52 results on '"M. Scherlinger"'
Search Results
2. French protocol for the diagnosis and management of systemic lupus erythematosus.
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Amoura Z, Bader-Meunier B, Antignac M, Bardin N, Belizna C, Belot A, Bonnotte B, Bouaziz JD, Chasset F, Chiche L, Cohen F, Costedoat-Chalumeau N, Daugas E, Devilliers H, Diot E, Elefant E, Faguer S, Ferreira N, Hachulla E, Hanslik T, Hie M, Jourde-Chiche N, Le Guern V, Martin T, Mathian A, Michel M, Miyara M, Papo T, Richez C, Scherlinger M, Sibilia J, Uzunhan Y, Wahl D, Wojtasik G, and Yelnik C
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- Humans, France epidemiology, Immunosuppressive Agents therapeutic use, Immunosuppressive Agents adverse effects, Clinical Protocols, Female, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic therapy, Lupus Erythematosus, Systemic complications
- Abstract
Because Systemic Lupus Erythematosus (SLE) is a rare disease, and due to the significant prognostic impact of early management, a diagnosis confirmed by a physician with experience in SLE is recommended, for example from an expert center. Once the diagnosis is confirmed, existing manifestations should be identified in particular, renal involvement by an assessment of proteinuria, disease activity and severity should be determined, potential complications anticipated, associated diseases searched for, and the patient's socioprofessional and family context noted. Therapeutic management of SLE includes patient education on recognizing symptoms, understanding disease progression as well as when they should seek medical advice. Patients are informed about routine checkups, treatment side effects, and the need for regular vaccinations, especially if they are receiving immunosuppressive treatment. They are also advised on lifestyle factors such as the risks of smoking, sun exposure, and dietary adjustments, especially when they are receiving corticosteroids. The importance of contraception, particularly when teratogenic medications are being used, and regular cancer screening are emphasized. Support networks can help relieve a patient's isolation. The first-line medical treatment of SLE is hydroxychloroquine (HCQ), possibly combined with an immunosuppressant and/or low-dose corticosteroid therapy. The treatment of flares depends on their severity, and typically involves HCQ and NSAIDs, but may be escalated to corticosteroid therapy with immunosuppressants or biologic therapies in moderate to severe cases. Because there is no curative treatment, the goals of therapy are patient comfort, preventing progression and flares, and preserving overall long-term health and fertility. The frequency of follow-up visits depends on disease severity and any new symptoms. Regular specialized assessments are necessary, especially when treatment changes, but a frequency of every 3 to 6 months is recommended during periods of remission and monthly during active or severe disease, especially in children. These assessments include both clinical and laboratory tests to monitor complications and disease activity, with specific attention to proteinuria., (Copyright © 2024. Published by Elsevier Masson SAS.)
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- 2024
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3. The PP2A regulatory subunit PPP2R2A controls NAD + biosynthesis to regulate T cell subset differentiation in systemic autoimmunity.
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Pan W, Tsokos MG, Scherlinger M, Li W, and Tsokos GC
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- Animals, Female, Humans, Mice, Forkhead Transcription Factors metabolism, Histones metabolism, Interferon-gamma metabolism, Interleukin-17 metabolism, Lupus Nephritis pathology, Lupus Nephritis immunology, Lupus Nephritis genetics, Lupus Nephritis metabolism, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Niacinamide analogs & derivatives, Poly (ADP-Ribose) Polymerase-1 metabolism, Pyridinium Compounds, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Regulatory immunology, Th17 Cells immunology, Th17 Cells metabolism, Autoimmunity, Cell Differentiation, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic pathology, NAD metabolism, NAD biosynthesis, Protein Phosphatase 2 metabolism
- Abstract
The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD
+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+ -dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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4. Combining ts- and a bDMARD in refractory rheumatoid arthritis: an unusual adverse event.
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Sztejkowski C, Sibilia J, Danion F, Mertz P, Elodie F, Kassegne L, Boyer P, Puéchal X, Gottenberg JE, and Scherlinger M
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- Humans, Female, Drug Therapy, Combination, Middle Aged, Methotrexate adverse effects, Methotrexate therapeutic use, Arthritis, Rheumatoid drug therapy, Antirheumatic Agents adverse effects, Antirheumatic Agents therapeutic use
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- 2024
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5. Mind-body practices in chronic inflammatory arthritis.
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Sibilia J, Berna F, Bloch JG, and Scherlinger M
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- Humans, Chronic Disease, Female, Male, Tai Ji methods, Treatment Outcome, Spondylarthritis therapy, Spondylarthritis psychology, Severity of Illness Index, Yoga, Mind-Body Therapies methods, Arthritis, Rheumatoid therapy, Arthritis, Rheumatoid psychology, Arthritis, Rheumatoid physiopathology
- Abstract
Mind-body practices are complementary approaches recognized by the World Health Organization (WHO). While these practices are very diverse, they all focus on the interaction between mind and body. These include mindful meditation, yoga, Tai Chi, sophrology, hypnosis and various relaxation techniques. There is growing interest in incorporating these strategies in the management of chronic rheumatic diseases including rheumatoid arthritis. The aim of this review is to describe the main mind-body practices and analyze the existing evidence in chronic rheumatic diseases. In rheumatoid arthritis, the Mindfulness-Based Stress Reduction program, yoga, Tai Chi and relaxation may improve patient-reported outcomes, but the benefit on inflammation and structural progression is unclear. In spondyloarthritis, very few studies are available but similar evidence exist. Further evaluations of these practices in chronic rheumatic diseases are needed since their risk/benefit ratio appears excellent., (Copyright © 2023. Published by Elsevier Masson SAS.)
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- 2024
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6. CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses.
- Author
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Scherlinger M, Li H, Pan W, Li W, Karino K, Vichos T, Boulougoura A, Yoshida N, Tsokos MG, and Tsokos GC
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- Animals, Humans, Mice, Autoimmunity, Cell Differentiation genetics, Immunoglobulin G metabolism, T-Lymphocytes, Helper-Inducer, Lupus Erythematosus, Systemic, T Follicular Helper Cells metabolism
- Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (T
fh ) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the Tfh -specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human Tfh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in Tfh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity., (© 2024. The Author(s).)- Published
- 2024
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7. Platelets are a major player and represent a therapeutic opportunity in systemic lupus erythematosus.
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Robert M and Scherlinger M
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- Humans, Blood Platelets, Platelet Activation, Inflammation, Lupus Erythematosus, Systemic, Antiphospholipid Syndrome complications
- Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and organ injury with a premature mortality due to cardiovascular diseases. Platelets, that are primarily known for their role in hemostasis, have been shown to play an active role in the pathogenesis and in the progression of immune-mediated inflammatory diseases. Here we summarize the evidence of their roles in SLE pathogenesis which supports the development of targeted treatments. Platelets and their precursors, the megakaryocytes, are intrinsically different in SLE patients compared with healthy controls. Different triggers related to innate and adaptive immunity activate platelets which release extracellular vesicles, soluble factors and interact with immune cells, thereby perpetuating inflammation. Platelets are involved in organ damage in SLE, especially in lupus nephritis and participate in the heightened cardiovascular mortality. They also play a clear role in antiphospholipid syndrome which can be associated with both thrombocytopenia and thrombosis. To tackle platelet activation and their interactions with immune cells now constitute promising therapeutic strategies in SLE., (Copyright © 2023. Published by Elsevier Masson SAS.)
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- 2024
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8. New and future therapies: Changes in the therapeutic armamentarium for SLE.
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Askanase A, Khalili L, Tang W, Mertz P, Scherlinger M, Sebbag E, Chasset F, Felten R, and Arnaud L
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- Humans, Cyclosporine therapeutic use, Molecular Targeted Therapy, Lupus Nephritis drug therapy, Lupus Nephritis immunology, Lupus Nephritis therapy, Immunosuppressive Agents therapeutic use, Hematopoietic Stem Cell Transplantation, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic therapy, Antibodies, Monoclonal, Humanized therapeutic use
- Abstract
Following better understanding of molecular pathways involved in the pathogenesis of Systemic lupus erythematosus (SLE), pharmaceutical companies have been investigating new targeted drugs for SLE. The purpose of this scoping review is to provide an updated view of the most promising targeted therapies currently in clinical development or recently approved for SLE treatment as well as of the most promising potential future therapeutic strategies in SLE. In the past several years, two new drugs have been developed for lupus treatment along with an extended indication for belimumab. Anifrolumab, the anti-interferon medication, to treat non-renal lupus; voclosporin, a calcineurin inhibitor, for the treatment of lupus nephritis; and belimumab for lupus nephritis. More than 90 investigational drugs are currently in clinical development for SLE treatment, with various targets including inflammatory cytokines and their receptors, intracellular signaling, B cells or plasma cells, co-stimulation molecules, complement fractions, T cells, plasmacytoid dendritic cells as well as various other immunological targets of interest. Researchers are also actively engaged in the development of new therapeutic strategies, including the use of monoclonal antibodies in combination with bispecific monoclonal antibodies, nanobodies and nanoparticles, therapeutic vaccines, utilizing siRNA interference techniques, autologous hematopoietic stem-cell transplantation and Chimeric Antigens Receptor (CAR)-T cells. The therapeutic management and prognosis of SLE have profoundly evolved with changes in the therapeutic armamentarium. With the broad pipeline of targeted treatments in clinical development and new treatment strategies in the future, current challenges are transitioning from the availability of new drugs to the selection of the most appropriate strategy at the patient level., Competing Interests: Declaration of competing interest, (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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9. Correspondence on 'Factors associated with progression to inflammatory arthritis in first-degree relatives of individuals with RA following autoantibody positive screening in a non-clinical setting'.
