasitic diseases ,Antibodies, Antiphospholipid ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Medicine ,skin and connective tissue diseases ,business ,human activities - Abstract
Introduction: Neuropsychiatric (NP) involvement represents an emerging frontier in systemic lupus erythematosus (SLE), posing significant challenges due to its clinical diversity and obscure pathop...
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- 2021
11. Investigation of Neutrophil Extracellular Trap (NET) Induction in Patients with Chronic Idiopathic Neutropenia Bearing Mutations in the Mediterranean Fever (MEFV) Gene
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Iris Karkempetzaki, Irene Mavroudi, Grigorios Tsaknakis, Dimitra Nikoleri, Spiros Georgakis, George Bertsias, George Goulielmos, Akrivi Chrysanthopoulou, Panagiotis Skendros, Konstantinos Ritis, and Helen A. Papadaki
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Update οn the diagnosis and management of systemic lupus erythematosus
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Antonis Fanouriakis, Dimitrios T. Boumpas, Nikolaos Tziolos, and George Bertsias
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Systemic disease ,Heart Valve Diseases ,Lupus nephritis ,Uterine Cervical Neoplasms ,Disease ,Severity of Illness Index ,Quality of life ,Pregnancy ,Recurrence ,Azathioprine ,Outcome Assessment, Health Care ,Lupus Erythematosus, Systemic ,Pericarditis ,Immunology and Allergy ,skin and connective tissue diseases ,Macrophage Activation Syndrome ,Lupus Vasculitis, Central Nervous System ,Disease Management ,Prognosis ,Lupus Nephritis ,Survival Rate ,Organ damage ,Myocarditis ,Phenotype ,Cardiovascular Diseases ,Female ,Rituximab ,Immunosuppressive Agents ,Hydroxychloroquine ,medicine.medical_specialty ,Hypertension, Pulmonary ,Calcineurin Inhibitors ,Immunology ,Antibodies, Monoclonal, Humanized ,General Biochemistry, Genetics and Molecular Biology ,Rheumatology ,Internal medicine ,medicine ,Humans ,Intensive care medicine ,Cyclophosphamide ,Glucocorticoids ,Autoantibodies ,Purpura, Thrombocytopenic, Idiopathic ,Lupus erythematosus ,business.industry ,Mycophenolic Acid ,medicine.disease ,Pregnancy Complications ,Methotrexate ,Quality of Life ,Anemia, Hemolytic, Autoimmune ,business ,Rheumatism - Abstract
Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is—by and large—a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents—used alone, in combination or sequentially—have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.
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- 2020
13. Cross-species transcriptome analysis for early detection and specific therapeutic targeting of human lupus nephritis
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Eleni Frangou, Panagiotis Garantziotis, Maria Grigoriou, Aggelos Banos, Dionysis Nikolopoulos, Antigone Pieta, Stavros A Doumas, Antonis Fanouriakis, Aikaterini Hatzioannou, Theodora Manolakou, Themis Alissafi, Panayotis Verginis, Emmanouil Athanasiadis, Emmanouil Dermitzakis, George Bertsias, Anastasia Filia, and Dimitrios T Boumpas
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Gene Expression Profiling ,Immunology ,Lupus Nephritis ,General Biochemistry, Genetics and Molecular Biology ,DNA-Binding Proteins ,Adaptor Proteins, Vesicular Transport ,Mice ,Early Diagnosis ,Rheumatology ,Immunology and Allergy ,Animals ,Humans ,Lupus Erythematosus, Systemic ,RNA - Abstract
ObjectivesPatients with lupus nephritis (LN) are in urgent need for early diagnosis and therapeutic interventions targeting aberrant molecular pathways enriched in affected kidneys.MethodsWe used mRNA-sequencing in effector (spleen) and target (kidneys, brain) tissues from lupus and control mice at sequential time points, and in the blood from 367 individuals (261 systemic lupus erythematosus (SLE) patients and 106 healthy individuals). Comparative cross-tissue and cross-species analyses were performed. The human dataset was split into training and validation sets and machine learning was applied to build LN predictive models.ResultsIn murine SLE, we defined a kidney-specific molecular signature, as well as a molecular signature that underlies transition from preclinical to overt disease and encompasses pathways linked to metabolism, innate immune system and neutrophil degranulation. The murine kidney transcriptome partially mirrors the blood transcriptome of patients with LN with 11 key transcription factors regulating the cross-species active LN molecular signature. Integrated protein-to-protein interaction and drug prediction analyses identified the kinases TRRAP, AKT2, CDK16 and SCYL1 as putative targets of these factors and capable of reversing the LN signature. Using murine kidney-specific genes as disease predictors and machine-learning training of the human RNA-sequencing dataset, we developed and validated a peripheral blood-based algorithm that discriminates LN patients from normal individuals (based on 18 genes) and non-LN SLE patients (based on 20 genes) with excellent sensitivity and specificity (area under the curve range from 0.80 to 0.99).ConclusionsMachine-learning analysis of a large whole blood RNA-sequencing dataset of SLE patients using human orthologs of mouse kidney-specific genes can be used for early, non-invasive diagnosis and therapeutic targeting of LN. The kidney-specific gene predictors may facilitate prevention and early intervention trials.
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- 2021
14. Dialogue: High-throughput studies in rheumatology: time for unsupervised clustering?
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George Bertsias
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autoantibodies ,Immunology ,Biomarker Studies ,General Medicine ,systemic ,Rheumatology ,Cluster Analysis ,Humans ,Lupus Erythematosus, Systemic ,autoimmune diseases ,skin and connective tissue diseases ,lupus erythematosus - Abstract
Objective Many autoantibodies are known to be associated with SLE, although their role in clinical practice is limited because of low sensitivity and weak associations with clinical manifestations. There has been great interest in the discovery of new autoantibodies to use in clinical practice. In this study, we investigated 57 new and known antibodies and their potential for diagnostics or risk stratification. Methods Between 2014 and 2017, residual sera of all anti-dsDNA tests in the UMC Utrecht were stored in a biobank. This included sera of patients with SLE, patients with a diagnosis of another immune-mediated inflammatory disease (IMID), patients with low (non-IMID) or medium levels of clinical suspicion of SLE but no IMID diagnosis (Rest), and self-reported healthy blood bank donors. Diagnosis and (presence of) symptoms at each blood draw were retrospectively assessed in the patient records with the Utrecht Patient-Oriented Database using a newly developed text mining algorithm. Sera of patients were analysed for the presence of 57 autoantibodies with a custom-made immunofluorescent microarray. Signal intensity cut-offs for all antigens on the microarray were set to the 95th percentile of the non-IMID control group. Differences in prevalence of autoantibodies between patients with SLE and control groups were assessed. Results Autoantibody profiles of 483 patients with SLE were compared with autoantibody profiles of 1397 patients from 4 different control groups. Anti-dsDNA was the most distinguishing feature between patients with SLE and other patients, followed by antibodies against Cytosine-phosphate-Guanine (anti-CpG) DNA motifs (p
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- 2021
15. 2021 DORIS definition of remission in SLE:Final recommendations from an international task force
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Yehuda Schoenfeld, Carlos Vasconcelos, Josef S Smolen, Blanca Rubio, Ricard Cervera, Nathalie Costedoat-Chalumeau, Y K Onno Teng, Søren Jacobsen, Hermine I. Brunner, Mandana Nikpour, Anne Voss, Cindy Coney, Rebecca Fischer, Sang Cheol Bae, M.W.P. Tsang-A-Sjoe, Angela Tincani, Frédéric Houssiau, Elena Zakharhova, Bernadette van Leeuw, Michelle Petri, Eric F Morand, Ian N. Bruce, Maarten Limper, Dimitrios T. Boumpas, Victoria P. Werth, Murat Inanc, Anka Askenase, Ann E. Clarke, Thomas Dörner, Cynthia Aranow, Bernardo A. Pons-Estel, Matthias Schneider, Marta Mosca, László Czirják, George Bertsias, Michael M. Ward, Hendrika Bootsma, Juanita Romero-Diaz, Marzena Olesińska, Guillermo J. Pons-Estel, Xavier Mariette, Andrea Doria, Ruth D E Fritsch-Stork, Graciela S. Alarcón, Eloisa Bonfa, David A. Isenberg, Manuel F. Ugarte-Gil, Annegret Kuhn, Martin Aringer, Laurent Arnaud, Sandra V. Navarra, David Jayne, Anisur Rahman, Raquel Faria, Caroline Gordon, Alexandre E. Voskuyl, Ronald F van Vollenhoven, van Vollenhoven, Ronald F [0000-0001-6438-8663], Doria, Andrea [0000-0003-0548-4983], Morand, Eric [0000-0002-9507-3338], Petri, Michelle A [0000-0003-1441-5373], Pons-Estel, Bernardo A [0000-0003-2518-0266], Ugarte-Gil, Manuel Francisco [0000-0003-1728-1999], Arnaud, Laurent [0000-0002-8077-8394], Bruce, Ian N [0000-0003-3047-500X], Houssiau, Frédéric A [0000-0003-1451-083X], Aringer, Martin [0000-0003-4471-8375], Bae, Sang-Cheol [0000-0003-4658-1093], Boumpas, Dimitrios T [0000-0002-9812-4671], Brunner, Hermine [0000-0001-9478-2987], Dörner, Thomas [0000-0002-6478-7725], Jacobsen, Søren [0000-0002-5654-4993], Teng, Y K Onno [0000-0001-9920-2195], Tsang-A-Sjoe, Michel [0000-0002-4982-3505], Werth, Victoria P [0000-0003-3030-5369], Aranow, Cynthia [0000-0001-9299-0053], Apollo - University of Cambridge Repository, Teng, YK Onno [0000-0001-9920-2195], Jayne, David [0000-0002-1712-0637], UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie
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medicine.medical_specialty ,Prednisolone ,Immunology ,Therapeutics ,Disease ,Severity of Illness Index ,Health care ,medicine ,therapeutics ,Humans ,Lupus Erythematosus, Systemic ,Medical physics ,healthcare ,lupus erythematosus ,outcome assessment ,systemic ,Clinical care ,skin and connective tissue diseases ,Lupus erythematosus ,Epidemiology and outcomes ,Task force ,business.industry ,Healthcare ,Systemic ,Remission Induction ,General Medicine ,RC581-607 ,medicine.disease ,Clinical trial ,Outcome assessment ,Research questions ,Observational study ,Immunologic diseases. Allergy ,business ,Immunosuppressive Agents - Abstract
ObjectiveTo achieve consensus on a definition of remission in SLE (DORIS).BackgroundRemission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation.MethodsSeveral systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on.ResultsBased on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator’s Global Assessment ConclusionThe 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies.
