48 results on '"Kaplanski, G."'
Search Results
2. Hypophysite, aussi une affaire d’interniste : étude rétrospective monocentrique de 60 cas
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Miquel, L., primary, Testud, B., additional, Albarel, F., additional, Sahakian, N., additional, Cuny, T., additional, Brue, T., additional, Schleinitz, N., additional, Kaplanski, G., additional, Ebbo, M., additional, and Castinetti, F., additional
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- 2024
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3. Retour sur le programme d’éducation thérapeutique du patient (ETP) souffrant de sclérodermie systémique (ScS) à l’APHM de Marseille
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Granel, B., primary, Benyamine, A., additional, Jouve, E., additional, Lodico, M., additional, Rossi, P., additional, Lagouanelle, M.C., additional, Gouiran, S., additional, Mallet, S., additional, Jego-Desplat, S., additional, Jean, R., additional, Mazodier, K., additional, Colombini, N., additional, and Kaplanski, G., additional
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- 2023
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4. French recommendations for the management of non-infectious chronic uveitis
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Quartier, P., primary, Saadoun, D., additional, Belot, A., additional, Errera, M.-H., additional, Kaplanski, G., additional, Kodjikian, L., additional, Kone-Paut, I., additional, Miceli-Richard, C., additional, Monnet, D., additional, Audouin-Pajot, C., additional, Seve, P., additional, Uettwiller, F., additional, Weber, M., additional, Bodaghi, B., additional, Abad, S., additional, Bayen, M., additional, Bielefeld, P., additional, Chalumeau, M., additional, Chiquet, C., additional, Cohen, J.-D., additional, Despert, V., additional, Devilliers, H., additional, Fardeau, C., additional, Georgin-Lavialle, S., additional, Guex-Crosier, Y., additional, Guillaume Czitrom, S., additional, Heron, E., additional, Hofer, M., additional, Agbo Kpati, K.P., additional, Labalette, P., additional, Lemelle, I., additional, Nouar, D., additional, Pugnet, G., additional, Sellam, J., additional, Sene, D., additional, Terrier, B., additional, and Trad, G.S., additional
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- 2023
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5. Hospitalisation pour infection chez les patients suivis pour une artérite à cellules géantes : étude monocentrique rétrospective
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Lavrard-Meyer, P., primary, Gomes De Pinho, Q., additional, Daumas, A., additional, Benyamine, A., additional, Ebbo, M., additional, Schleinitz, N., additional, Harlé, J.R., additional, Jarrot, P.A., additional, Kaplanski, G., additional, Berbis, J., additional, and Granel, B., additional
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- 2023
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6. Effets indésirables associés aux traitements immunomodulateurs de l’artérite à cellules géantes : une étude monocentrique rétrospective
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Gomes de Pinho, Q., primary, Daumas, A., additional, Benyamine, A., additional, Koubi, M., additional, Devos, M., additional, Kaplanski, G., additional, Jarrot, P.A., additional, Schleinitz, N., additional, Ebbo, M., additional, Rossi, P., additional, and Granel, B., additional
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- 2022
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7. Cutaneous manifestations of monogenic auto-inflammatory diseases: An international cohort study from the Juvenile Inflammatory Rheumatism cohort
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Monfort, J.B., primary, Deshayes, S., additional, Dusser, P., additional, Bourguiba, R., additional, Savey, L., additional, Vinit, C., additional, Koné-Paut, I., additional, Amaryan, G., additional, Theodoropoulou, K., additional, Guedri, R., additional, Pachlopnik, J., additional, Belot, A., additional, Melki, I., additional, Perveen Maldar, N., additional, Hentgen, V., additional, Georgin-Lavialle, S., additional, Wouters, C., additional, Woerner, A., additional, Kaiser, D., additional, Berthet, G., additional, Merlin, E., additional, Pillet, P., additional, Richer, O., additional, Barbier, C., additional, Ballot, C., additional, Bolt, I., additional, Wittkowski, H., additional, Rotornaz, K., additional, Jurquet, A.L., additional, Poignant, S., additional, Meinzer, U., additional, Vanoni, F., additional, Dan, D., additional, Lega, J.C., additional, Brunner, J., additional, Aouba, A., additional, Uettwiller, F., additional, Kaplanski, G., additional, Ardois, S., additional, Schleinitz, N., additional, and Dehoorne, J., additional