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Scherlinger M and Schaeverbeke T
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- Humans, Rheumatoid Factor, Autoantibodies, Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid genetics
- Abstract
Competing Interests: Competing interests: None declared.
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- 2023
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10. The role of platelets in immune-mediated inflammatory diseases.
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Scherlinger M, Richez C, Tsokos GC, Boilard E, and Blanco P
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- Humans, Immunomodulating Agents, Platelet Activation, Inflammation, Blood Platelets, Thrombosis
- Abstract
Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ damage, morbidity and death. Platelets have long been known for their role in primary haemostasis, but they are now also considered to be components of the immune system and to have a central role in the pathogenesis of IMIDs. In patients with IMIDs, platelets are activated by disease-specific factors, and their activation often reflects disease activity. Here we summarize the evidence showing that activated platelets have an active role in the pathogenesis and the progression of IMIDs. Activated platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis. Targeting platelet activation and targeting the interaction of platelets with the immune system are novel and promising therapeutic strategies in IMIDs., (© 2023. Springer Nature Limited.)
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- 2023
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11. Novel therapeutic strategies for autoimmune and inflammatory rheumatic diseases.
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Felten R, Mertz P, Sebbag E, Scherlinger M, and Arnaud L
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- Humans, Immunomodulating Agents, Antibodies, Monoclonal therapeutic use, Immunotherapy, Rheumatic Diseases drug therapy, Autoimmune Diseases drug therapy
- Abstract
Drugs of unknown mechanisms of action are no longer being developed because we have largely capitalized on our improved understanding of the immunopathogenesis of immune-mediated inflammatory diseases (IMIDs) to develop therapeutic monoclonal antibodies (mAbs) and targeted treatments. These therapies have profoundly revolutionized the care of IMIDs. However, because of the heterogeneity of IMIDs and the redundancy of the targeted molecular pathways, some patients with IMIDs might not respond to a specific targeted drug or their disease might relapse secondarily. Therefore, there is much at stake in the development of new therapeutic strategies, which include combinations of mAbs or bispecific mAbs (BsMAbs), nanobodies and nanoparticles (NPs), therapeutic vaccines, small interfering RNA (siRNA) interference, autologous hematopoietic stem cell transplantation (aHSCT), or chimeric antigen receptor (CAR)-T cells. With the broad pipeline of targeted treatments in clinical development, the therapeutic paradigm is rapidly evolving from whether new drugs will be available to the complex selection of the most adequate targeted treatment (or treatment combination) at the patient level. This paradigm change highlights the need to better characterize the heterogeneous immunological spectrum of these diseases. Only then will these novel therapeutic strategies be able to fully demonstrate their potential to treat IMIDs., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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12. Author Correction: The role of platelets in immune-mediated inflammatory diseases.
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Scherlinger M, Richez C, Tsokos GC, Boilard E, and Blanco P
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- 2023
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13. Neurotransmitters arrive to control systemic autoimmunity.
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Scherlinger M and Tsokos GC
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- Mice, Humans, Animals, B-Lymphocytes metabolism, Neurotransmitter Agents metabolism, Autoimmunity, Lupus Erythematosus, Systemic metabolism
- Abstract
Immune cell microenvironment plays a major role in the aberrant function of immune cells in systemic lupus erythematosus. Zeng and co-authors show that in human and murine lupus, splenic stromal cell-derived acetylcholine switches B cell metabolism to fatty acid oxidation and promotes B cell autoreactivity and disease development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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14. Immunological and translational key challenges in systemic lupus erythematosus: A symposium update.
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Renaudineau Y, Muller S, Hedrich CM, Chauveau D, Bellière J, De Almeida S, Damoiseaux J, Scherlinger M, Guery JC, Sailler L, and Bost C
- Abstract
The first LBMR-Tim (Toulouse Referral Medical Laboratory of Immunology) symposium convened on December 16, 2022 in Toulouse, France to address challenging questions in systemic lupus erythematosus (SLE). Special focus was put on (i) the role played by genes, sex, TLR7, and platelets on SLE pathophysiology; (ii) autoantibodies, urinary proteins, and thrombocytopenia contribution at the time of diagnosis and during follow-up; (iii) neuropsychiatric involvement, vaccine response in the COVID-19 era, and lupus nephritis management at the clinical frontline; and (iv) therapeutic perspectives in patients with lupus nephritis and the unexpected adventure of the Lupuzor/P140 peptide. The multidisciplinary panel of experts further supports the concept that a global approach including basic sciences, translational research, clinical expertise, and therapeutic development have to be prioritized in order to better understand and then improve the management of this complex syndrome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (©2023PublishedbyElsevierB.V.)
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- 2023
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15. Chronic stimulation with SARS-CoV-2 spike protein does not trigger autoimmunity.
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Scherlinger M, Sibilia J, Tsokos GC, and Gottenberg JE
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- Animals, Humans, Mice, Autoimmunity, Spike Glycoprotein, Coronavirus, SARS-CoV-2, Mice, Inbred C57BL, Antibodies, Viral, COVID-19, Autoimmune Diseases
- Abstract
Autoimmune manifestations were reported in people infected with SARS-CoV-2. Repetitive exposure of mice to foreign antigen may lead to the onset of autoimmunity. We therefore investigated whether repetitive exposure to the SARS-CoV-2 spike protein could result in autoimmunity. To address this hypothesis, we repeatedly immunized C57Bl/6 mice with spike protein injected intraperitoneally. At the end of the immunization, mice which received spike protein produced anti-spike IgG but none of them developed anti-dsDNA antibodies or proteinuria. In conclusion, repetitive immunization with SARS-CoV-2 spike protein does not induce autoimmunity in the present mice model. Albeit reassuring, these results need to be confirmed by large epidemiological study evaluating the incidence of autoimmune diseases in individuals with repetitive SARS-CoV-2 antigen exposure., Competing Interests: Declaration of Competing Interest GCT reports no competing interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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16. New biologics and targeted therapies in systemic lupus: From new molecular targets to new indications. A systematic review.
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Felten R, Scherlinger M, Mertz P, Chasset F, and Arnaud L
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- Humans, Antibodies, Monoclonal therapeutic use, Drugs, Investigational therapeutic use, Lupus Erythematosus, Systemic drug therapy, Antirheumatic Agents therapeutic use, Biological Products therapeutic use
- Abstract
Introduction: Despite available therapies, persistently active and corticosteroid-dependent Systemic Lupus Erythematosus (SLE) represent a significant therapeutic challenge. The purpose of this systematic review was to provide an updated view of targeted therapies currently in clinical development in SLE, with a special focus on the most promising ones., Methods: We performed a systematic review of targeted therapies in clinical development in SLE in clinicaltrials.gov (search date: 28th of August 2022). Targeted therapies (defined as drugs specifically designed to block certain molecules, receptors, or pathways involved in the development of SLE) were extracted. For each investigational drug, we considered only the study at the most advanced stage of clinical development., Results: The systematic review yielded a total of 92 targeted therapies (58 biological DMARDs [bDMARDs] and 34 targeted synthetic [ts]DMARDs) assessed in a total of 203 clinical trials. The candidate drugs reached phase I (n=20), Ia/IIb (n=6), phase II (n=51), phase II/III (n=1), phase III (n=13) and phase IV (n=1). These trials were reported as recruiting (n=31), active but not recruiting (n=8), not yet recruiting (n=4), enrolling by invitation (n=2), completed (n=31), prematurely terminated (n=12) and withdrawn in 1 (status unknown in 3). The main investigational drugs for SLE target inflammatory cytokines, chemokines or their receptors (n=19), intracellular signaling pathways (n=18), B cells (n=14) or plasma cells (n=7),T/B cells co-stimulation molecules (n=10), complement molecules (n=5),T lymphocytes (n=2), plasmacytoid dendritic cells (n=2), as well as various other immune targets (n=15)., Conclusion: The pipeline of investigational drugs in SLE is highly diversified and will hopefully enable more optimal Treat-To-Target with the goal of disease modification. Companion biomarkers will be needed to better characterized SLE heterogeneity and optimize treatment selection at the individual-patient level., (Copyright © 2023 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)
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- 2023
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17. Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.