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- 2021
16. Treatment of lupus: more options after a long wait
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Myrto Kostopoulou, Antonis Fanouriakis, George Bertsias, and Dimitrios T Boumpas
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Rheumatology ,Immunology ,Immunology and Allergy ,Humans ,Lupus Erythematosus, Systemic ,Lupus Nephritis ,General Biochemistry, Genetics and Molecular Biology - Published
- 2021
17. Achieving remission or low disease activity is associated with better outcomes in patients with systemic lupus erythematosus: a systematic literature review
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Bernardo A. Pons-Estel, Ronald F van Vollenhoven, George Bertsias, Cristina Reátegui-Sokolova, Graciela S. Alarcón, Claudia Mendoza-Pinto, Manuel F. Ugarte-Gil, and Guillermo J. Pons-Estel
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medicine.medical_specialty ,Immunology ,Cochrane Library ,Disease activity ,Indirect costs ,Quality of life ,systemic lupus erythematosus ,Internal medicine ,Health care ,medicine ,Humans ,Lupus Erythematosus, Systemic ,In patient ,outcome assessment ,business.industry ,General Medicine ,RC581-607 ,Epidemiology and Outcomes ,health care ,Organ damage ,Systematic review ,Cross-Sectional Studies ,quality of life ,Immunologic diseases. Allergy ,business - Abstract
BackgroundRemission and low disease activity (LDA) have been proposed as the treatment goals for patients with systemic lupus erythematosus (SLE). Several definitions for each have been proposed in the literature.ObjectiveTo assess the impact of remission/LDA according to various definitions on relevant outcomes in patients with SLE.MethodsThis systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using PubMed (1946–week 2, April 2021), Cochrane library (1985–week 2, week 2, April 2021) and EMBASE (1974–week 2, April 2021). We included longitudinal and cross-sectional studies in patients with SLE reporting the impact of remission and LDA (regardless their definition) on mortality, damage accrual, flares, health-related quality of life and other outcomes (cardiovascular risk, hospitalisation and direct costs). The quality of evidence was evaluated using the Newcastle-Ottawa Scale.ResultsWe identified 7497 articles; of them, 31 studies met the inclusion criteria and were evaluated. Some articles reported a positive association with survival, although this was not confirmed in all of them. Organ damage accrual was the most frequently reported outcome, and remission and LDA were reported as protective of this outcome (risk measures varying from 0.04 to 0.95 depending on the definition). Similarly, both states were associated with a lower probability of SLE flares, hospitalisations and a better health-related quality of life, in particular the physical domain.ConclusionRemission and LDA are associated with improvement in multiple outcomes in patients with SLE, thus reinforcing their relevance in clinical practice.PROSPERO registration numberCRD42020162724.
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- 2021
18. Remission or low disease activity at pregnancy onset are linked to improved foetal outcomes in women with systemic lupus erythematosus: results from a prospective observational study
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Styliani Ntali, Dionysis Nikolopoulos, Lamprini Pantazi, Evgenia Emmanouilidou, Charalampos Papagoras, Antonis Fanouriakis, Despoina Dimopoulou, Ioannis Kallitsakis, Kyriaki Boki, Vicky Dania, Prodromos I. Sidiropoulos, Dimitrios T. Boumpas, and George Bertsias
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Immunology ,Infant, Newborn ,Pregnancy Outcome ,Pregnancy Complications ,Rheumatology ,Pregnancy ,Azathioprine ,Antibodies, Antiphospholipid ,Immunology and Allergy ,Humans ,Lupus Erythematosus, Systemic ,Female ,Glucocorticoids ,Hydroxychloroquine ,Retrospective Studies - Abstract
Systemic lupus erythematosus (SLE) patients show variably increased risk for pregnancy complications. We analysed pregnancy outcomes (foetal and maternal), patterns of disease activity and use of medications in a contemporary Caucasian SLE population.Prospective observational study, involving hospital units and private rheumatologists in Greece, of incident pregnancies (period 2015-2018) in women with SLE. Clinical and obstetrical monitoring was performed at regular intervals up to 9 months post-partum. Regression and mixed model analyses were used to determine predictors for adverse foetal outcomes and flares.We monitored 82 pregnancies in 64 SLE patients. Foetal loss, prematurity and small for gestational age neonate occurred at 15.8%, 34.1% and 8.5%, respectively; 53.7% of pregnancies were complicated with at least one adverse outcome. Patients with antiphospholipid antibodies (aPL) had increased risk (odds ratio [OR] 5.67, p=0.015), whereas those at low disease activity at pregnancy onset were protected (OR 0.20, p=0.024) against foetal complications. Persistent activity and glucocorticoid intake during pregnancy also predicted poor foetal outcomes. SLE patients experienced an average 1.08 mild/moderate and 0.27 severe flares. The latter occurred more frequently post-partum, in patients with alopecia (OR 8.92, p=0.003), hypocomplementaemia (OR 10.34, p=0.038) and nephritis (OR 7.32, p=0.052). Lupusactivity post-labour was paralleled by decreased use of hydroxychloroquine, glucocorticoids and azathioprine.In SLE women, foetal complications are common especially in the presence of aPL and increased activity, which corroborates the importance of pregnancy planning and tight disease control at pregnancy onset. Flares, mostly mild or moderate, can occur both during and after pregnancy.
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- 2021
19. Response to: Correspondence on 'Update on the diagnosis and management of systemic lupus erythematosus' by Fanouriakis
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Nikolaos Tziolos, George Bertsias, Dimitrios T. Boumpas, and Antonis Fanouriakis
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medicine.medical_specialty ,Lupus erythematosus ,business.industry ,Immunology ,Lupus nephritis ,medicine.disease ,Dermatology ,General Biochemistry, Genetics and Molecular Biology ,Rheumatology ,immune system diseases ,Clinical diagnosis ,Health care ,medicine ,Immunology and Allergy ,In patient ,skin and connective tissue diseases ,business - Abstract
We thank Zhou et al for their interest in our manuscript and their insightful comments.1 In figure 4 of our manuscript (Diagnostic approach to a patient with suspected systemic lupus erythematosus and the use of classification criteria to aid clinical diagnosis), we propose an algorithm to aid clinical diagnosis, especially in patients not fulfilling the classification criteria.2 As opposed to classification, diagnosis by definition may include the notion of probability (ie, possible systemic lupus erythematosus (SLE)). Moreover, as …
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- 2021
20. In an early SLE cohort the ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria classify non-overlapping groups of patients: use of all three criteria ensures optimal capture for clinical studies while their modification earlier classification and treatment
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Irini Genitsaridi, Dimitrios T. Boumpas, Alessandra Bortoluzzi, George Bertsias, Dionysis Nikolopoulos, Prodromos Sidiropoulos, Christina Adamichou, Irini Gergianaki, Emmanouil Papastefanakis, Eleni Kalogiannaki, and Antonis Fanouriakis
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Adult ,Male ,musculoskeletal diseases ,medicine.medical_specialty ,Immunology ,Disease ,Sensitivity and Specificity ,Severity of Illness Index ,General Biochemistry, Genetics and Molecular Biology ,NO ,autoimmune diseases, outcomes research, systemic lupus erythematosus ,outcomes research ,systemic lupus erythematosus ,Rheumatology ,Internal medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Medicine ,autoimmune diseases ,skin and connective tissue diseases ,Disease burden ,Retrospective Studies ,High prevalence ,Systemic lupus erythematosus ,business.industry ,Middle Aged ,medicine.disease ,Cohort ,Female ,Symptom Assessment ,Outcomes research ,business ,Algorithms ,Rheumatism - Abstract
ObjectivesClassification criteria are biased towards classifying long-standing disease. We compared the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)-2019, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and ACR-1997 criteria in an early (median 48 months) systemic lupus erythematosus (SLE) cohort.MethodsPatients diagnosed with SLE (n=690) or control diseases (n=401). Sensitivity, specificity of the criteria and time-to-classification were calculated. Modified classification algorithms were derived from a random 80% and validated in the remaining 20% of the dataset running multiple iterations.ResultsAt last assessment, sensitivities of ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria were 85.7%, 91.3% and 88.6%, with specificities 93.0%, 93.8% and 97.3%, respectively. Both SLICC and EULAR/ACR enabled earlier classification. Only 76.7% of patients with SLE met all three criteria suggesting non-overlapping groups. Notably, unclassified patients had high prevalence of British Isles Lupus Assessment Group moderate/severe manifestations (43.3%–60%) and SLICC/ACR organ damage (30%–50%). At diagnosis, criteria missed 25.6%–30.5% of patients. Modification of EULAR/ACR and SLICC algorithms to include hypocomplementaemia and/or positive anti-phospholipid antibodies as alternative entry criterion, and/or allow classification with fewer clinical criteria from multiple organs, increased their sensitivity at diagnosis (median 82.0% and 86.2%) and overall (93.7% and 97.1%) with modest decreases in specificity. Importantly, patients who were still missed by the modified criteria had lower incidence of major organ involvement, use of immunosuppressive/biological therapies and organ damage.ConclusionsThe SLICC and EULAR/ACR are more sensitive than the ACR and the EULAR/ACR criteria have superior specificity in early SLE, although patients with significant disease can be missed. Combination and/or modification of the classification algorithms may enhance their sensitivity, allowing earlier classification and treatment of more patients with high disease burden.
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- 2019
21. Cytokine targets in lupus nephritis: Current and future prospects
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Spyros Georgakis, George Bertsias, and Christina Adamichou
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0301 basic medicine ,medicine.medical_treatment ,Immunology ,Anti-Inflammatory Agents ,Lupus nephritis ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Maintenance therapy ,medicine ,Humans ,Immunology and Allergy ,Kidney ,Systemic lupus erythematosus ,business.industry ,medicine.disease ,Lupus Nephritis ,Belimumab ,Blockade ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Cytokines ,Personalized medicine ,business ,Immunosuppressive Agents ,030215 immunology ,medicine.drug - Abstract
Despite advancements in the care of lupus nephritis, a considerable proportion of patients may respond poorly or flare while on conventional immunosuppressive agents. Studies in murine and human lupus have illustrated a pathogenic role for several cytokines by enhancing T- and B-cell activation, autoantibodies production and affecting the function of kidney resident cells, therefore supporting their potential therapeutic targeting. To this end, there is limited post-hoc randomized evidence to suggest beneficial effect of belimumab, administered on top of standard-of-care, during maintenance therapy in lupus nephritis. Type I interferon receptor blockade has yielded promising results in preliminary SLE trials yet data on renal activity are unavailable. Conversely, targeting interleukin-6 and interferon-γ both failed to demonstrate a significant renal effect. For several other targets, preclinical data are encouraging but will require confirmation. We envision that high-throughput technologies will enable accurate patient stratification, thus offering the opportunity for personalized implementation of cytokine-targeting therapies.