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- 2022
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8. Facteurs de risque de rechute au diagnostic d’une artérite à cellules géantes : une étude rétrospective
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Gomes de Pinho, Q., primary, Daumas, A., additional, Benyamine, A., additional, Bertolino, J., additional, Schleinitz, N., additional, Ebbo, M., additional, Harlé, J.R., additional, Jarrot, P.A., additional, Kaplanski, G., additional, Berbis, J., additional, Boucekine, M., additional, Rossi, P., additional, and Granel, B., additional
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- 2022
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9. La neurotoxine dérivée des éosinophiles (EDN) : intérêt du dosage dans les pathologies mastocytaires
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Abecassis, A., primary, Vitte, J., additional, Sahli, W., additional, Perrier, R., additional, Blanchard, P., additional, Arnaud, C., additional, Kaplanski, G., additional, and Michel, M., additional
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- 2022
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10. Épanchement péricardique au diagnostic d’artérite à cellules géantes
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Gomes de Pinho, Q., primary, Daumas, A., additional, Benyamine, A., additional, Ebbo, M., additional, Jarrot, P.A., additional, Kaplanski, G., additional, Schleinitz, N., additional, Rossi, P., additional, Bernard-Guervilly, F., additional, Harlé, J.R., additional, Berbis, J., additional, and Granel, B., additional
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- 2021
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11. Syndrome catastrophique des antiphospholipides traité par éculizumab : à propos de deux cas
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Le Roux, A., primary, Cauchois, R., additional, Roumieu, V., additional, Jean, R., additional, Mazodier, K., additional, and Kaplanski, G., additional
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- 2021
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12. Hypophysite : la nécéssité d’une collaboration entre endocrinologue et interniste
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Miquel, L., Testud, B., Albarel, F., Sahakian, N., Cuny, T., Brue, T., Schleinitz, N., Kaplanski, G., Ebbo, M., and Castinetti, F.
- Abstract
L’hypophysite est une atteinte inflammatoire de l’hypophyse et/ou de l’infundibulum, pouvant entraîner des séquelles cliniques, radiologiques et hormonales. Sa caractérisation est limitée dans la littérature.
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- 2024
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13. Les auteurs
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Adotévi., O., Amé-Thomas., P., Arnulf., B., Baron., C., Batteux., F., Beauvillain., C., Bérard., F., Blancho., G., Bourdenet., G., Boyer., O., Caillat-Zucman., S., Candon., S., Carapito., R., Carcelain., G., Carnoy., C., Cesbron., J.-Y., Chevailler., A., Chollet-Martin., S., Colombo., B., Contin-Bordes., C., Coutant., F., Dantal., J., de Carvalho Bittencourt., M., de Chaisemartin., L., Delfau-Larue., M.-H., Desplat-Jégo., S., Dragon-Durey., M.-A., Dubucquoi., S., Dumestre-Perard., C., Fischer., A., Fisson., S., Flament., H., Fournel., S., Galaine., J., Garraud., O., Godet., Y., Gorochov., G., Gros., F., Gubler., B., Guffroy., A., Hacein-Bey-Abina., S., Hoarau., C., Hüe., S., Kaplanski., G., Kervella., D., Kolopp Sarda., M.-N., Labalette., M., Lambotte., O., Le Gouvello., S., Le Naour., R., Lelièvre., J.-D., Lemoine., F., Liégeois., S., Martinet., J., Miyara., M., Moins-Teisserenc., H., Molinier-Frenkel., V., Nel., I., Pagès., F., Paul., S., Picard., C., Radosavljevic., M., Renaudineau., Y., Rosain., J., Rosenzwajg., M., Seillès., E., Soulas-Sprauel., P., Sterlin., D., Tartour., É., Taupin., J.-L., Thibault., G., Tiberghien., P., Toubert., A., Visentin., J., Vitte., J., Vivier., É., Watier., H., and Weiss., L.