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Koga T, Umeda M, Yoshida N, Satyam A, Jha M, Scherlinger M, Bhargava R, Tsokos MG, Sato T, Furukawa K, Endo Y, Fukui S, Iwamoto N, Abiru N, Okita M, Ito M, Kawakami A, and Tsokos GC
- Subjects
- Animals, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 4 metabolism, Calcium therapeutic use, Th17 Cells, Cytokines metabolism, Cell Differentiation, Osteogenesis, Arthritis, Experimental metabolism
- Abstract
Objective: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA., Methods: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively., Results: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors., Conclusion: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2023
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18. Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
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Scherlinger M, Pan W, Hisada R, Boulougoura A, Yoshida N, Vukelic M, Umeda M, Krishfield S, Tsokos MG, and Tsokos GC
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- Animals, Mice, Autoimmunity, T-Lymphocytes, Regulatory, Immunotherapy, Phosphofructokinases, Lupus Erythematosus, Systemic genetics
- Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (T
reg ) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6. lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.- Published
- 2022
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19. Excess of Post-Acute Sequelae of COVID-19 After the First Wave of the Pandemic.
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Scherlinger M, Lemogne C, Felten R, and Sibilia J
- Abstract
Introduction: To compare the time distribution of initial COVID-19 among patients with self-reported post-acute sequelae of COVID-19 (PASC)., Methods: We compared the distribution of the date of the reported initial COVID-19 among patients with self-reported PASC and the COVID-19 cases in France between the first wave (January 1-May 11, 2020) and the later period (May 12, 2020-June 30, 2021) using the chi-squared test. COVID-19 cases in France were assessed using previous modeling of COVID-19 burden in France for the first time period, and positive RT-PCR testing for the second time period., Results: The study included 567 individuals with PASC (median age 44, [IQR 37-50]; 83.4% women). A total of 293 (51.7%) patients reported an initial COVID-19 infection during the first period while 272 (48%) reported it during the later period (missing data, n = 2; 0.3%). Patients with PASC were 82% more likely to report initial COVID-19 during the first pandemic wave than afterward (OR 1.82, 95% CI [1.55-2.15]; p < 0.0001)., Conclusions: The incidence of self-reported PASC wave was significantly higher when initial COVID-19 happened during the first pandemic wave than afterward, suggesting the importance of non-viral factors in PASC development., (© 2022. The Author(s).)
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- 2022
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20. PPP2R2D Suppresses Effector T Cell Exhaustion and Regulatory T Cell Expansion and Inhibits Tumor Growth in Melanoma.
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Pan W, Scherlinger M, Yoshida N, Tsokos MG, and Tsokos GC
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- Animals, Cell Proliferation, Humans, Interleukin-2 metabolism, Mice, Programmed Cell Death 1 Receptor metabolism, Protein Phosphatase 2 metabolism, Melanoma metabolism, T-Lymphocytes, Regulatory
- Abstract
We had shown previously that the protein phosphatase 2A regulatory subunit PPP2R2D suppresses IL-2 production, and PPP2R2D deficiency in T cells potentiates the suppressive function of regulatory T (Treg) cells and alleviates imiquimod-induced lupus-like pathology. In this study, in a melanoma xenograft model, we noted that the tumor grew in larger sizes in mice lacking PPP2R2D in T cells (Lck
Cre R2Dfl/fl ) compared with wild type (R2Dfl/fl ) mice. The numbers of intratumoral T cells in LckCre R2Dfl/fl mice were reduced compared with R2Dfl/fl mice, and they expressed a PD-1+ CD3+ CD44+ exhaustion phenotype. In vitro experiments confirmed that the chromatin of exhaustion markers PD-1, LAG3, TIM3, and CTLA4 remained open in LckCre R2Dfl/fl CD4 T conventional compared with R2Dfl/fl T conventional cells. Moreover, the percentage of Treg cells (CD3+ CD4+ Foxp3+ CD25hi ) was significantly increased in the xenografted tumor of LckCre R2Dfl/fl mice compared with R2Dfl/fl mice probably because of the increase in the percentage of IL-2-producing LckCre R2Dfl/fl T cells. Moreover, using adoptive T cell transfer in mice xenografted with melanoma, we demonstrated that PPP2R2D deficiency in T cells enhanced the inhibitory effect of Treg cells in antitumor immunity. At the translational level, analysis of publicly available data from 418 patients with melanoma revealed that PPP2R2D expression levels correlated positively with tumor-infiltration level of CD4 and CD8 T cells. The data demonstrate that PPP2R2D is a negative regulator of immune checkpoint receptors, and its absence exacerbates effector T cell exhaustion and promotes Treg cell expansion. We conclude that PPP2R2D protects against melanoma growth, and PPP2R2D-promoting regimens can have therapeutic value in patients with melanoma., (Copyright © 2022 by The American Association of Immunologists, Inc.)- Published
- 2022
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21. Role of Glutaminase 2 in Promoting CD4+ T Cell Production of Interleukin-2 by Supporting Antioxidant Defense in Systemic Lupus Erythematosus.
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Hisada R, Yoshida N, Orite SYK, Umeda M, Burbano C, Scherlinger M, Kono M, Krishfield S, and Tsokos GC
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- Animals, Mice, Reactive Oxygen Species metabolism, Antioxidants metabolism, CD4-Positive T-Lymphocytes metabolism, Glutaminase metabolism, Interleukin-2 metabolism, Lupus Erythematosus, Systemic immunology
- Abstract
Objective: Glutaminase (GLS) isoenzymes GLS1 and GLS2 catalyze the first step of glutaminolysis. GLS1 is requisite for Th17 cell differentiation, and its inhibition suppresses autoimmune disease in animals, but the function of GLS2 is not known. The aim of this study was to investigate the role of GLS2 in CD4+ T cell function and systemic lupus erythematosus (SLE) pathogenesis., Methods: We measured reactive oxygen species (ROS) levels, lipid peroxidation, and mitochondrial mass and polarization by flow cytometry, interleukin-2 (IL-2) production by a dual luciferase assay, and CpG DNA methylation of Il2 by a real-time polymerase chain reaction system. The impact of the overexpression of wild-type GLS1, wild-type GLS2, or mutated GLS2 at the PDZ domain-binding motif in CD4+ T cells was examined. Furthermore, GLS2 expression in CD4+ T cells from lupus-prone mice and patients with SLE was analyzed by Western blotting., Results: GLS2, but not GLS1, reduced ROS levels and lipid peroxidation and restored mitochondrial function in T cells. GLS2 promoted IL-2 production through the demethylation of the Il2 promoter. Mutation of the PDZ domain-binding motif abated the ability of GLS2 to regulate IL-2 and ROS levels. In lupus-prone mice and patients with SLE, the expression of GLS2 was decreased in CD4+ T cells. Finally, GLS2 overexpression corrected ROS levels and restored IL-2 production by CD4+ T cells from lupus-prone mice and SLE patients., Conclusion: Our findings suggest that GLS2 has a crucial role in IL-2 production by CD4+ T cells by supporting antioxidant defense, and they offer a new approach to correcting IL-2 production by T cells in SLE., (© 2022 American College of Rheumatology.)
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- 2022
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22. The deacetylase SIRT2 contributes to autoimmune disease pathogenesis by modulating IL-17A and IL-2 transcription.
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Hisada R, Yoshida N, Umeda M, Burbano C, Bhargava R, Scherlinger M, Kono M, Kyttaris VC, Krishfield S, and Tsokos GC
- Subjects
- Animals, Humans, Interleukin-2 genetics, Interleukin-2 immunology, Mice, Mice, Inbred MRL lpr, Th17 Cells immunology, Interleukin-17 genetics, Interleukin-17 immunology, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic immunology, Sirtuin 2 immunology
- Abstract
Aberrant IL-17A expression together with reduced IL-2 production by effector CD4
+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report that Sirtuin 2 (SIRT2), a member of the family of NAD+ -dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while promoting their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K, activation of the mTORC1/HIF-1α/RORγt pathway and induction of Th17-cell differentiation. Additionally, SIRT2 was shown to be responsible for the deacetylation of c-Jun and histones at the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, bound directly to the Sirt2 promoter and promoted its transcription. AK-7, a SIRT2 inhibitor, limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis in mice and limited disease in lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated the ability of these cells to differentiate into Th17 cells and promoted the generation of IL-2-producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential in the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new SLE therapies., (© 2022. The Author(s), under exclusive licence to CSI and USTC.)- Published
- 2022
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23. Difficulties and Psychological Impact of the SARS-CoV-2 Pandemic in Patients with Systemic Lupus Erythematosus: A Nationwide Patient Association Study.