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- 2019
22. REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A)
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Eleni Frangou, Stella Arelaki, Dimitrios T. Boumpas, George Bertsias, Hariklia Gakiopoulou, Alexandros Mitsios, Panayotis Verginis, Konstantinos Ritis, Athanasios Arampatzioglou, Iliana Angelidou, Konstantinos Kambas, and Akrivi Chrysanthopoulou
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0301 basic medicine ,autophagy ,Immunology ,Cell Culture Techniques ,Extracellular Traps ,Systemic Lupus Erythematosus ,General Biochemistry, Genetics and Molecular Biology ,Thromboplastin ,Pathogenesis ,03 medical and health sciences ,Tissue factor ,0302 clinical medicine ,neutrophils ,Rheumatology ,Fibrosis ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,skin and connective tissue diseases ,Inflammation ,030203 arthritis & rheumatology ,Systemic lupus erythematosus ,business.industry ,Interleukin-17 ,fibrosis ,Autophagy ,Thrombosis ,Hydroxychloroquine ,lupus ,Neutrophil extracellular traps ,Fibroblasts ,medicine.disease ,3. Good health ,030104 developmental biology ,thromboinflammation ,Interleukin 17 ,business ,Signal Transduction ,Transcription Factors ,medicine.drug - Abstract
ObjectivesThe release of neutrophil extracellular traps (NETs) represents a novel neutrophil effector function in systemic lupus erythematosus (SLE) pathogenesis. However, the molecular mechanism underlying NET release and how NETs mediate end-organ injury in SLE remain elusive.MethodsNET formation and NET-related proteins were assessed in the peripheral blood and biopsies from discoid lupus and proliferative nephritis, using immunofluorescence, immunoblotting, quantitative PCR and ELISA. Autophagy was assessed by immunofluorescence and immunoblotting. The functional effects of NETs in vitro were assessed in a primary fibroblast culture.ResultsNeutrophils from patients with active SLE exhibited increased basal autophagy levels leading to enhanced NET release, which was inhibited in vitro by hydroxychloroquine. NETosis in SLE neutrophils correlated with increased expression of the stress-response protein REDD1. Endothelin-1 (ET-1) and hypoxia-inducible factor-1α (HIF-1α) were key mediators of REDD1-driven NETs as demonstrated by their inhibition with bosentan and L-ascorbic acid, respectively. SLE NETs were decorated with tissue factor (TF) and interleukin-17A (IL-17A), which promoted thrombin generation and the fibrotic potential of cultured skin fibroblasts. Notably, TF-bearing and IL-17A-bearing NETs were abundant in discoid skin lesions and in the glomerular and tubulointerstitial compartment of proliferative nephritis biopsy specimens.ConclusionsOur data suggest the involvement of REDD1/autophagy/NET axis in end-organ injury and fibrosis in SLE, a likely candidate for repositioning of existing drugs for SLE therapy. Autophagy-mediated release of TF-bearing and IL-17A-bearing NETs provides a link between thromboinflammation and fibrosis in SLE and may account for the salutary effects of hydroxychloroquine.
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- 2018
23. Response to: 'Correspondence on 'Lupus or not? SLE Risk Probability Index (SLERPI): a simple, clinician-friendly machine learning-based model to assist the diagnosis of systemic lupus erythematosus' by Batu
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George Bertsias and Christina Adamichou
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030203 arthritis & rheumatology ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Systemic lupus erythematosus ,Lupus erythematosus ,Index (economics) ,Receiver operating characteristic ,Binary outcome ,business.industry ,Immunology ,Lupus nephritis ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,medicine ,Immunology and Allergy ,Risk probability ,business - Abstract
We would like to thank Batu et al 1 for the interest in our work and for evaluating the performance of SLE Risk Probability Index (SLERPI)2 in paediatric SLE patients. In their analysis using the simple scoring version of the index as a binary outcome, the sensitivity and specificity was 90.0% and 81.2%, respectively.1 Applying a more stringent cut-off of >8 resulted in a sensitivity of 81.2% and a specificity of 89.4%. Notably, the area under the receiver operating characteristic curve of the scoring version of SLERPI was 0.94 (95% CI 0.919 to 0.968), suggesting a …
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- 2021
24. Rituximab for refractory eosinophilic fasciitis: a case series with long-term follow-up and literature review
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George Bertsias, Ioannis Papalopoulos, Argiro Repa, Nestor Avgoustidis, Nikolaos Kougkas, and Prodromos Sidiropoulos
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Adult ,Male ,medicine.medical_specialty ,Demographics ,Long term follow up ,Immunology ,Rheumatology ,Refractory ,Internal medicine ,Eosinophilia ,medicine ,Immunology and Allergy ,Humans ,Fasciitis ,business.industry ,Middle Aged ,University hospital ,medicine.disease ,Alternative treatment ,Eosinophilic fasciitis ,Treatment Outcome ,Rituximab ,Female ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
RTX could be an effective and safe alternative treatment for refractory EF. Rituximab (RTX) is a successful therapeutic option for various autoimmune diseases. Our aim is to report our experience with RTX in eosinophilic fasciitis (EF) and review published data on its efficacy for the treatment of EF. We reviewed the medical charts of all patients with a diagnosis of EF treated with RTX from 2008 to 2020 in the Department of Rheumatology and Clinical Immunology in the University Hospital of Heraklion, Crete, Greece. We also reviewed the English literature for cases of EF treated with RTX. Demographics, clinical manifestations, laboratory findings, prior treatments, response to RTX, cumulative RTX dose, duration of treatment and follow-up are reported. We report three cases of EF refractory to conventional DMARDs (cDMARDs) that responded to RTX. Furthermore, literature review revealed five cases. In our case series in all patients, RTX was the first biologic. RTX could be effective in cases of (EF) refractory to standard immunosuppressive treatment.
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- 2021
25. European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance
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Carlos Vasconcelos, Zahi Touma, Elena Massarotti, Chiara Tani, Ivan Padjen, Gabriela Schmajuk, Ricard Cervera, Guillermo Ruiz-Irastorza, Matthias Schneider, Florence Assan, Edward M Vital, Bernadett Halda-Kiss, Pier Luigi Meroni, Marvin J. Fritzler, Georg Stummvoll, Murray B. Urowitz, Diane L. Kamen, Dinesh Khanna, Maria G Tektonidou, Falk Hiepe, Raphaèle Seror, Søren Jacobsen, Michelle Jung, Marta Mosca, Sule Yavuz, László Czirják, Winfried Graninger, Sara K. Tedeschi, Bimba F. Hoyer, David I. Daikh, Bevra H. Hahn, Karen H. Costenbader, Rosalind Ramsey-Goldman, David Wofsy, Sindhu R. Johnson, Ann E. Clarke, Joseph M. McCune, Nicolai Leuchten, Kirsten Lerstrøm, Yoshiya Tanaka, Betty Diamond, David Jayne, Peter M. Izmirly, Josef S Smolen, George Bertsias, Ralph Brinks, Dimitrios T. Boumpas, Ray Naden, Juanita Romero-Diaz, Mary K. Crow, Gábor Kumánovics, Iñigo Rúa-Figueroa, Daniel J. Wallace, Thomas Dörner, José M. Pego-Reigosa, Jorge Sanchez-Guerrero, Martin Aringer, Xavier Mariette, Branimir Anić, Sarfaraz Hasni, Andrea Doria, Dafna D. Gladman, Nathalie Costedoat-Chalumeau, Tak Mao Chan, Aringer, Martin [0000-0003-4471-8375], Dörner, Thomas [0000-0002-6478-7725], Boumpas, Dimitrios T [0000-0002-9812-4671], Costedoat-Chalumeau, Nathalie [0000-0002-1555-9021], Diamond, Betty [0000-0002-3250-3804], Gladman, Dafna D [0000-0002-9074-0592], Khanna, Dinesh [0000-0003-1412-4453], Ruiz-Irastorza, Guillermo [0000-0001-7788-1043], Urowitz, Murray [0000-0001-7506-9166], Tedeschi, Sara K [0000-0001-9475-1363], Touma, Zahi [0000-0001-5177-2076], Assan, Florence [0000-0001-6988-6178], Crow, Mary K [0000-0002-7881-2020], Doria, Andrea [0000-0003-0548-4983], Rúa-Figueroa, Íñigo [0000-0002-7894-1690], Tanaka, Yoshiya [0000-0002-0807-7139], Tektonidou, Maria G [0000-0003-2238-0975], Vital, Edward M [0000-0003-1637-4755], Wallace, Daniel J [0000-0002-2502-1372], Yavuz, Sule [0000-0001-5053-6426], Meroni, Pier Luigi [0000-0002-3394-1451], Fritzler, Marvin J [0000-0003-1652-6608], Johnson, Sindhu R [0000-0003-0591-2976], and Apollo - University of Cambridge Repository
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musculoskeletal diseases ,medicine.medical_specialty ,Anti-nuclear antibody ,autoantibodies ,Immunology ,Population ,Acr criteria ,Sensitivity and Specificity ,General Biochemistry, Genetics and Molecular Biology ,Cohort Studies ,Rheumatology ,immune system diseases ,Internal medicine ,Rheumatic Diseases ,medicine ,Immunology and Allergy ,antibodies ,Humans ,Lupus Erythematosus, Systemic ,education ,skin and connective tissue diseases ,education.field_of_study ,Lupus erythematosus ,business.industry ,Autoantibody ,systemic ,medicine.disease ,United States ,antiphospholipid ,lupus erythematosus ,synovitis ,Antibodies, Antinuclear ,Delirium ,medicine.symptom ,business ,Rheumatism - Abstract
Background/objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. Methods We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. Results Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia Conclusions Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.
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- 2021
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26. Quality indicators for systemic lupus erythematosus based on the 2019 EULAR recommendations: development and initial validation in a cohort of 220 patients
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Martin Aringer, Marta Mosca, Konstantina Togia, John Boletis, George Bertsias, Dionysis Nikolopoulos, Andrea Doria, Myrto Kostopoulou, David Jayne, Antonis Fanouriakis, O. Gioti, Angela Tincani, Elisabet Svenungsson, Dimitrios T. Boumpas, Laura Andreoli, Frédéric Houssiau, K. Chavatza, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie
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Male ,autoimmune diseases ,glucocorticoids ,health care ,lupus erythematosus ,quality indicators ,systemic ,Angiotensin-Converting Enzyme Inhibitors ,Antirheumatic Agents ,Aspirin ,Drug Tapering ,Europe ,Female ,Glucocorticoids ,Guideline Adherence ,Hospitalization ,Humans ,Hydroxychloroquine ,Immunosuppressive Agents ,Kidney ,Lupus Erythematosus, Systemic ,Lupus Nephritis ,Mass Screening ,Osteoporosis ,Platelet Aggregation Inhibitors ,Practice Guidelines as Topic ,Pre-Eclampsia ,Prednisone ,Pregnancy ,Remission Induction ,Reproducibility of Results ,Risk Assessment ,Societies, Medical ,Symptom Flare Up ,Quality Indicators, Health Care ,Immunology and Allergy ,Medicine ,Cohort ,Platelet aggregation inhibitor ,Risk assessment ,medicine.drug ,medicine.medical_specialty ,Immunology ,General Biochemistry, Genetics and Molecular Biology ,Rheumatology ,Internal medicine ,Medical ,Mass screening ,Lupus erythematosus ,Lupus Erythematosus ,business.industry ,Systemic ,medicine.disease ,business ,Societies ,Rheumatism - Abstract
BackgroundQuality of care is receiving increased attention in systemic lupus erythematosus (SLE). We developed quality indicators (QIs) for SLE based on the 2019 update of European League Against Rheumatism recommendations.MethodsA total of 44 candidate QIs corresponding to diagnosis, monitoring and treatment, were independently rated for validity and feasibility by 12 experts and analysed by a modified Research and Development Corporation/University of California Los Angeles model. Adherence to the final set of QIs and correlation with disease outcomes (flares, hospitalisations and organ damage) was tested in a cohort of 220 SLE patients with a median monitoring of 2 years (IQR 2–4).ResultsThe panel selected a total of 18 QIs as valid and feasible. On average, SLE patients received 54% (95% CI 52.3% to 56.2%) of recommended care, with adherence ranging from 44.7% (95% CI 40.8% to 48.6%) for diagnosis-related QIs to 84.3% (95% CI 80.6% to 87.5%) for treatment-related QIs. Sustained remission or low disease activity were achieved in 26.8% (95% CI 21.1% to 33.2%). Tapering of prednisone dose to less than 7.5 mg/day was achieved in 93.6% (95% CI 88.2% to 97.0%) while 73.5% (95% CI 66.6% to 79.6%) received the recommended hydroxychloroquine dose. Higher adherence to monitoring-related QIs was associated with reduced risk for a composite adverse outcome (flare, hospitalisation or damage accrual) during the last year of observation (OR 0.97 per 1% adherence rate, 95% CI 0.96 to 0.99).ConclusionWe developed QIs for assessing and improving the care of SLE patients. Initial real-life data suggest face validity, but a variable degree of adherence and a need for further improvement.
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- 2021
27. NETs decorated with bioactive IL-33 infiltrate inflamed tissues and induce IFN-α production in patients with SLE
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Katerina Gkirtzimanaki, Hariklia Gakiopoulou, Maija-Leena Eloranta, Manousos Makridakis, Georgia Kontostathi, Garyfalia Papadaki, Eirini Baira, Panayotis Verginis, Prodromos Sidiropoulos, Dimitrios T. Boumpas, Lars Rönnblom, Jerome Zoidakis, George Bertsias, Spiros Georgakis, and Elias Drakos
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Neutrophils ,Lupus ,Inflammation ,Autoimmunity ,Cathepsin G ,medicine.disease_cause ,Extracellular Traps ,chemistry.chemical_compound ,Interferon ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Rheumatology and Autoimmunity ,Reumatologi och inflammation ,Systemic lupus erythematosus ,Innate immune system ,Elastase ,Interferon-alpha ,Dendritic Cells ,General Medicine ,Neutrophil extracellular traps ,Interleukin-33 ,medicine.disease ,chemistry ,Case-Control Studies ,Immunology ,Cytokines ,medicine.symptom ,Research Article ,medicine.drug - Abstract
Interleukin-33 (IL-33), a nuclear alarmin released during cell death, exerts context-specific effects on adaptive and innate immune cells eliciting potent inflammatory responses. We screened blood, skin and kidney tissues from patients with Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease driven by unabated type I interferon (IFN) production, and found increased amounts of extracellular IL-33 complexed with Neutrophil Extracellular Traps (NETs), correlating with severe, active disease. Using a combination of molecular, imaging and proteomic approaches, we show that SLE neutrophils -activated by disease immunocomplexes- release IL-33-decorated NETs that stimulate robust IFNα synthesis by plasmacytoid dendritic cells (pDCs) in an IL-33-receptor (ST2L)-dependent manner. IL33-silenced neutrophil-like cells cultured under lupus-inducing conditions generated NETs with diminished interferogenic effect. Importantly, SLE patient-derived NETs are enriched in mature bioactive isoforms of IL-33 processed by the neutrophil proteases elastase and cathepsin G. Pharmacological inhibition of these proteases neutralized IL-33-dependent IFNα production elicited by NETs. These data demonstrate a novel role for cleaved IL-33 alarmin decorating NETs in human SLE, linking neutrophil activation, type I IFN production and end-organ inflammation with skin pathology mirroring that observed in the kidneys.
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- 2021
28. Performance of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in early disease, across sexes and ethnicities
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Diane L. Kamen, Pier Luigi Meroni, Sarfaraz Hasni, Martin Aringer, Edward M Vital, Xavier Mariette, Maria G Tektonidou, Jorge Sanchez-Guerrero, Michelle Jung, Falk Hiepe, Gábor Kumánovics, Carlos Vasconcelos, George Bertsias, David Jayne, Branimir Anić, Juanita Romero-Diaz, Marta Mosca, Nathalie Costedoat-Chalumeau, Ivan Padjen, Ricard Cervera, László Czirják, Dafna D. Gladman, Bimba F. Hoyer, Søren Jacobsen, Sindhu R. Johnson, Zahi Touma, Kirsten Lerstrøm, Tak Mao Chan, Florence Assan, David I. Daikh, Karen H. Costenbader, Rosalind Ramsey-Goldman, Sara K. Tedeschi, Guillermo Ruiz-Irastorza, Elena Massarotti, Chiara Tani, Josef S Smolen, Andrea Doria, Betty Diamond, Mary K. Crow, Bernadett Halda-Kiss, Ralph Brinks, Murray B. Urowitz, Bevra H. Hahn, Iñigo Rúa-Figueroa, Winfried Graninger, Sule Yavuz, Daniel J. Wallace, José M. Pego-Reigosa, Nicolai Leuchten, Peter M. Izmirly, Ray Naden, Thomas Dörner, Dinesh Khanna, Raphaèle Seror, David Wofsy, Ann E. Clarke, Joseph M. McCune, Matthias Schneider, Georg Stummvoll, Gabriela Schmajuk, Yoshiya Tanaka, Marvin J. Fritzler, Dimitrios T. Boumpas, Johnson, Sindhu R [0000-0003-0591-2976], Boumpas, Dimitrios T [0000-0002-9812-4671], Costedoat-Chalumeau, Nathalie [0000-0002-1555-9021], Gladman, Dafna D [0000-0002-9074-0592], Khanna, Dinesh [0000-0003-1412-4453], Ruiz-Irastorza, Guillermo [0000-0001-7788-1043], Urowitz, Murray [0000-0001-7506-9166], Assan, Florence [0000-0001-6988-6178], Doria, Andrea [0000-0003-0548-4983], Rúa-Figueroa, Íñigo [0000-0002-7894-1690], Tanaka, Yoshiya [0000-0002-0807-7139], Tektonidou, Maria G [0000-0003-2238-0975], Yavuz, Sule [0000-0001-5053-6426], Meroni, Pier Luigi [0000-0002-3394-1451], Dörner, Thomas [0000-0002-6478-7725], Aringer, Martin [0000-0003-4471-8375], and Apollo - University of Cambridge Repository
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musculoskeletal diseases ,Male ,medicine.medical_specialty ,Immunology ,Lupus nephritis ,Ethnic group ,Sensitivity and Specificity ,Severity of Illness Index ,General Biochemistry, Genetics and Molecular Biology ,outcomes research ,Rheumatology ,systemic lupus erythematosus ,immune system diseases ,Internal medicine ,Epidemiology ,medicine ,Immunology and Allergy ,Humans ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,epidemiology ,lupus nephritis ,business.industry ,Patient Selection ,Early disease ,medicine.disease ,Cohort ,Female ,Outcomes research ,business ,Rheumatism - Abstract
Funder: American College of Rheumatology Research and Education Foundation; FundRef: http://dx.doi.org/10.13039/100000960, Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases; FundRef: http://dx.doi.org/10.13039/100000069, Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to
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- 2020
29. Extensive fragmentation and re-organization of transcription in Systemic Lupus Erythematosus
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Maria G Tektonidou, Vasilis F Ntasis, Emmanouil T. Dermitzakis, Dimitrios T. Boumpas, Nikolaos I Panousis, George Bertsias, and Christoforos Nikolaou
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Male ,Transcription, Genetic ,Immunology ,lcsh:Medicine ,Datasets as Topic ,Computational biology ,DNA Fragmentation ,Biology ,Genome ,Article ,Transcription (biology) ,Gene expression ,Humans ,Lupus Erythematosus, Systemic ,Epigenetics ,lcsh:Science ,Gene ,Genomic organization ,Multidisciplinary ,Gene Expression Profiling ,lcsh:R ,Phenotype ,Chromatin ,Computational biology and bioinformatics ,Gene Expression Regulation ,Immune System ,lcsh:Q ,Female ,Systems biology ,Transcriptome ,Genome-Wide Association Study - Abstract
Systemic Lupus Erythematosus (SLE) is the prototype of autoimmune diseases, characterized by extensive gene expression perturbations in peripheral blood immune cells. Circumstantial evidence suggests that these perturbations may be due to altered epigenetic profiles and chromatin accessibility but the relationship between transcriptional deregulation and genome organization remains largely unstudied. In this work we propose a genomic approach that leverages patterns of gene coexpression from genome-wide transcriptome profiles in order to identify statistically robust Domains of Co-ordinated gene Expression (DCEs). Application of this method on a large transcriptome profiling dataset of 148 SLE patients and 52 healthy individuals enabled the identification of significant disease-associated alterations in gene co-regulation patterns, which also correlate with SLE activity status. Low disease activity patient genomes are characterized by extensive fragmentation leading to overall fewer DCEs of smaller size. High disease activity genomes display extensive redistribution of co-expression domains with expanded and newly-appearing (emerged) DCEs. The dynamics of domain fragmentation and redistribution are associated with SLE clinical endophenotypes, with genes of the interferon pathway being highly enriched in DCEs that become disrupted and with functions associated to more generalized symptoms, being located in domains that emerge anew in high disease activity genomes. Our results suggest strong links between the SLE phenotype and the underlying genome structure and underline an important role for genome organization in shaping gene expression in SLE.
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- 2020
30. 2019 update of the joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis
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Bernadette Van Leew, Gabriella Moroni, Hans-Joachim Anders, Stephen D. Marks, Ingeborg M. Bajema, Josef S Smolen, Myrto Kostopoulou, Ioannis Parodis, George Bertsias, Y K Onno Teng, Frédéric Houssiau, A E Voskuyl, Maria Trachana, Martin Aringer, David Jayne, Antonis Fanouriakis, Ronald F van Vollenhoven, A. Karras, Matthias Schneider, Eleni Frangou, Dimitrios T. Boumpas, Manuel Praga, Francesca Marchiori, John Boletis, Kim Cheema, Marta Mosca, Jane L Hollis, Vladimir Tesar, Clinical Immunology and Rheumatology, AII - Inflammatory diseases, AMS - Ageing & Morbidty, AMS - Amsterdam Movement Sciences, AMS - Musculoskeletal Health, Rheumatology, Fanouriakis, Antonis [0000-0003-2696-031X], Aringer, Martin [0000-0003-4471-8375], Houssiau, Frederic A [0000-0003-1451-083X], Moroni, Gabriella [0000-0003-3256-476X], Parodis, Ioannis [0000-0002-4875-5395], van Vollenhoven, Ronald F [0000-0001-6438-8663], Boumpas, Dimitrios T [0000-0002-9812-4671], and Apollo - University of Cambridge Repository
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medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Calcineurin Inhibitors ,Lupus nephritis ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,systemic lupus erythematosus ,Internal medicine ,Azathioprine ,medicine ,Immunology and Allergy ,Humans ,030212 general & internal medicine ,Glucocorticoids ,Dialysis ,Societies, Medical ,030203 arthritis & rheumatology ,lupus nephritis ,treatment ,business.industry ,Immunosuppression ,Mycophenolic Acid ,Recommendation ,medicine.disease ,Transplantation ,Calcineurin ,Europe ,Proteinuria ,Systematic review ,Antirheumatic Agents ,Kidney Failure, Chronic ,Drug Therapy, Combination ,business ,Rheumatism ,Immunosuppressive Agents ,Kidney disease ,Glomerular Filtration Rate ,Hydroxychloroquine - Abstract
Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, Objective: To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN). Methods: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. Results: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria 1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. Conclusions: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.