- Author
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Scherlinger M, Zein N, Gottenberg JE, Rivière M, Kleinmann JF, Sibilia J, and Arnaud L
- Abstract
Objectives: We aimed to evaluate the difficulties encountered by systemic lupus erythematosus (SLE) patients during the early COVID-19 pandemic and to evaluate their impact on patient mental health., Methods: We conducted a nationwide survey including SLE patients from France, recruited by their treating specialist or through a patient association. The survey was administered online or in paper form between November 2020 and April 2021 and included questions aiming at evaluating the difficulties encountered during the early COVID-19 pandemic (March to August 2020). The impact on mental health was evaluated using the Hospital Anxiety and Depression Scale (HADS) and the Post-Traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5)., Results: 536 SLE patients (91.9% women) of mean age 50 (±14.1) years responded to the survey. The main reported difficulties were issues regarding access to medical care ( n = 136, 25.4%) or hydroxychloroquine treatment ( n = 98/389, 25.2%), the loss of employment ( n = 85/349, 24.4%), and financial difficulties ( n = 75/536, 11%). In 328 patients with complete mental health assessments, 161 (47.2%) screened positive for anxiety, 141 (41.2%) screened positive for depressive syndrome, and 128 (38.7%) screened positive for PTSD. The multivariate analysis showed that female sex (OR = 4.29 [95%CI: 1.39-13.24]), financial issues (OR = 2.57 [1.27-5.22]), and difficulties accessing medical care (OR = 2.15 [1.26-3.69]) or hydroxychloroquine treatment (OR = 1.90 [1.06-3.40]) were independently associated with a positive screening for PTSD., Conclusions: The COVID-19 pandemic resulted in a severe burden in SLE patients, including difficulties accessing care and treatment along with high psychological distress. Better understanding these difficulties will allow for better prevention and care in times of crisis.
- Published
- 2022
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24. Effect of SARS-CoV-2 Vaccination on Symptoms from Post-Acute Sequelae of COVID-19: Results from the Nationwide VAXILONG Study.
- Author
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Scherlinger M, Pijnenburg L, Chatelus E, Arnaud L, Gottenberg JE, Sibilia J, and Felten R
- Abstract
Introduction: Few data are available concerning the effect of SARS-CoV-2 vaccination on the persistent symptoms associated with COVID-19, also called long-COVID or post-acute sequelae of COVID-19 (PASC)., Patients and Methods: We conducted a nationwide online study among adult patients with PASC as defined by symptoms persisting over 4 weeks following a confirmed or probable COVID-19, without any identified alternative diagnosis. Information concerning PASC symptoms, vaccine type and scheme and its effect on PASC symptoms were studied., Results: 620 questionnaires were completed and 567 satisfied the inclusion criteria and were analyzed. The respondents' median age was 44 (IQR 25-75: 37-50) and 83.4% were women. The initial infection was proven in 365 patients (64%) and 5.1% had been hospitalized to receive oxygen. A total of 396 patients had received at least one injection of SARS-CoV-2 vaccine at the time of the survey, after a median of 357 (198-431) days following the initially-reported SARS-CoV-2 infection. Among the 380 patients who reported persistent symptoms at the time of SARS-CoV-2 vaccination, 201 (52.8%) reported a global effect on symptoms following the injection, corresponding to an improvement in 21.8% and a worsening in 31%. There were no differences based on the type of vaccine used. After a complete vaccination scheme, 93.3% (28/30) of initially seronegative patients reported a positive anti-SARS-CoV-2 IgG. A total of 170 PASC patients had not been vaccinated. The most common reasons for postponing the SARS-CoV-2 vaccine were fear of worsening PASC symptoms (55.9%) and the belief that vaccination was contraindicated because of PASC (15.6%)., Conclusion: Our study suggests that SARS-CoV-2 vaccination is well tolerated in the majority of PASC patients and has good immunogenicity. Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with PASC.
- Published
- 2021
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25. Shortage of aspartate in mitochondria fuels arthritis.
- Author
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Scherlinger M and Tsokos GC
- Subjects
- Humans, Mitochondria, Arthritis, Aspartic Acid
- Published
- 2021
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26. Refining "Long-COVID" by a Prospective Multimodal Evaluation of Patients with Long-Term Symptoms Attributed to SARS-CoV-2 Infection.
- Author
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Scherlinger M, Felten R, Gallais F, Nazon C, Chatelus E, Pijnenburg L, Mengin A, Gras A, Vidailhet P, Arnould-Michel R, Bibi-Triki S, Carapito R, Trouillet-Assant S, Perret M, Belot A, Bahram S, Arnaud L, Gottenberg JE, Fafi-Kremer S, and Sibilia J
- Abstract
Introduction: COVID-19 long-haulers, also decribed as having "long-COVID" or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied., Methods: In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group., Results: The median age was 40 [interquartile range: 35-54] years and 18 (60%) were female. At a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5-8] and 5 [2-6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively., Conclusions: Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress., (© 2021. The Author(s).)
- Published
- 2021
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27. Reactive oxygen species: The Yin and Yang in (auto-)immunity.
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Scherlinger M and Tsokos GC
- Subjects
- Autoimmunity, Humans, Reactive Oxygen Species, Autoimmune Diseases, Lupus Erythematosus, Systemic
- Abstract
Reactive oxygen species (ROS) are produced by immune cells in response to antigens. They are produced mostly in the mitochondria and their levels are tightly controlled by a series of metabolic processes. ROS are necessary for the development of the immune response but the role of ROS in the development of autoimmune disease needs further clarification. Early clinical information points to the beneficial role of supplementation of antioxidant agents or the reduction of ROS production. We review recent information in the field in an effort to identify areas more studies are needed., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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28. Incidence and predictors of COVID-19 and flares in patients with rare autoimmune diseases: a systematic survey and serological study at a national reference center in France.
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Felten R, Scherlinger M, Guffroy A, Poindron V, Meyer A, Giannini M, Korganow AS, Sordet C, Chatelus E, Javier RM, Meyer A, Pijnenburg L, Kleinmann JF, Gottenberg JE, Sibilia J, Martin T, and Arnaud L
- Subjects
- Cross-Sectional Studies, France epidemiology, Humans, Incidence, SARS-CoV-2, Seroepidemiologic Studies, Autoimmune Diseases diagnosis, Autoimmune Diseases epidemiology, COVID-19
- Abstract
Background: The risk of severe COVID-19 and its determinants remain largely unknown in patients with autoimmune and inflammatory rheumatic diseases. The objective of this study was to assess the prevalence of COVID-19 infection in patients followed for rare autoimmune diseases as well as the predictors of COVID-19 and disease flare-ups., Methods: Cross-sectional phone survey from April 9, 2020, to July 2, 2020, during which patients with autoimmune diseases followed at the National Reference Center for Rare Autoimmune diseases of Strasbourg were systematically contacted by phone and sent a prescription for a SARS-CoV-2 serology., Results: One thousand two hundred thirty-two patients were contacted. One thousand fifty-five patients with a confirmed diagnosis of systemic autoimmune disease were included (4 unreachable, 4 moves abroad, 5 deaths before pandemic, 50 without consent, and 114 without autoimmune disease). Among them, 469 (44.5%) patients were tested for SARS-CoV-2 serology. Thirty-nine patients (7.9%) had SARS-CoV-2 infection (either through chest CT-scan [n = 5], RT-PCR on nasopharyngeal swab [n = 14], or serology [n = 31]) among the 496 who underwent at least one of those 3 diagnosis modalities. Of the 39 proven cases, 33 had clinical manifestations (6 asymptomatic patients were diagnosed through systematic serology testing), 31 were managed by home care, 3 were hospitalized due to a need for oxygenation, two required admission to an intensive care unit, and one died. Among patients with confirmed SARS-CoV-2 infection, reported flares were more frequent than in uninfected patients (26.3% [10/38] vs. 7.0% [32/457], p < 0.0001). Preventive sick leave had no significant impact on the prevalence of SARS-CoV-2 infection (5.8% [3/53]) compared to work continuation (7.6% [30/397], p = 0.64). Overall, the seroprevalence of SARS-CoV-2 was 6.6% (31/469) which was numerically lower to the Grand-Est general population estimated to be 9.0%., Conclusions: This systematic survey of more than 1000 patients with rare systemic autoimmune diseases reports a low prevalence of proven SARS-CoV-2 infection and very rare severe infections, probably related to good compliance with prophylactic measures in these patients., (© 2021. The Author(s).)
- Published
- 2021
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29. Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis.