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- 2020
31. P0359CROSS-TISSUE AND MURINE-HUMAN COMPARATIVE TRANSCRIPTOME ANALYSES IDENTIFY TARGETABLE GENES FOR HUMAN SYSTEMIC LUPUS ERYTHEMATOUS AND LUPUS NEPHRITIS
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Eleni Frangou, Dimitrios T. Boumpas, Nikolaos I Panousis, Emmanouil T. Dermitzakis, Panagiotis Garantziotis, Anastasia Filia, George Bertsias, Maria Grigoriou, and Angelos Banos
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Transcriptome ,Transplantation ,Nephrology ,Systemic lupus ,business.industry ,Immunology ,Lupus nephritis ,medicine ,medicine.disease ,business ,Gene - Abstract
Background and Aims Systemic Lupus Erythematosus (SLE) is a complex disease associated with non-synchronous multi-tissue dysfunction of varying severity. Involvement of major organs, such as kidneys, contributes significantly to morbidity and mortality. We sought to unravel new pathways to be used as potential biomarkers and therapeutic targets. To this end, we compared the patterns of gene transcription -as determined by the use of RNA-sequencing- across tissues between healthy and lupus-prone mice at different stages of the disease, and explored their implications for human disease and prediction of kidney involvement, in our whole blood RNA sequencing dataset comprised of 120 SLE [55 lupus nephritis (LN), 65 non-LN] patients and 58 healthy individuals (HI). Method NZB/W-F1 lupus-prone mice were sacrificed at the pre-puberty, pre-autoimmunity and nephritic stage. Age-matched C57BL/6 mice were used as controls. An “effector” tissue (spleen) and major end-organ tissues (kidneys, brain) were collected. Total RNA was isolated, and mRNA-sequencing was performed. Differential expression and time-series analyses were performed using DESeq2. Differentially expressed genes (DEGs) were hierarchically clustered and functionally interpreted using gProfiler enrichment analysis. Human orthologous genes of mouse common DEGs in each tissue and across all disease stages, were compared to human DEGs. Using machine learning techniques, human orthologs identified in the common DEGs across all stages in the kidneys of lupus-prone vs healthy mice were used to predict kidney involvement in the human dataset, which was split in training and validation sets. Results: Gene signatures: the common cross-tissue signature was identified by the comparison of DEGs between tissues of lupus-prone vs healthy mice at each stage of the disease. A total 134 genes (including C4A, LYRM7 and HDDC3) were found, suggesting their involvement in a common pathogenic mechanism across “effector” and end-organ tissues. Tissue-specific signatures showed enrichment of FCERI mediated NF-kB activation pathway in the spleen, steroid hormone biosynthesis pathway in the kidney and phosphatidylcholine metabolic process in the brain, suggesting distinct pathways implicated in end-organ injury. Comparative murine-human transcriptome analysis: 76 human orthologs (including CCL5, IFIT and HLA genes) identified in the murine spleen signature were also differentially expressed in SLE patients vs HI, suggesting their involvement in systemic autoimmunity. A total of 68 human orthologs (including FCGR2A, C1R and JAK1) identified in the mouse kidney-signature and 25 human orthologs (including APOA2) identified in the mouse brain-signature, were differentially expressed in LN patients vs HI and neuropsychiatric SLE patients vs HI, respectively. Kidney involvement prediction in human SLE: using a neural network model, 193 human orthologs predicted LN patients vs HI with high accuracy (accuracy=0.86, sensitivity=0.82, specificity=0.91 in the validation set). Using a support vector machine model, 30 human orthologs and age and gender were the best predictors of LN vs non-LN SLE patients (accuracy=0.71, sensitivity=0.73, specificity=0.69 in the validation set). Conclusion Murine RNA-sequencing uncovered both shared cross-tissue and tissue-specific gene signatures that could be potentially targeted in SLE. Murine-human comparative transcriptome analysis revealed common gene signatures suggesting that similar biological processes and pathways are disturbed across species, with murine kidney lupus signature predicting kidney involvement in human SLE. Validation in other datasets is ongoing.
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- 2020
32. Response to: 'Hydroxychloroquine is neutral in risk of chronic kidney disease in patients with systemic lupus erythematosus' by Wu
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George Bertsias, Dimitrios T. Boumpas, and Antonis Fanouriakis
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medicine.medical_specialty ,Side effect ,Immunology ,Lupus nephritis ,Renal function ,Inflammation ,urologic and male genital diseases ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,Excretion ,Rheumatology ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Lupus Erythematosus, Systemic ,Risk factor ,Renal Insufficiency, Chronic ,business.industry ,Hydroxychloroquine ,medicine.disease ,medicine.symptom ,business ,medicine.drug ,Kidney disease - Abstract
We thank Drs Wu et al for their interest in our manuscript1 and the stimulating data they provide regarding the value of hydroxychloroquine (HCQ) in the prevention of chronic kidney disease (CKD) in patients with systemic lupus erythematosus (SLE).2 We agree with the authors that the evidence behind the recommendation for a 50% reduction in HCQ dose in patients with lupus nephritis (LN) and a glomerular filtration rate (GFR) less than 30% is not supported by high-level evidence (although it is known that excretion of the drug is carried out principally by direct renal clearance).3 4 Nevertheless, CKD is considered a risk factor for the most important side effect of HCQ, retinal toxicity ; …
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- 2020
33. Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations
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Kim Cheema, George Bertsias, Antonis Fanouriakis, John Boletis, David Jayne, Dimitrios T. Boumpas, and Myrto Kostopoulou
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medicine.medical_specialty ,medicine.medical_treatment ,Biopsy ,Immunology ,Clinical Decision-Making ,030232 urology & nephrology ,Lupus nephritis ,Drug Resistance ,lcsh:Medicine ,Lupus ,Therapeutics ,Kidney ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Internal medicine ,Immunology and Allergy ,Medicine ,Humans ,Molecular Targeted Therapy ,Renal response ,Dialysis ,030203 arthritis & rheumatology ,Lupus erythematosus ,Proteinuria ,Lupus Erythematosus ,business.industry ,Calcineurin ,lcsh:R ,Systemic ,Disease Management ,Immunosuppression ,Evidence-based medicine ,medicine.disease ,Lupus Nephritis ,Systematic review ,Treatment Outcome ,Practice Guidelines as Topic ,Kidney Failure, Chronic ,Disease Susceptibility ,medicine.symptom ,business ,Biomarkers ,Immunosuppressive Agents - Abstract
ObjectivesTo analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations.MethodsAccording to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012.ResultsWe identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (ConclusionsThere is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.
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- 2020
34. I13 Neutrophils and innate immunity in the pathogenesis of SLE
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George Bertsias
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UNC93B1 ,Cell type ,Innate immune system ,business.industry ,Lupus nephritis ,Germinal center ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Interferon ,Immunology ,medicine ,business ,B cell ,medicine.drug - Abstract
Background Innate immunity cells, cytokines and inflammatory pathways have been recognised as inducers and amplifiers of autoimmune responses and tissue injury in SLE. Methods Published experimental data during the last five years on the contribution of innate immunity, particularly neutrophils and type I interferon, are summarized and their clinical implications are discussed. Results Recent genome-wide expression studies have implicated neutrophils in human SLE and lupus nephritis. Through a combined transcriptomic, epigenetic, and functional analysis, distinct subtypes of these cells have been identified in patients with SLE, with low-density granulocytes exhibiting excessive death by generation of extracellular chromatin traps (NETs) that are decorated with immunostimulatory/alarmin molecules such as interleukin-33 and promote the activation of other immune cells, type I interferon (IFN) production and endothelial injury. Intracellular protein citrullination mediated by neutrophil peptidylarginine deiminases (PADs) is critical for NETs formation and accordingly, targeting PADs ameliorates lupus disease by reducing autoantibodies, type I IFN, immune cell activation, vascular dysfunction, and NET immunogenicity. Notably, activation of Toll-like receptors (TLR)-7/8 in neutrophils causes proteolytic cleavage of the N-terminal part of Fc-γ-receptors (FcgrIIA), thus abrogating their capacity to phagocytose immunocomplexes while promoting their death by NETosis. Mechanistically, recruitment of syntenin-1 by UNC93B1 has been reported to facilitate the sorting of TLR-7 into multivesicular bodies, therefore offering dynamic regulation of TLR-7 activation/signaling. Besides NETs, a number of other pathways may enhance IFN production in SLE such as apoptosis-derived membrane vesicles through activation of cGAS–STING, and photosensitivity-induced IFN-kappa released by keratinocytes. The latter is in line with clinical observations that therapeutic blockade of IFN or downstream signaling may be particularly beneficial in cutaneous manifestations of SLE. Remarkably, IFN signature is present in multiple immune cell types in SLE such as in B-cells where it causes breach of tolerance, promoting autoreactive B cell development into the autoantibody-forming cell and germinal center pathways. In T-cells, SLE patients who carry the STAT4 risk allele rs7574865[t] display augmented inflammatory responses to IL-12 and IFN-α, and vice versa, IFN-α may augment the IL-12-induced STAT4 activation, therefore highlighting a subgroup of patients who may benefit from IFNa/JAK/STATs targeting. Conclusions Culminating research further supports the critical role of neutrophils and innate immune pathways in SLE pathogenesis. Elucidation of intracellular pathways pertaining to production and regulation of important mediators such as IFN may provide novel insights towards development of targeted therapies. Acknowledgements This work was supported by Special Research Account of the University of Crete (grant no. 4718).
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- 2020
35. P107 Interferon-induced metabolic perturbations shape the inflammatory status of human monocytes: implications for innovative therapeutic engineering in SLE autoimmunity
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George Bertsias, Christina Adamichou, Katerina Gkirtzimanaki, Aggelos Banos, Vasilis Ntassis, Chrysoula Stathopoulou, Antonis Myridakis, and Prodromos Sidiropoulos
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business.industry ,medicine.disease_cause ,Autoimmunity ,Proinflammatory cytokine ,Transcriptome ,Pathogenesis ,Immune system ,Interferon ,Metabolic flux analysis ,Immunology ,medicine ,skin and connective tissue diseases ,business ,Flux (metabolism) ,medicine.drug - Abstract
Immune cells have unique metabolic requirements to support the energetic and biosynthetic burden during their activation. Delineation of the metabolic tuning of immune cells could lead to novel strategies in treating metabolically-demanding processes including autoimmune diseases. Among innate effectors, monocytes have a distinct role in systemic lupus erythematosus (SLE) pathogenesis. We have previously described robust type-I interferon (IFNα) signaling in patients with SLE. IFNα-stimulated monocytes from healthy individuals (IFN-Mo) develop mitochondrial hyperpolarization and increased oxidative stress resembling SLE monocytes (SLE-Mo). Here we sought to delineate the metabolic repercussion of IFNα-mediated signaling that could explain metabolic shifts pertaining to autoimmunity. To this end, we combined transcriptomic data with metabolic flux analysis (Seahorse technology) and Gas Chromatography (GC-MS) in healthy monocytes, IFN-Mo and SLE-Mo. Our preliminary results indicate an increased, glucose-dose dependent glycolytic flux in IFNα-treated healthy monocytes recapitulating the SLE-Mo phenotype. Blockade of hexokinase 2 (HK-2)-dependent glycolysis with the use of 2-DG inhibitor attenuated proinflammatory cytokine secretion and the expression of surface markers characteristic of activated monocytes, supporting the deregulated metabolic profile in SLE autoimmunity. Combination of these data with targeted metabolomics (LC-MS) analyses and the application of pathway-specific inhibitors are implemented in vitro to reverse the inflammatory state of SLE monocytes. Together, our data are expected to yield unique insights into the role of immunometabolism in SLE and the potential use of metabolites as novel therapeutic targets in autoimmunity.
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- 2020
36. Development and preliminary validation of the Behçet’s syndrome Overall Damage Index (BODI)
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Ricard Cervera, Marcello Govoni, Vittorio Pirani, Ana Martins da Silva, Luca Cantarini, Carlos Vasconcelos, Nikolaos Kougkas, Alberto Cauli, Monica Muntoni, Alberto Floris, Giuseppe Lopalco, João R. Correia, Florenzo Iannone, Alessandro Mathieu, Luísa Serpa Pinto, Gerard Espinosa, George Bertsias, Ida Orlando, Piergiorgio Neri, Matteo Piga, Ernestina Santos, and Andrea Lo Monaco
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Vasculitis ,Adult ,Male ,medicine.medical_specialty ,Clinical Decision-Making ,Immunology ,Behcet’s disease ,Outcomes research ,Systemic vasculitis ,Context (language use) ,Behcet's disease ,Severity of Illness Index ,NO ,Young Adult ,Rheumatology ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Face validity ,S syndrome ,business.industry ,Behcet Syndrome ,Disease Management ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Organ damage ,Cross-Sectional Studies ,Cohort ,Female ,Observational study ,business - Abstract
ObjectiveTo develop and validate the evidence-based and consensus-based Behçet’s Syndrome Overall Damage Index (BODI).MethodsStarting from 120 literature-retrieved preliminary items, the BODI underwent multiple Delphi rounds with an international multidisciplinary panel consisting of rheumatologists, internists, ophthalmologists, neurologists, and patient delegates until consensus was reached on the final content. The BODI was validated in a cross-sectional multicentre cohort of 228 patients with Behçet’s syndrome (BS) through the study of (a) correlation between BODI and Vasculitis Damage Index (VDI) and (b) correlation between BODI and disease activity measures (ie, Behçet’s Disease Current Activity Form (BDCAF), Physician Global Assessment (PGA), Patient Global Assessment (PtGA)), c) content and face validity and (d) feasibility.ResultsThe final BODI consists of 4 overarching principles and 46 unweighted-items grouped into 9 organ domains. It showed good to excellent reliability, with a mean Cohen’s k of 0.84 (95% CI 0.78 to 0.90) and a mean intra-class correlation coefficient of 0.88 (95% CI 0.80 to 0.95). Overall, 128 (56.1%) patients had a BODI score ≥1, with a median score of 1.0 (range 0–14). The BODI significantly correlated with the VDI (r=0.693, pConclusionsPending further validation, the BODI may be used to assess organ damage in patients with BS in the context of observational and controlled trials.
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- 2020
37. Epidemiology and burden of systemic lupus erythematosus in a Southern European population: data from the community-based lupus registry of Crete, Greece
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Alexandra Pompieri, Antonios Bertsias, Dimitrios T. Boumpas, Antonis Fanouriakis, Prodromos Sidiropoulos, Michalis Tzanakakis, Christina Adamichou, Giorgis Spirou, Ioannis Tzanakis, Leda Chatzi, George Bertsias, Irini Gergianaki, Argyro Repa, Eleni Kabouraki, Complexe Genetica, RS: NUTRIM - R4 - Gene-environment interaction, and RS: NUTRIM - R3 - Respiratory & Age-related Health
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Male ,Rural Population ,Pediatrics ,Urban Population ,Lupus nephritis ,0302 clinical medicine ,Cost of Illness ,Epidemiology ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Registries ,030212 general & internal medicine ,DISEASE-ACTIVITY INDEX ,Community based ,education.field_of_study ,Systemic lupus erythematosus ,Greece ,Incidence ,Incidence (epidemiology) ,Lupus Vasculitis, Central Nervous System ,STAGE RENAL-DISEASE ,Middle Aged ,Lupus Nephritis ,COLLEGE-OF-RHEUMATOLOGY ,PREVALENCE ,Female ,Neuropsychiatric disease ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,Population ,CLINICS CLASSIFICATION CRITERIA ,White People ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,Age Distribution ,Rheumatology ,medicine ,Humans ,DAMAGE INDEX ,NEPHRITIS ,education ,030203 arthritis & rheumatology ,business.industry ,NORTHWEST GREECE ,UPDATED VERSION ,European population ,medicine.disease ,business ,BILAG 2004 - Abstract
ObjectivesSeveral population-based studies on systemic lupus erythematosus (SLE) have been reported, yet community-based, individual-case validated, comprehensive reports are missing. We studied the SLE epidemiology and burden on the island of Crete during 1999–2013.MethodsMultisource case-finding included patients ≥15 years old. Cases were ascertained by the ACR 1997, SLICC 2012 criteria and rheumatologist diagnosis, and validated through synthesis of medical charts, administrative and patient-generated data.ResultsOverall age-adjusted/sex-adjusted incidence was 7.4 (95% CI 6.8 to 7.9) per 100 000 persons/year, with stabilising trends in women but increasing in men, and average (±SD) age of diagnosis at 43 (±15) years. Adjusted and crude prevalence (December 2013) was 123.4 (113.9 to 132.9) and 143 (133 to 154)/105 (165/105 in urban vs 123/105 in rural regions, pConclusionsBy the use of a comprehensive methodology, we describe the full spectrum of SLE from the community to tertiary care, with almost half of the cases having mild disease, yet with significant damage accrual. SLE is not rare, affects predominantly middle-aged women and is increasingly recognised in men. Neuropsychiatric disease is an emerging frontier in lupus prevention and care.
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- 2017
38. A framework for remission in SLE
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Marzena Olesińska, Ronald H. W. M. Derksen, Jamil Missaykeh, Eloisa Bonfa, Anne Voss, Marta Mosca, Ole Petter Rekvig, Martin Aringer, Murray B. Urowitz, Laurent Arnaud, Sandra V. Navarra, Asad Zoma, Ruth D E Fritsch-Stork, Caroline Gordon, Victoria P. Werth, David A. Isenberg, Alexandre E. Voskuyl, Josef S Smolen, Jozef Rovensky, Cynthia Aranow, Nathalie Costedoat-Chalumeau, Véronique Le Guern, Roger A. Levy, Ronald F van Vollenhoven, Annegret Kuhn, George Bertsias, Xavier Mariette, Thomas Dörner, Hendrika Bootsma, Kirsten Lerstrøm, Ann E. Clarke, Rebecca Fischer-Betz, László Czirják, Petra Balážová, Bernadette van Leeuw, N. Györi, Murat Inanc, Michelle Petri, Ian N. Bruce, Ricard Cervera, Dimitrios T. Boumpas, Angela Tincani, Winfried Graninger, Francinne Machado-Ribeiro, Cindy Coney, Søren Jacobsen, David Jayne, Anisur Rahman, Carlos Vasconcelos, Yehuda Shoenfeld, Frédéric Houssiau, Eric F Morand, Irmgard Neumann, Helena Zakharova, Anca Askanase, Andrea Doria, Matthias Schneider, Michael E. Ward, Universitat de Barcelona, Rheumatology, AII - Inflammatory diseases, and Translational Immunology Groningen (TRIGR)
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Genetics and Molecular Biology (all) ,Pediatrics ,Autoimmune diseases ,NEPHRITIS PATIENTS ,DISEASE-ACTIVITY ,Severity of Illness Index ,Biochemistry ,RETROSPECTIVE ANALYSIS ,0302 clinical medicine ,Quality of life ,Prednisone ,Adrenal Cortex Hormones ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,CHINESE PATIENTS ,030212 general & internal medicine ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,skin and connective tissue diseases ,PREDICTORS ,OUTCOMES ,Systemic lupus erythematosus ,Malalties autoimmunitàries ,Remission Induction ,INITIAL VALIDATION ,AMERICAN-COLLEGE ,RENAL FLARES ,Symptom Flare Up ,Connective tissue disease ,Manchester Institute for Collaborative Research on Ageing ,Estudi de casos ,Outcomes research ,Antibodies, Antinuclear ,DNA/immunology ,Immunosuppressive Agents ,medicine.drug ,medicine.medical_specialty ,Farmacologia ,ResearchInstitutes_Networks_Beacons/MICRA ,Consensus ,Immunology ,Adrenal Cortex Hormones/therapeutic use ,Lupus Erythematosus, Systemic/blood ,Systemic Lupus Erythematosus ,General Biochemistry, Genetics and Molecular Biology ,Maintenance Chemotherapy ,03 medical and health sciences ,Antimalarials ,Rheumatology ,Severity of illness ,medicine ,Disease Activity ,Biochemistry, Genetics and Molecular Biology (all) ,Humans ,030203 arthritis & rheumatology ,Pharmacology ,Antibodies, Antinuclear/blood ,Lupus erythematosus ,business.industry ,Task force ,Construct validity ,Complement System Proteins ,DNA ,medicine.disease ,Lupus eritematós ,Antimalarials/therapeutic use ,Physical therapy ,Immunosuppressive Agents/therapeutic use ,Complement System Proteins/metabolism ,Case studies ,business - Abstract
ObjectivesTreat-to-target recommendations have identified ‘remission’ as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.MethodsAn international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.ResultsThe task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.ConclusionsThe work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.