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Scherlinger M, Guillotin V, Douchet I, Vacher P, Boizard-Moracchini A, Guegan JP, Garreau A, Merillon N, Vermorel A, Ribeiro E, Machelart I, Lazaro E, Couzi L, Duffau P, Barnetche T, Pellegrin JL, Viallard JF, Saleh M, Schaeverbeke T, Legembre P, Truchetet ME, Dumortier H, Contin-Bordes C, Sisirak V, Richez C, and Blanco P
- Subjects
- Animals, Humans, Mice, Selectins, Transforming Growth Factor beta, Lupus Erythematosus, Systemic, T-Lymphocytes, Regulatory
- Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (T
reg ) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor-β axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin-dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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30. Systemic sclerosis overlap and non-overlap syndromes share clinical characteristics but differ in prognosis and treatments.
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Scherlinger M, Lutz J, Galli G, Richez C, Gottenberg JE, Sibilia J, Arnaud L, Blanco P, Schaeverbeke T, Chatelus E, and Truchetet ME
- Subjects
- Humans, Prognosis, Syndrome, Arthritis, Rheumatoid, Lupus Erythematosus, Systemic, Scleroderma, Systemic complications, Scleroderma, Systemic drug therapy
- Abstract
Objectives: To screen for concomitant autoimmune disease in patients with systemic sclerosis (overlap SSc) and to describe their clinical characteristics and prognosis., Methods: This was a two-center retrospective observational study. Patients diagnosed with SSc according to the 2013 ACR-EULAR scleroderma classification criteria were screened for concomitant rheumatoid arthritis (RA), Sjögren syndrome (SgS) and systemic lupus erythematosus (SLE). Patient characteristics were retrieved from the medical records and were compared to those of a non-overlap SSc cohort., Results: Among the 534 SSc patients studied, thirty-four (6.4%) were identified as having overlap SSc. There were 21 (3.9%) patients with RA, 14 (2.6%) with SgS and 4 (0.7%) with SLE (5 patients had 2 AISD) . The disease phenotype of overlap SSc was similar to that of non-overlap SSc in terms of cutaneous phenotype, prevalence of pulmonary arterial hypertension, interstitial lung disease, digital ulcers and mortality. Using a multivariate Cox model, age (HR = 1.04, 95% CI [1.02-1.07]), the modified Rodnan skin score (HR = 1.08 per point, 95% CI [1.05-1.11]), and the presence of concomitant SgS (HR = 3.79, 95% CI [1.38-10.40]) were significantly associated with mortality. Overlap SSc were more likely to receive corticosteroids (85.3% vs. 45%, p < 0.001), immunosuppressive drugs (82.4% vs. 49.2%, p < 0.001) and biologics (52.9% vs. 3.8%, p < ZZ0.001)., Conclusions: While overlap and non-overlap SSc shared common characteristics, patients with SgS/SSc had a higher risk of mortality, and those with RA/SSc received more corticosteroids, methotrexate and biologics. Screening for an associated AISD should be promoted since their co-occurrence with SSc may affect prognosis and treatments., Competing Interests: Declaration of Competing Interest Disclosure of competing interests: MS, PB and JL, LA, JS, JEG, EC and TS declare that they have no competing interests. CR has received consultancy and speaking fees from Roche, Sanofi, Abbvie, Pfizer, MSD, UCB, Amgen and Mylan. MET has received consultancy fees and/or research funding from BMS, Roche, Lilly and UCB., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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31. Role of stress in the development of rheumatoid arthritis: a case-control study.
- Author
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Germain V, Scherlinger M, Barnetche T, Pichon C, Balageas A, Lequen L, Shipley E, Foret J, Dublanc S, Capuron L, and Schaeverbeke T
- Subjects
- Adult, Arthritis, Rheumatoid epidemiology, Arthritis, Rheumatoid psychology, Case-Control Studies, Female, France epidemiology, Humans, Incidence, Male, Middle Aged, Stress, Psychological psychology, Surveys and Questionnaires, Adaptation, Psychological, Arthritis, Rheumatoid etiology, Stress, Psychological complications
- Abstract
Objectives: The primary objective of this study was to assess the stressful life events preceding the onset of symptoms in RA. The secondary objectives were to assess how early RA patients perceive stress and cope with stressors., Methods: A case-control study was performed, comparing patients recently diagnosed with RA to age- and gender-matched control subjects recently hospitalized for an unplanned surgical procedure not known to be influenced by stress. The Social Readjustment Rating Scale assessed the cumulative stress induced by stressful life events in the year preceding the onset of symptoms. Coping strategies, stress and anxiety symptoms were evaluated using validated psychological scales., Results: Seventy-six subjects were included in each group. The mean Social Readjustment Rating Scale score was twice as high in cases compared with controls [respectively, 167.0 (172.5) vs 83.3 (124.4), P < 0.001]. The association between cumulative stress and RA was statistically significant only in women, with a dose-dependent association between stress and RA. While female patients with RA attributed more often the onset of symptoms to a life event than female controls (70.2 vs 24.5%, P < 0.001), no significant difference was found when comparing male RA patients with male controls (26.9 vs 18.5%, respectively, P = 0.46). Increased perceived stress score (P = 0.04) and coping based on emotions (P = 0.001) were found in cases compared with controls., Conclusion: Patients with early RA reported more life events in the year preceding the onset of symptoms than controls. Gender specificities were found with a significant association between cumulative stress and RA only in women., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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32. Ascorbate maintains a low plasma oxygen level.
- Author
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Injarabian L, Scherlinger M, Devin A, Ransac S, Lykkesfeldt J, and Marteyn BS
- Subjects
- Animals, Cell Line, Cell Lineage physiology, Erythrocytes metabolism, Guinea Pigs, HEK293 Cells, Hep G2 Cells, Humans, Hypoxia blood, Hypoxia metabolism, Oxidation-Reduction, Solubility, Ubiquinone analogs & derivatives, Ubiquinone metabolism, Ascorbic Acid blood, Ascorbic Acid metabolism, Oxygen blood, Plasma metabolism
- Abstract
In human blood, oxygen is mainly transported by red blood cells. Accordingly, the dissolved oxygen level in plasma is expected to be limited, although it has not been quantified yet. Here, by developing dedicated methods and tools, we determined that human plasma pO
2 = 8.4 mmHg (1.1% O2 ). Oxygen solubility in plasma was believed to be similar to water. Here we reveal that plasma has an additional ascorbate-dependent oxygen-reduction activity. Plasma experimental oxygenation oxidizes ascorbate (49.5 μM in fresh plasma vs < 2 μM in oxidized plasma) and abolishes this capacity, which is restored by ascorbate supplementation. We confirmed these results in vivo, showing that the plasma pO2 is significantly higher in ascorbate-deficient guinea pigs (Ascorbateplasma < 2 μM), compared to control (Ascorbateplasma > 15 μM). Plasma low oxygen level preserves the integrity of oxidation-sensitive components such as ubiquinol. Circulating leucocytes are well adapted to these conditions, since the abundance of their mitochondrial network is limited. These results shed a new light on the importance of oxygen exposure on leucocyte biological study, in regards with the reducing conditions they encounter in vivo; but also, on the manipulation of blood products to improve their integrity and potentially improve transfusions' efficacy.- Published
- 2020
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33. Worldwide trends in all-cause mortality of auto-immune systemic diseases between 2001 and 2014.
- Author
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Scherlinger M, Mertz P, Sagez F, Meyer A, Felten R, Chatelus E, Javier RM, Sordet C, Martin T, Korganow AS, Guffroy A, Poindron V, Richez C, Truchetet ME, Blanco P, Schaeverbeke T, Sibilia J, Devillers H, and Arnaud L
- Subjects
- Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis mortality, Humans, Lupus Erythematosus, Systemic mortality, Mixed Connective Tissue Disease mortality, Myositis mortality, Scleroderma, Systemic mortality, Sjogren's Syndrome mortality, Autoimmune Diseases mortality, Cause of Death, Internationality
- Abstract
Aim: To describe changes in the 2001-2014 mortality of 6 autoimmune systemic diseases (AISDs), namely Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Idiopathic Inflammatory Myopathies (IIM), Sjögren's Syndrome (SS), Mixed Connective Tissue Disease (MCTD) and ANCA-associated vasculitis (AAV) at the country-, continent-, and world-levels., Methods: Mortality data were retrieved from the World Health Organization (WHO) mortality database for each disease, based on ICD-10 codes. We computed age-standardized mortality rate (ASMR) as the estimated number of deaths per million inhabitants and its 95% confidence interval (95%CI). The association between gender, geographical areas and disease-specific mortality was analyzed using multivariate Poisson regression. The 2001-2014 temporal trends were analyzed using Jointpoint software., Results: In 2014, the worldwide ASMR for SLE was 2.68 (95%CI: 2.62-2.75) deaths/millions inhabitants, 1.46 (1.42-1.51) for SSc, 0.47 (0.44-0.49) for IIM, 0.17 (0.15-0.18) for SS, 0.11 (0.10-0.13) for MCTD and 0.53 (0.50-0.56) for AAV, with ASMRs generally lower in Europe than in North America, Latin America and Asia. Between 2001 and 2014, the worldwide ASMR decreased significantly for SSc (-0.71%/year), IIM (-1.65%/year) and AAV (-1.01%/year; p < .001 for all) and increased for SS (+1.53%/year, p = .01). The worldwide ASMR of SLE decreased significantly between 2001 and 2003 (-6.37%, p < .05) before increasing slightly between 2004 and 2014 (+0.58%, p < .01)., Conclusions: We observed a strong heterogeneity of standardized mortality rates across all countries analyzed for 6 autoimmune diseases. Those results further highlight the impact of world-wide inequities and major gaps in access to care and strategies for diagnosis and management of rare diseases, a crucial finding for world-wide physicians, patient associations and policy makers., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
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34. Characteristics and opinions of MD-PhD students and graduates from different European countries: a study from the European MD-PhD Association.