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- 2017
39. Population-based studies in systemic lupus erythematosus: immune thrombocytopenic purpura or ‘blood-dominant’ lupus?
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Dimitrios T. Boumpas, Antonis Fanouriakis, and George Bertsias
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Purpura, Thrombocytopenic, Idiopathic ,education.field_of_study ,Lupus erythematosus ,Systemic lupus erythematosus ,business.industry ,Immunology ,Population ,Autoantibody ,Disease ,medicine.disease ,Thrombocytopenic purpura ,General Biochemistry, Genetics and Molecular Biology ,Cohort Studies ,Immune system ,medicine.anatomical_structure ,Rheumatology ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Bone marrow ,education ,business - Abstract
Thanks to their large sample size, thus reducing the risk of selection and participation bias, population-based studies can provide high-quality data on the prevalence and incidence, natural history and treatment, correlates and associations of a disease, and healthcare utilisation.1 Several nationwide research databases exist in the world, one of the oldest in Sweden dating back to 1955. The Taiwan National Health Insurance Research Database (NHIRD) is one of the largest nationwide population databases, covering approximately 23 million residents in Taiwan and data of more than 99% of the population. Using this unique database, investigators have asked important questions regarding the heredity and coaggregation of autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjogren’s syndrome and myasthenia gravis.2–4 Immune thrombocytopenic purpura (ITP), formerly known as idiopathic thrombocytopenic purpura, is an immune-mediated acquired disease of adults and children characterised by a transient or persistent decrease of platelet counts and, depending on the degree of thrombocytopenia, increased risk of bleeding.5 In ΙΤP, an abnormal T cell response, supported by splenic T follicular helper cells, stimulates the proliferation and differentiation of autoreactive B cells producing antiplatelet autoantibodies that facilitate platelet phagocytosis by macrophages, predominantly in the spleen. Macrophages also contribute to the perpetuation of the autoimmune response in ITP, functioning as the principal antigen-presenting cells. Inappropriate bone marrow production due to an immune response against megakaryocytes may also exacerbate thrombocytopenia, while the level of …
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- 2020
40. Response to: 'Treatment of systemic lupus erythematosus: don't forget hydroxychloroquine' by Michaud
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George Bertsias, Dimitrios T. Boumpas, and Antonis Fanouriakis
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030203 arthritis & rheumatology ,0301 basic medicine ,medicine.medical_specialty ,business.industry ,Immunology ,MEDLINE ,Hydroxychloroquine ,Response to treatment ,Dermatology ,General Biochemistry, Genetics and Molecular Biology ,Disease activity ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,medicine ,Immunology and Allergy ,Humans ,Lupus Erythematosus, Systemic ,business ,medicine.drug - Abstract
We thank Michaud et al for their comment and thorough overview of the multiple benefits of hydroxychloroquine (HCQ) in systemic lupus erythematosus (SLE).1 We fully agree with the authors’ punchline that ‘HCQ is still in 2019 the cornerstone of the treatment of SLE’; a detailed description of its beneficial actions can be found in the Supplementary …
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- 2019
41. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus
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George Bertsias, Ricard Cervera, Ingeborg M. Bajema, John Boletis, Alessia Alunno, Marcello Govoni, Ronald F van Vollenhoven, Jörg Wenzel, Kirsten Lerstrøm, Antonis Fanouriakis, Marios Kouloumas, Annegret Kuhn, Vladimir Tesar, Angela Tincani, Marta Mosca, Josef S Smolen, Caroline Gordon, Elisabet Svenungsson, David Jayne, Dimitrios T. Boumpas, Myrto Kostopoulou, Anne Troldborg, Frédéric Houssiau, Matthias Schneider, Martin Aringer, Gabriella Moroni, Andrea Doria, Janni Lisander Larsen, Clinical Immunology and Rheumatology, AII - Inflammatory diseases, AMS - Ageing & Morbidty, Jayne, David [0000-0002-1712-0637], Apollo - University of Cambridge Repository, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie
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0301 basic medicine ,medicine.medical_specialty ,Immunology ,Lupus nephritis ,Genetics and Molecular Biology ,Azathioprine ,Comorbidity ,Severity of Illness Index ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Economica ,0302 clinical medicine ,Rheumatology ,systemic lupus erythematosus ,immune system diseases ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,Glucocorticoids ,030203 arthritis & rheumatology ,lupus nephritis ,Biological Products ,Systemic lupus erythematosus ,Lupus erythematosus ,Evidence-Based Medicine ,Lupus Erythematosus ,treatment ,business.industry ,Systemic ,Disease Management ,Hydroxychloroquine ,medicine.disease ,Belimumab ,Discontinuation ,030104 developmental biology ,General Biochemistry ,Rituximab ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
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- 2019
42. Immunometabolism: an overview and therapeutic prospects in autoimmune diseases
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George Bertsias, Dimitra Nikoleri, and Chrysoula Stathopoulou
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0301 basic medicine ,Multiple Sclerosis ,Immunology ,Autoimmune Diseases ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Glycolysis ,PI3K/AKT/mTOR pathway ,Autoimmune disease ,Innate immune system ,Glutaminolysis ,business.industry ,Models, Immunological ,medicine.disease ,Acquired immune system ,Metabolic pathway ,030104 developmental biology ,Glucose ,Oncology ,030220 oncology & carcinogenesis ,Immune System ,business ,Metabolic Networks and Pathways - Abstract
Metabolism is a critical immune regulator under physiologic and pathologic conditions. Culminating evidence has disentangled the contribution of distinct metabolic pathways, namely glucolysis, pentose phosphate, fatty acid oxidation, glutaminolysis, Krebs cycle and oxidative phosphorylation, in modulating innate and adaptive immune cells based on their activation/differentiation state. Metabolic aberrations and changes in the intracellular levels of specific metabolites are linked to the inflammatory phenotype of immune cells implicated in autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and diabetes. Notably, targeting metabolism such as the mTOR by rapamycin, hexokinase by 2-deoxy-D-glucose, AMP-activated protein kinase by metformin, may be used to ameliorate autoimmune inflammation. Accordingly, research in immunometabolism is expected to offer novel opportunities for monitoring and treating immune-mediated diseases.
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- 2019
43. Lupus and the Brain: Advances in Neuropsychiatric Systemic Lupus Erythematosus
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George Bertsias, Antonis Fanouriakis, and Marcello Govoni
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lcsh:R5-920 ,Systemic lupus erythematosus ,diagnosis ,Systemic lupus ,business.industry ,biomarkers ,General Medicine ,attribution ,central nervous system ,medicine.disease ,Neuropsychiatric systemic lupus erythematosus ,Editorial ,systemic lupus erythematosus ,Immunology ,medicine ,Medicine ,lcsh:Medicine (General) ,business - Published
- 2019
44. Changing paradigms in the treatment of systemic lupus erythematosus
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Antonis Fanouriakis and George Bertsias
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medicine.medical_specialty ,Immunology ,Lupus nephritis ,Disease ,Review ,03 medical and health sciences ,0302 clinical medicine ,systemic lupus erythematosus ,medicine ,biologics ,030212 general & internal medicine ,Intensive care medicine ,Adverse effect ,030203 arthritis & rheumatology ,lupus nephritis ,treatment ,business.industry ,Hydroxychloroquine ,General Medicine ,medicine.disease ,Belimumab ,Clinical Practice ,Calcineurin ,Rituximab ,business ,medicine.drug - Abstract
SLE poses formidable therapeutic challenges due to its heterogeneity and treatment decisions often cannot be guided by data of high quality. In this review, we attempt to provide insights regarding the treatment of SLE in everyday clinical practice, based on contemporary evidence and our own personal experience. We focus on common therapeutic issues and dilemmas arising in routine care, including monitoring for retinal toxicity associated with hydroxychloroquine, handling of glucocorticoid regimens in order to minimise their adverse events, choice of immunosuppressive medications based on prevailing disease manifestations and optimal use of available biological agents (belimumab and rituximab). We also provide our view on the position of calcineurin inhibitors in the management of lupus nephritis and conclude with remarks on the future perspectives for this challenging disease.
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- 2019
45. Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus
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Ioannis Mitroulis, Maria Grigoriou, George Bertsias, Aggelos Banos, Vassiliki Karali, Stavroula Giannouli, Panayotis Verginis, Dimitrios T. Boumpas, Anastasia Filia, Dionysis Nikolopoulos, Antigone Pieta, and Pavlos Pavlidis
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CCAAT-Enhancer-Binding Protein-delta ,0301 basic medicine ,Myeloid ,Cellular differentiation ,Immunology ,CD34 ,Fluorescent Antibody Technique ,Apoptosis ,Systemic Lupus Erythematosus ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Granulocyte Colony-Stimulating Factor ,Animals ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Medicine ,Myeloid Cells ,Lymphocytes ,Progenitor cell ,business.industry ,Cell Cycle ,autoimmunity ,Chromosome Mapping ,Cellular Reprogramming ,Flow Cytometry ,Hematopoietic Stem Cells ,3. Good health ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,inflammation ,CCAAT-Enhancer-Binding Proteins ,Cancer research ,Myelopoiesis ,business ,Reprogramming ,DNA Damage ,Granulocytes ,030215 immunology - Abstract
ObjectivesHaematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs.MethodsA global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence.ResultsTranscriptomic analysis of Lin−Sca-1+c-Kit+haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)—but not of common lymphoid progenitors—reminiscent of a ‘trained immunity’ signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such asCebpe,CebpdandCsf3r, and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data.ConclusionsAberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare.Trial registration number4948/19-07-2016.
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- 2019
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46. POS0370 TYPE I INTERFERON PATHWAY ASSAYS IN PATIENTS WITH RHEUMATIC AND MUSCULOSKELETAL DISEASES - SYSTEMATIC LITERATURE REVIEW (SLR) AND DEVELOPMENT OF CONSENSUS TERMINOLOGY FROM A EULAR TASKFORCE
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P.G. Conaghan, M. Visser, George Bertsias, R. Biesen, Maija-Leena Eloranta, W. A. Dik, G. Cavalli, J Rodríguez Carrio, Marjan A. Versnel, E.M. Vital, Agata Burska, Dimitrios T. Boumpas, Lars Rönnblom, J. Rehwinkel, Marie Wahren-Herlenius, M. L. Frémond, and M. K. Crow
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medicine.medical_specialty ,business.industry ,Immunology ,General Biochemistry, Genetics and Molecular Biology ,Terminology ,Systematic review ,Rheumatology ,Interferon ,Immunology and Allergy ,Medicine ,In patient ,business ,Intensive care medicine ,medicine.drug - Abstract