- Author
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Dos Santos Rocha A, Scherlinger M, Ostermann L, Mehler DMA, Nadiradze A, Schulze F, Feldmeyer L, de Koning M, Berbecar VT, Buijs R, Kijlstra JD, and Jawaid A
- Subjects
- Career Choice, Europe, Humans, Students, Biomedical Research, Education, Medical, Graduate
- Abstract
Background: MD-PhD programmes throughout the world provide a platform for medical trainees to commit to a physician-scientist career, qualifying with both a medical degree (MD or equivalent) and Doctor of Philosophy (PhD). However, there are limited studies assessing the characteristics of MD-PhD programmes in Europe and the outcomes of MD-PhD students and graduates., Purpose: This study aims at a first country-wise exploration of characteristics, opinions, and academic outcomes of MD-PhD students and graduates in Europe., Methods: Two questionnaires were developed to assess the demographics, MD-PhD programme characteristics, opinions, future career paths and academic outcomes of European MD-PhD students and graduates. An online survey of 278 MD-PhD students and 121 MD-PhD graduates from nine and six European countries, respectively, was completed between April 2016 and December 2017. The country-wise categorical responses were then compared through chi-square analysis followed by multiple logistic regression., Results: Responses from 266 MD-PhD students and 117 MD-PhD graduates were considered valid. Significant country-wise differences (p <0.05) were observed for age group, resident status, clinical time allocation, duration of studies, sources of funding, publications, average impact factor of the journals in which the research was published, satisfaction with the duration of MD-PhD studies and future career choices of MD-PhD students. Responses related to self-perception about clinical and research competence and challenges faced during MD-PhD training did not show a significant country-wise difference., Conclusion: The MD-PhD workforce in Europe is highly diverse in their demographics, programme characteristics and career paths but does not differ in opinions related to the challenges faced. The results of this study may be helpful for implementation and improvement of MD-PhD programmes.
- Published
- 2020
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35. 'To switch or not to switch': the missing piece in the puzzle of biosimilar literature?
- Author
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Scherlinger M and Schaeverbeke T
- Subjects
- Etanercept, Humans, Registries, Treatment Outcome, Antirheumatic Agents, Biosimilar Pharmaceuticals
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2020
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36. Platelets and IgE: Shaping the Innate Immune Response in Systemic Lupus Erythematosus.
- Author
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Brilland B, Scherlinger M, Khoryati L, Goret J, Duffau P, Lazaro E, Charrier M, Guillotin V, Richez C, and Blanco P
- Subjects
- Alarmins metabolism, Animals, Biomarkers, Complement System Proteins immunology, Complement System Proteins metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Humans, Lupus Erythematosus, Systemic pathology, Lupus Erythematosus, Systemic therapy, Receptors, Pattern Recognition metabolism, Toll-Like Receptors metabolism, Blood Platelets immunology, Blood Platelets metabolism, Disease Susceptibility, Immunity, Innate, Immunoglobulin E immunology, Lupus Erythematosus, Systemic etiology, Lupus Erythematosus, Systemic metabolism
- Abstract
Systemic lupus erythematosus (SLE) is a systemic and potentially fatal autoimmune disease. SLE pathophysiology is complex and involves the interplay between the innate and adaptive immune systems, with a particularly significant role for type I interferons. Recently, the participation of other actors such as platelets and IgE has been described in SLE. On the one hand, platelets activated by different stimuli (antiphospholipid antibodies, immune complexes…) participate in immune dysregulation through direct interactions with immune cells. On the other hand, autoreactive IgE can activate basophils, promoting a Th2 environment and subsequent antibody production by plasma cells. In synergy with IgG, IgE is also able to activate plasmacytoid DCs (pDCs) increasing interferon alpha production. Mirroring the IgG paradox, total nonautoreactive IgE is described as a potential regulator of IFNα production. This review summarizes recent and novel data on innate immunity in SLE pathophysiology with a focus on platelets and IgE, as they represent novel players in immune dysregulation and potential therapeutic targets.
- Published
- 2020
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37. Long-term follow-up after switching from originator infliximab to its biosimilar CT-P13: the weight of nocebo effect.
- Author
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Germain V, Scherlinger M, Barnetche T, and Schaeverbeke T
- Subjects
- Biosimilar Pharmaceuticals, Humans, Longitudinal Studies, Antibodies, Monoclonal therapeutic use, Antirheumatic Agents therapeutic use, Drug Substitution, Infliximab therapeutic use, Nocebo Effect, Spondylitis, Ankylosing drug therapy
- Abstract
Competing Interests: Competing interests: TS received honoraria as consultant from: Amgen, AbbVie, BMS, Janssen, MSD, Novartis, Pfizer, Roche Chugaï, UCB. TS received a research grant from Pfizer (unrelated to this work). The other authors report no conflicts of interests.
- Published
- 2020
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38. Osseous sarcoidosis: A multicenter retrospective case-control study of 48 patients.
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Ben Hassine I, Rein C, Comarmond C, Glanowski C, Saidenberg-Kermanac'h N, Meunier B, Schleinitz N, Chanson N, Sacré K, Scherlinger M, Richez C, Hirschi S, Groh M, Devilliers H, Bielefeld P, Saadoun D, Chapelon-Abric C, Arnaud L, and Cacoub P
- Subjects
- Adult, Biopsy, Needle, Case-Control Studies, Drug Therapy, Combination, Female, France, Glucocorticoids therapeutic use, Humans, Hydroxychloroquine therapeutic use, Immunohistochemistry, Magnetic Resonance Imaging methods, Male, Methotrexate therapeutic use, Middle Aged, Prognosis, Retrospective Studies, Risk Assessment, Severity of Illness Index, Treatment Outcome, Bone Diseases diagnosis, Bone Diseases drug therapy, Lymph Nodes pathology, Sarcoidosis diagnosis, Sarcoidosis drug therapy
- Abstract
Objective: To describe the clinical presentation, distribution of lesions, treatment, and outcomes of osseous sarcoidosis., Methods: A French retrospective multicenter study of patients with biopsy-proven sarcoidosis analyzed patients with 1) a biopsy-proven granuloma without caseous necrosis, and either 2) osseous clinical manifestations, or 3) abnormal osseous imaging. Sarcoidosis patients with osseous involvement (cases) were compared with 264 age- and sex-matched sarcoidosis patients with no osseous manifestations (controls)., Results: In the osseous sarcoidosis group (n=88), forty-two (48%) patients had osseous-related symptoms involving the axial (69%) and/or appendicular (58%) skeleton. On imaging, the most commonly affected bones were in the spine (52%), pelvis (42%), hands (22%) and femur (19%). Compared with controls, cases had higher rates of mediastinal (93% vs. 47%) and extra-thoracic lymph node involvement (66% vs. 21%), pulmonary (90% vs. 65%) and cutaneous involvement (44% vs. 23%) (all P<0.0001), and hypercalcemia (8.5% vs. 2%, P=0.014). Spleen/liver and gastrointestinal involvement were less frequent in the osseous sarcoidosis group (29% vs. 45%, and 1% vs. 17%, respectively, P<0.0001). Response rates to with glucocorticoids alone, glucocorticoids plus methotrexate or glucocorticoids plus hydroxychloroquine were 23/44 (52%), 9/13 (69%) and 4/6 (67%), respectively., Conclusion: In patients with osseous sarcoidosis the spine and pelvis were the most commonly affected bones. Compared with controls, cases with osseous sarcoidosis have higher rates of thoracic and extra-thoracic lymph node involvement, pulmonary and cutaneous involvement, and hypercalcemia. Most patients with osseous sarcoidosis had a good response to glucocorticoids in combination with methotrexate or hydroxychloroquine., (Copyright © 2019 Société française de rhumatologie. All rights reserved.)