Background:The interferon (IFN) pathway is a complex system with multiple proteins and diverse downstream effects on gene and protein expression. IFNs have been implicated in multiple RMDs. Despite significant potential, IFN assays have not progressed into clinical practice.Objectives:To perform a SLR on IFN assays in RMDs and propose a consensus terminology.Methods:OvidMedline, Embase and Web of Science were searched for reports of IFN and RMDs up to October 2019. Information about the properties of assays measuring type I IFN and measures of truth were extracted and summarised. Terminology was agreed through an interactive consensus process with reference to the existing evidence.Results:10037 abstracts were identified. 275 fulfilled eligibility criteria, and were used for data extraction. Some used more than one technique to measure IFN-I pathway activation. Hence, 275 papers generated data on 393 methods. There was great heterogeneity in the methods used and presentation of results. IFN-I pathway activation was measured using: qPCR (n=121), immunoassays (n=101), microarray (n=69), reporter cell assay (n=38), DNA methylation (n=14), flow cytometry (n=14), cytopathic effect assay (n=11), RNA sequencing (n=9), Plaque reduction assay (n=8), Nanostring (n=5), bisulphite sequencing (n=3). All papers fulfilled Face Validity. Due to lack of gold standard for IFN-I pathway activation, evidence of criterion validity was variable. Concurrent validity was presented for n=150 assays. The terminology used to describe aspects of type I IFN pathway activation was not consistent, so a consensus terminology for IFN research (Table 1) was proposed by the taskforce.Table 1.Consensus terminologyTermAbbreviationDefinitionInterferonIFNProteins with anti-viral activity; IFNs are mediators of an anti-viral response. They belong to the Type I, Type II and Type III IFN families.Type I interferonIFN-IThe IFNs alpha, beta, omega, kappa, epsilon, secreted by any nucleated cell, and binding to the IFNAR, which is expressed on any nucleated cell.Type II interferonIFN-IIIFN gamma, mostly secreted by T cells, binding to the IFNGR, which is expressed on most leucocytes.Type III interferonIFN-IIIIFN lambda, which are structurally more similar to IL-10 but share downstream signalling and gene expression with IFN-I.Interferon-stimulated genesISGsGenes whose expression is known to be upregulated by any kind of IFN. Individual ISGs may not exclusively represent Type I IFN pathway activation.Type I Interferon pathway activationAny evidence for function of the components of the Type I IFN pathway. This includes: secretion of a Type I IFN protein, binding to the IFNAR, initiation of JAK/STAT signalling pathways, expression of IFN-stimulated genes, expression of IFN-stimulated proteins.Type I interferon pathway assayAn assay measuring one or more components of the Type I IFN pathway at a molecular or functional level.Interferon stimulated gene expression signatureA qualitative description of coordinated expression of a set of ISGs that is indicative of Type I IFN pathway activation.Interferon stimulated gene expression scoreA quantitative variable derived from expression of a defined set of ISGs that is indicative of Type I IFN pathway activation.Interferon stimulated protein scoreA variable derived from expression of a defined set of soluble biomarkers known to be upregulated by IFN, although not specific for Type I IFN.InterferonopathyMonogenic diseases in which there is constitutive Type I IFN pathway activation with a causal role in pathology. The clinical picture may resemble rheumatic musculoskeletal diseases. However, most diseases with IFN pathway activation are not Interferonopathies.Conclusion:Diverse methods have been reported as IFN assays and these differ in what elements of type IFN-I pathway activation they measure. The taskforce consensus terminology on type I IFN reporting should be considered for research and clinical applications.Disclosure of Interests:Agata Burska: None declared, Javier Rodriguez Carrio: None declared, Philip G Conaghan: None declared, Willem A Dik: None declared, Robert Biesen: None declared, Maija-leena Eloranta: None declared, Giulio Cavalli: None declared, Marianne Visser: None declared, Dimitrios Boumpas: None declared, George Bertsias: None declared, Marie Wahren-Herlenius: None declared, Jan Rehwinkel: None declared, Marie-Louise Frémond: None declared, Mary K. Crow Consultant of: AstraZeneca, Bristol Meyers Squibb, Lilly, Shannon Pharmaceuticals, Grant/research support from: Gilead, Lars Ronnblom Consultant of: AstraZeneca, Edward Vital Speakers bureau: GSK, Consultant of: AURINIA, SANDOZ, GSK, AstraZeneca, Roche, Modus, Grant/research support from: AstraZeneca, Marjan Versnel: None declared
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- 2021
47. Elimination of Granulocytic Myeloid-Derived Suppressor Cells in Lupus-Prone Mice Linked to Reactive Oxygen Species-Dependent Extracellular Trap Formation
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Panayotis Verginis, Garyfalia Papadaki, Marianna Ioannou, Konstantinos Mintzas, Prodromos Sidiropoulos, Dimitrios T. Boumpas, George Bertsias, K. Vlachou, and Maria Glymenaki
- Subjects
0301 basic medicine ,Systemic lupus erythematosus ,Lupus erythematosus ,medicine.diagnostic_test ,Cell growth ,T cell ,Immunology ,Cell sorting ,Biology ,medicine.disease ,Molecular biology ,Flow cytometry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,medicine.anatomical_structure ,Rheumatology ,immune system diseases ,medicine ,Myeloid-derived Suppressor Cell ,Cancer research ,Immunology and Allergy ,skin and connective tissue diseases ,030215 immunology - Abstract
Objective Emerging evidence supports a crucial role of myeloid-derived suppressor cells (MDSCs) in the regulation of autoimmune diseases. However, their role in systemic lupus erythematosus (SLE) remains unknown. This study sought to address the role of MDSCs in the pathogenesis of SLE. Methods MDSCs from (NZB × NZW)F1 lupus-prone mice were assessed for phenotype by flow cytometry, and the function of MDSCs was analyzed by in vitro T cell proliferation assay and real-time quantitative polymerase chain reaction. Extracellular trap (ET) formation was evaluated by immunofluorescence and confocal microscopy. The production of reactive oxygen species (ROS) by Ly-6G+ cells was determined by fluorescence-activated cell sorting analysis. Results Expansion of MDSCs was impaired and the function of MDSCs was defective in the lymphoid organs of (NZB × NZW)F1 lupus-prone mice with established disease, in which involvement of predominantly the granulocytic MDSC (G-MDSC) cell subset was observed. More specifically, the results showed that increased elimination of G-MDSCs, driven by the inflammatory milieu of lupus, could be attributed to ET formation, and that cytokines, such as interferon-α (IFNα), IFNγ, and interleukin-6, play a role in this process. Induction of ET release by G-MDSCs was mediated by the production of ROS, since inhibition of ROS generation significantly reduced ET release. Conclusion Collectively, the results of this study reveal that elimination of a crucial regulatory immune cell subset is a feature of the SLE microenvironment. These findings provide new insights into the pathogenetic mechanisms of the disease.
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- 2016
48. Update on the cellular and molecular aspects of lupus nephritis
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Spyros Georgakis, Eleni Frangou, and George Bertsias
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0301 basic medicine ,Immunology ,Lupus nephritis ,Adaptive Immunity ,Biology ,Kidney ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Extracellular ,Animals ,Humans ,Immunology and Allergy ,Autoantibodies ,B-Lymphocytes ,Systemic lupus erythematosus ,Podocytes ,Autoantibody ,Germinal center ,T-Lymphocytes, Helper-Inducer ,Germinal Center ,Type I interferon production ,medicine.disease ,Lupus Nephritis ,Immunity, Innate ,Chromatin ,Cell biology ,030104 developmental biology ,030215 immunology - Abstract
Recent progress has highlighted the involvement of a variety of innate and adaptive immune cells in lupus nephritis. These include activated neutrophils producing extracellular chromatin traps that induce type I interferon production and endothelial injury, metabolically-rewired IL-17–producing T-cells causing tissue inflammation, follicular and extra-follicular helper T-cells promoting the maturation of autoantibody-producing B-cells that may also sustain the formation of germinal centers, and alternatively activated monocytes/macrophages participating in tissue repair and remodeling. The role of resident cells such as podocytes and tubular epithelial cells is increasingly recognized in regulating the local immune responses and determining the kidney function and integrity. These findings are corroborated by advanced, high-throughput genomic studies, which have revealed an unprecedented amount of data highlighting the molecular heterogeneity of immune and non-immune cells implicated in lupus kidney disease. Importantly, this research has led to the discovery of putative pathogenic pathways, enabling the rationale design of novel treatments.
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- 2020
49. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus
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Sara K. Tedeschi, Pier Luigi Meroni, Jorge Sanchez-Guerrero, Martin Aringer, Zahi Touma, Josef S Smolen, Peter M. Izmirly, Ray Naden, Mary K. Crow, Thomas Dörner, Xavier Mariette, Maria G Tektonidou, George Bertsias, Juanita Romero-Diaz, Elena Massarotti, Chiara Tani, Dinesh Khanna, Edward M Vital, Diane L. Kamen, Íñigo Rúa-Figueroa Fernández, Falk Hiepe, Ivan Padjen, Michelle Jung, Gabriela Schmajuk, David Jayne, Ann E. Clarke, Joseph M. McCune, Karen H. Costenbader, Ricard Cervera, Branimir Anić, Andrea Doria, Betty Diamond, Guillermo Ruiz-Irastorza, Winfried Graninger, Ralph Brinks, Kirsten Lerstrøm, Dimitrios T. Boumpas, Sarfaraz Hasni, Bernadett Halda-Kiss, Murray B. Urowitz, Sule Yavuz, Marta Mosca, László Czirják, Bimba F. Hoyer, Gábor Kumánovics, Sindhu R. Johnson, José M. Pego-Reigosa, David Wofsy, Søren Jacobsen, Dafna D. Gladman, Florence Assan, Carlos Vasconcelos, Raphaèle Seror, Matthias Schneider, Marvin J. Fritzler, Georg Stummvoll, Bevra H. Hahn, Nicolai Leuchten, Daniel J. Wallace, Rosalind Ramsey-Goldman, David I. Daikh, Yoshiya Tanaka, Nathalie Costedoat-Chalumeau, and Tak Mao Chan
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Male ,0301 basic medicine ,Delphi Technique ,Anti-nuclear antibody ,International Cooperation ,Delphi method ,classification criteria ,consensus methods ,lupus ,multi-criteria decision analysis ,systemic lupus erythematosus ,validation ,Antiphospholipid ,Cohort Studies ,0302 clinical medicine ,immune system diseases ,Antinuclear ,Immunology and Allergy ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,Societies, Medical ,Systemic lupus erythematosus ,Middle Aged ,Multiple-criteria decision analysis ,Europe ,Antibodies, Antinuclear ,Cohort ,Public Health and Health Services ,Antibodies, Antiphospholipid ,Female ,Cohort study ,Adult ,medicine.medical_specialty ,Systemic lupus erythematosus, lupus, classification criteria, consensus methods, multi-criteria decision analysis, validation ,Clinical Sciences ,Immunology ,MEDLINE ,Lupus ,Autoimmune Disease ,Sensitivity and Specificity ,Antibodies ,Article ,General Biochemistry, Genetics and Molecular Biology ,Decision Support Techniques ,03 medical and health sciences ,Rheumatology ,Medical ,Internal medicine ,Rheumatic Diseases ,medicine ,Humans ,Autoantibodies ,030203 arthritis & rheumatology ,Lupus erythematosus ,Lupus Erythematosus ,business.industry ,Inflammatory and immune system ,Systemic ,Complement System Proteins ,medicine.disease ,United States ,Arthritis & Rheumatology ,030104 developmental biology ,Societies ,business ,Rheumatism - Abstract
ObjectiveTo develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).MethodsThis international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects.ResultsThe 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.ConclusionThese new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.
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- 2018
50. P009 Transcriptomic analysis of plasmacytoid dendritic cells from rheumatoid arthritis patients reveals novel targets for therapy
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Andreas Grützkau, Dimitrios T. Boumpas, Joachim R. Grün, Panagiota Goutakoli, Panayotis Verginis, Garyfalia Papadaki, George Bertsias, A. Fanouriakis, Ioannis Iliopoulos, Prodromos Sidiropoulos, and George Pavlopoulos
- Subjects
business.industry ,hemic and immune systems ,Neutrophil extracellular traps ,Gene signature ,medicine.disease ,Immune tolerance ,Transcriptome ,Antigen ,Rheumatoid arthritis ,Immunology ,Medicine ,Tumor necrosis factor alpha ,Receptor ,business - Abstract
Introduction Reestablishing immune tolerance and long term remission represent major therapeutic goals in rheumatoid arthritis (RA). Our laboratory previously demonstrated that plasmacytoid dendritic cells (pDCs) from RA patients in remission have the ability to induce IL-10 producing regulatory T cells in vitro. However, the molecular pathway of RA pDC-mediated Treg induction remains elusive. Objectives Herein, we sought to identify the molecular mechanism through which pDCs contribute to restoration of tolerance in RA. Methods pDCs were isolated from peripheral blood of RA patients responding to anti-TNF therapy (DAS28 Results pDCs from RA patients (n=5) exhibited a differential gene signature (6741 deregulated genes) compared to pDCs from healthy controls (n=5). Notably, IL-6 receptor (IL-6R) gene, exhibited increased expression levels in pDCs isolated from RA patients compared to healthy pDCs and the surface expression levels of IL-6 receptor were verified in a subsequent cohort of patients responding to therapy (n=9) versus active patients or healthy donors. Moreover, assessment of IL-6 signalling pathway in RA patients versus healthy donors revealed a significant increase of pSTAT1 expression levels in RA patients (n=9) compared with healthy donors (n=6) (MFI±SEM, 7.98±0.8 versus 12.65±1.18, p=0.0076). Importantly, IL-6-treated pDCs exhibited a vast decrease in TNF-α production (p=0.0002) whereas no differences were found in the production of IFN-α and in their antigen presenting capacity between CpG-treated pDCs in the presence or absence of rIL-6. Moreover, confocal experiments in progress will assess the expression levels of TNF-α in pDCs isolated from RA patients in remission versus active or healthy donors. The functional importance of the previous findings will be addressed in coculture experiments of IL-6 stimulated pDCs with neutrophils isolated from healthy donors and monitor the neutrophil extracellular trap formation. Conclusions We found that pDCs from RA patients in remission display increased IL-6R expression levels and an activated IL-6 signalling pathway. Activation of IL-6 signalling on pDCs in vitro significantly decreases the production of TNF-α whereas it does not alter IFN-α production and their antigen presenting capacity. This novel finding that may drive pDCs towards a previously described tolerogenic phenotype, need to be further addressed. Disclosure of interest None declared
- Published
- 2018
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