- Published
- 2019
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39. Rituximab in moderate to severe non-renal systemic lupus erythematosus: a reanalysis of the EXPLORER study.
- Author
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Scherlinger M, Carcaud C, Truchetet ME, Barnetche T, Duffau P, Couzi L, Seneschal J, Blanco P, Lazaro E, and Richez C
- Subjects
- Adult, Female, Humans, Lupus Erythematosus, Systemic pathology, Male, Middle Aged, Randomized Controlled Trials as Topic, Treatment Failure, Antirheumatic Agents therapeutic use, Lupus Erythematosus, Systemic drug therapy, Rituximab therapeutic use, Severity of Illness Index
- Abstract
Competing Interests: Competing interests: MS, TB, PD, LC, JS, PB and CC declare no conflict of interest. CR has received consultancy and speaking fees from AstraZeneca, Roche, Glenmark, BMS, Lilly, UCB and Janssen. EL has received consultancy and speaking fees from GSK and UCB. M-ET has received consultancy fees and/or research funding from BMS, Roche, Lilly and UCB. Roche Pharmaceuticals provided freely EXPLORER raw data but did not take part in neither the analysis nor the writing of the manuscript.
- Published
- 2019
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40. Characteristics and clinical outcomes after treatment of a national cohort of PCR-positive Lyme arthritis.
- Author
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Grillon A, Scherlinger M, Boyer PH, De Martino S, Perdriger A, Blasquez A, Wipff J, Korganow AS, Bonnard C, Cantagrel A, Eyer D, Guérin F, Monteiro I, Woehl JM, Moreau P, Pennaforte JL, Lechevallier J, Bastides F, Colombey A, Imbert I, Maugars Y, Gicquel P, Cuchet F, Brax M, Sibilia J, Zilliox L, Barthel C, Arnaud L, and Jaulhac B
- Subjects
- Adolescent, Adult, Aged, Child, Female, France, Humans, Lyme Disease microbiology, Male, Middle Aged, Polymerase Chain Reaction, Treatment Outcome, Young Adult, Anti-Bacterial Agents therapeutic use, Borrelia isolation & purification, Lyme Disease drug therapy, Synovial Fluid microbiology
- Abstract
Objectives: To describe the clinical and microbiological characteristics and outcomes after antibiotic treatment of a national cohort of patients with Lyme arthritis confirmed by PCR testing on synovial fluid and by serology, when available., Methods: Using the French National Reference Center for Borrelia database, patients with a positive PCR on synovial fluid for Borrelia were identified. Patient clinical and biological characteristics were reviewed from patient records. Long-term outcomes after treatment were studied through a questionnaire and with follow-up data., Results: Among 357 synovial fluid testing by PCR between 2010 and 2016, 37 (10.4%) were positive for Borrelia. Patients' median age was 36 years (range 6-78) with 61% of men and 28% patients under 18. The presentation was monoarticular in 92% and the knee was involved in 97%. Contrary to the Borrelia species repartition in European ticks, B. burgdorferi sensu stricto was the most prevalent species found in synovial fluid (54%) followed by B. azfelii (29%) and B. garinii (17%). Antibiotic treatments were mainly composed of doxycycline (n = 24), ceftriaxone (n = 10) and amoxicillin (n = 6), for a median duration of 4 weeks (range 3-12). Despite a properly conducted treatment, 34% of patients (n = 12) developed persistent synovitis for at least 2 months (median duration 3 months, range 2-16). Among those, 3 developed systemic inflammatory oligo- or polyarthritis in previously unaffected joints with no signs of persistent infection (repeated PCR testing negative), which mandated Disease-Modifying Antirheumatic Drugs (DMARD) introduction, leading to remission., Conclusion: In France and contrary to ticks ecology, Lyme arthritis is mainly caused by B. burgdorferi sensu stricto. Despite proper antibiotic therapy, roughly one third of patients may present persistent inflammatory synovitis and a small proportion may develop systemic arthritis. In such cases, complete remission can be reached using DMARD., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2019
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41. Acceptance rate and sociological factors involved in the switch from originator to biosimilar etanercept (SB4).
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Scherlinger M, Langlois E, Germain V, and Schaeverbeke T
- Subjects
- Adult, Age Factors, Antirheumatic Agents economics, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid psychology, Biosimilar Pharmaceuticals economics, Etanercept economics, Female, Humans, Male, Medication Adherence psychology, Medication Adherence statistics & numerical data, Middle Aged, Patient Preference psychology, Prospective Studies, Spondylarthritis drug therapy, Spondylarthritis psychology, Antirheumatic Agents therapeutic use, Biosimilar Pharmaceuticals therapeutic use, Etanercept therapeutic use, Health Knowledge, Attitudes, Practice
- Abstract
Objective: To study acceptance rate and factors influencing acceptance of the switch from originator etanercept (Enbrel©) to biosimilar etanercept (SB4, Bénépali©) in patients with rheumatic disease., Methods: Patients with a well-controlled rheumatic disease consulting in our rheumatology department were offered the switch for SB4. After oral and written information concerning biosimilar, free choice to accept the switch was left to the patients. The main outcome was primary switch acceptance rate defined by switch acceptance during the initial consult. Real switch adherence, socio-cultural factors and beliefs influencing switch acceptance rate were retrieved during a telephonic interview at distance from the consultation., Results: Fifty-two patients were eligible for the switch: 32 (62%) with spondyloarthritis and 20 (38%) with rheumatoid arthritis. The primary acceptance rate was 92% (48/52). Patients refusing the switch were more likely to report a bad opinion on generic drugs (100% vs 11%, p < 0.001). Other patient characteristics were roughly identical except for a statistical trend in the refusal group toward older age (61.4vs 50.7years, p = 0.08) and longer disease duration (26vs 12.1years, p = 0.05). Despite initial acceptance, two patients did not begin SB4 after receiving negative information by their regular pharmacist. Real SB4 switch rate was 85% (44/52) and 86% (38/44) of patients reported a good experience of the switch., Conclusions: Acceptance rate of the switch from originator to biosimilar etanercept is high. Patient information, physician and pharmacist knowledge on biosimilars should be taken into account in order to improve their diffusion., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2019
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42. Additional response to the correspondence: 'Switching from the bio-originators to biosimilar: is it premature to recommend this procedure?' by Cantini and Bennuci.
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Scherlinger M and Schaeverbeke T
- Subjects
- Consensus, Humans, Antirheumatic Agents, Arthritis, Rheumatoid, Biosimilar Pharmaceuticals
- Abstract
Competing Interests: Competing interests: None declared.
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- 2019
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43. Response to: 'Switching from the bio-originators to biosimilar: is it premature to recommend this procedure?' by Cantini and Benucci.
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Scherlinger M and Schaeverbeke T
- Subjects
- Consensus, Female, Humans, Pregnancy, Biosimilar Pharmaceuticals, Premature Birth, Rheumatic Diseases
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2019
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44. OX40L/OX40 axis impairs follicular and natural Treg function in human SLE.
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Jacquemin C, Augusto JF, Scherlinger M, Gensous N, Forcade E, Douchet I, Levionnois E, Richez C, Lazaro E, Duffau P, Truchetet ME, Seneschal J, Couzi L, Pellegrin JL, Viallard JF, Schaeverbeke T, Pascual V, Contin-Bordes C, and Blanco P
- Subjects
- Antigen-Presenting Cells, Autoimmune Diseases immunology, Cell Proliferation, Cytokines, Dendritic Cells immunology, Down-Regulation, Female, Forkhead Transcription Factors metabolism, Humans, Immunity, Cellular immunology, Lymphocyte Activation, Male, Myeloid Cells immunology, OX40 Ligand metabolism, Receptors, OX40 metabolism, T-Lymphocytes, T-Lymphocytes, Helper-Inducer, T-Lymphocytes, Regulatory metabolism, Lupus Erythematosus, Systemic immunology, OX40 Ligand immunology, Receptors, OX40 immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Tregs are impaired in human systemic lupus erythematosus (SLE) and contribute to effector T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. We hypothesized that the OX40L/OX40 axis is implicated in Treg and regulatory follicular helper T (Tfr) cell dysfunction in human SLE. OX40L/OX40 axis engagement on Tregs and Tfr cells not only specifically impaired their ability to regulate effector T cell proliferation, but also their ability to suppress T follicular helper (Tfh) cell-dependent B cell activation and immunoglobulin secretion. Antigen-presenting cells from patients with active SLE mediated Treg dysfunction in an OX40L-dependent manner, and OX40L-expressing cells colocalized with Foxp3+ cells in active SLE skin lesions. Engagement of the OX40L/OX40 axis resulted in Foxp3 downregulation in Tregs, and expression in SLE Tregs correlated with the proportion of circulating OX40L-expressing myeloid DCs. These data support that OX40L/OX40 signals are implicated in Treg dysfunction in human SLE. Thus, blocking the OX40L/OX40 axis appears to be a promising therapeutic strategy.
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- 2018
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45. Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance.
- Author
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Scherlinger M, Germain V, Labadie C, Barnetche T, Truchetet ME, Bannwarth B, Mehsen-Cetre N, Richez C, and Schaeverbeke T
- Subjects
- Arthritis, Rheumatoid diagnosis, Biological Products administration & dosage, Cohort Studies, Female, France, Humans, Male, Patient Compliance statistics & numerical data, Patient Safety statistics & numerical data, Prognosis, Prospective Studies, Retrospective Studies, Risk Assessment, Severity of Illness Index, Treatment Outcome, Antibodies, Monoclonal administration & dosage, Arthritis, Rheumatoid drug therapy, Biosimilar Pharmaceuticals administration & dosage, Drug Substitution, Infliximab administration & dosage, Patient Acceptance of Health Care statistics & numerical data
- Abstract
Objective: To explore acceptance and retention rate of biosimilar CT-P13 after switching from originator infliximab (OI) in patients with various rheumatic diseases., Methods: Patients with stable rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA) under OI were proposed to switch to CT-P13 at the same regimen. A prospective cohort of infliximab-naïve patients beginning CT-P13 and a retrospective cohort of patients treated with OI were used as controls. The primary outcome was to evaluate the retention rate of CT-P13. Secondary outcomes were the switch acceptance rate, reasons of failure and safety., Results: Switch was proposed to 100 patients and accepted by 89 of them (63 AS, 12 PsA and 14 RA). After a median follow-up of 33 weeks, 72% of patients were still treated with CT-P13. This retention rate was significantly lower than the one found in our retrospective and prospective control cohorts: 88% and 90% respectively (P-value=0.0002). Within patients who asked to be reswitched to OI, 13/25 (52%) presented clinical disease activity, one developed serum sickness and 11 (44%) presented no objective activity. A subanalysis excluding these 11 patients abrogated difference in retention rates between the 3 cohorts (P-value=0.453). After reswitching to OI, patients without objective disease activity claimed to recover original efficacy., Conclusions: Retention rate was lower after switching from OI to CT-P13 compared to our control cohorts. However, this difference faded after excluding patients without objective clinical activity, suggesting a reluctance of patients to the switch and a negative perception of the biosimilar., (Copyright © 2017. Published by Elsevier Masson SAS.)
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- 2018
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46. Systemic lupus erythematosus and systemic sclerosis: All roads lead to platelets.
- Author
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Scherlinger M, Guillotin V, Truchetet ME, Contin-Bordes C, Sisirak V, Duffau P, Lazaro E, Richez C, and Blanco P
- Subjects
- Antibodies, Antiphospholipid blood, Antigen-Antibody Complex blood, Blood Platelets immunology, Humans, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic immunology, Raynaud Disease blood, Raynaud Disease immunology, Scleroderma, Systemic blood, Scleroderma, Systemic immunology, Blood Platelets physiology, Lupus Erythematosus, Systemic etiology, Scleroderma, Systemic etiology
- Abstract
Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are two phenotypically distincts inflammatory systemic diseases. However, SLE and SSc share pathogenic features such as interferon signature, loss of tolerance against self-nuclear antigens and increased tissue damage such as fibrosis. Recently, platelets have emerged as a major actor in immunity including auto-immune diseases. Both SLE and SSc are characterized by strong platelet system activation, which is likely to be both the witness and culprit in their pathogenesis. Platelet activation pathways are multiple and sometimes redundant. They include immune complexes, Toll-like receptors activation, antiphospholipid antibodies and ischemia-reperfusion associated with Raynaud phenomenon. Once activated, platelet promote immune dysregulation by priming interferon production by immune cells, providing CD40L supporting B lymphocyte functions and providing a source of autoantigens. Platelets are actively implicated in SLE and SSc end-organ damage such as cardiovascular and renal disease and in the promotion of tissue fibrosis. Finally, after understanding the main pathogenic implications of platelet activation in both diseases, we discuss potential therapeutics targeting platelets., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
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47. Monitoring of Epstein-Barr virus (EBV)/cytomegalovirus (CMV)/varicella-zoster virus (VZV) load in patients receiving tocilizumab for rheumatoid arthritis.
- Author
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Scherlinger M, Alain S, and Richez C
- Subjects
- Antibodies, Monoclonal, Humanized, Cytomegalovirus, Herpesvirus 3, Human, Herpesvirus 4, Human, Humans, Arthritis, Rheumatoid, Cytomegalovirus Infections
- Published
- 2018
- Full Text
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48. Serum sickness-like disease after switching to biosimilar infliximab.
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Scherlinger M, Schaeverbeke T, and Truchetet ME
- Subjects
- Antirheumatic Agents administration & dosage, Arthritis, Rheumatoid drug therapy, Biosimilar Pharmaceuticals administration & dosage, Drug Therapy, Combination, Humans, Infliximab administration & dosage, Male, Methotrexate administration & dosage, Middle Aged, Prednisone administration & dosage, Antirheumatic Agents adverse effects, Biosimilar Pharmaceuticals adverse effects, Drug Substitution adverse effects, Infliximab adverse effects, Serum Sickness chemically induced
- Published
- 2017
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49. New Insights on Platelets and Platelet-Derived Microparticles in Systemic Lupus Erythematosus.
- Author
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Scherlinger M, Sisirak V, Richez C, Lazaro E, Duffau P, and Blanco P
- Subjects
- Humans, Lupus Erythematosus, Systemic immunology, Autoimmunity physiology, Blood Platelets immunology, Cell-Derived Microparticles immunology, Lupus Erythematosus, Systemic blood
- Abstract
Purpose of Review: Current knowledge on the role of platelets and platelet-derived microparticles (PMPs) on the immune system has been fast-growing. Systemic lupus erythematosus (SLE) is a systemic auto-immune disorder characterized by a loss of tolerance toward nuclear auto-antigens. Although recent studies allowed a better understanding of SLE pathogenesis, there is an urgent need for the development of new treatments and the identification of new biomarkers to assess the disease activity. We describe here the state-of-the-art knowledge linking platelets and PMPs to SLE., Recent Findings: Platelet system activation is a key event in the pathogenesis of SLE. Circulating immune complexes, anti-phospholipid antibodies, and infectious agents such as virus are the main activators of platelets in SLE. Platelet activation can be monitored through different ways such as P-selectin expression, mean platelet volume, or circulating PMP levels, suggesting their potential use as biomarkers. Upon activation, platelets promote type I interferon production, NETosis, dendritic cell activation, and T and B lymphocyte activation, all essential events contributing to the development of SLE. Of interest, platelets also play a fundamental role in SLE organ disease such as the development of cardiovascular, thrombotic, and renal diseases. Finally, we review current knowledge on drugs targeting platelet activation and their potential impact on SLE pathogenesis. Platelets play a major role in SLE pathogenesis and organ disease and represent a great potential for novel biomarkers and drug development.
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- 2017
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50. Biotherapies in systemic lupus erythematosus: New targets.
- Author
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Lazaro E, Scherlinger M, Truchetet ME, Chiche L, Schaeverbeke T, Blanco P, and Richez C
- Subjects
- Biological Therapy, Humans, Biological Factors therapeutic use, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic therapy
- Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with a polymorphic presentation. The variability in the clinical expression and severity of SLE makes new treatments both essential and challenging to develop. Several biotherapies targeting different pathophysiological pathways have been developed over the past 15 years. The results of Phase II trials were encouraging but rarely borne out by Phase III trials. Recent data, which are discussed in detail in this review, allowed belimumab - a monoclonal antibody against BLyS (B-lymphocyte stimulator) - to become the first biotherapy approved for use in SLE. Other molecules targeting B cells include the two anti-BLyS antibodies tabalumab and blisibimod; atacicept, which targets both BLyS and APRIL (a proliferation-inducing ligand); and the monoclonal antibody to CD22 epratuzumab. The rekindling of interest in the B-cell pathway has also driven new clinical research into rituximab, a monoclonal antibody targeting CD20 with evaluations of new strategies. A new and promising approach is the use of inhibitors of the type 1 interferon (IFN) pathway, of which the most promising is anifrolumab, a monoclonal antibody targeting the type 1 IFN receptor. In this review, we discuss study findings and their clinical relevance, present the most promising targets, and analyze possible explanations to negative results, such as inappropriate patient selection and treatment response criteria or the erratic use of high-dose glucocorticoid therapy., (Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
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