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- 2023
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14. Vascular endothelial-cadherin is involved in endothelial cell detachment during thrombotic thrombocytopenic purpura.
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Cauchois R, Lagarde M, Muller R, Faccini J, Leroyer A, Arnaud L, Poullin P, Dignat-George F, Kaplanski G, and Tellier E
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- Humans, Animals, Phosphorylation, Male, Middle Aged, Female, Case-Control Studies, Adult, Calcium metabolism, Calcium blood, Endothelial Cells metabolism, ADAMTS13 Protein blood, ADAMTS13 Protein metabolism, Cells, Cultured, Mice, Mice, Inbred C57BL, Severity of Illness Index, Aged, Cadherins metabolism, Purpura, Thrombotic Thrombocytopenic blood, Human Umbilical Vein Endothelial Cells metabolism, Antigens, CD metabolism, Capillary Permeability, Cell Adhesion
- Abstract
Background: Immune thrombotic thrombocytopenic purpura (i-TTP) is a life-threatening thrombotic microangiopathy linked to ADAMTS-13 deficiency. It has long been assumed that the activation of endothelial cells is the triggering factor for the thrombotic thrombocytopenic purpura crisis. Circulating endothelial cells (CECs) have been shown to be a biomarker of vascular damage and are associated with the clinical severity of i-TTP. However, the mechanisms leading to endothelial cell detachment remain unclear., Objectives: We investigated junctional destabilization the mechanisms underlying cell detachment in thrombotic thrombocytopenic purpura., Methods: We quantified CECs in i-TTP patients and investigated the effect of plasmas in vitro by measuring phosphorylation and internalization of vascular endothelial (VE)-Cadherin and in vivo in a vascular permeability model., Results: In plasma from i-TTP patients, we show that CEC count is associated with severity and correlated to intracellular calcium influx (P < .01). In vitro, serum from i-TTP patients induced stronger detachment of human umbilical vein endothelial cells than serum from control patients (P < .001). Plasma from i-TTP patients induced a higher calcium-dependent phosphorylation (P < .05) and internalization (P < .05) of VE-cadherin compared with plasma from control patients. This effect could be reproduced by immunoglobulin (Ig)G fraction isolated from patient plasma and, in particular, by the F(ab)'2 fragments of the corresponding IgG. In addition, subcutaneous injection of i-TTP plasma into mice resulted in higher vascular permeability than plasma from control patients. An inhibitor of endothelial calcium influx, ITF1697, normalized this increase in permeability., Conclusion: Our results suggest that plasma-induced endothelial activation also leads to an increase in vascular permeability. They contribute to the understanding of the mechanisms behind the presence of elevated CECs in patients' blood by linking endothelial activation to endothelial injury., Competing Interests: Declaration of competing interests P.P. is a member of the scientific advisory boards of Ablynx-Sanofi. The other authors declare no competing financial interests., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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15. Deciphering the Presentation and Etiologies of Hypophysitis Highlights the Need for Repeated Systematical Investigation.
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Miquel L, Testud B, Albarel F, Sahakian N, Cuny T, Graillon T, Brue T, Dufour H, Schleinitz N, Kaplanski G, Ebbo M, and Castinetti F
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Aims: Hypophysitis is defined as an inflammation of the pituitary gland and/or infundibulum. Our aim was to characterize the initial course and evolution of patients with hypophysitis according to the different etiologies., Patients and Methods: Retrospective observational study conducted in a universitary referral hospital center. Patients over 15 years of age were included if they had a diagnosis of hypophysitis between January 2014 and October 2023, with the exclusion of hypophysitis secondary to immune checkpoint inhibitors., Results: Sixty-one patients (64% women; median age, 34 years) were included. Polyuria-polydipsia, headache and asthenia were present in 64%, 48% and 44% of cases respectively. At diagnosis, at least one anterior pituitary deficiency was present in 91.5% of cases and vasopressin deficiency in 56%. MRI was abnormal in 97% of cases. Secondary hypophysitis was found in 46% of cases (n=28), including sarcoidosis in 28% (n=17) and L-group histiocytoses in 13.1% (n=8). Among patients with secondary hypophysitis, pituitary deficiency preceded systemic manifestations in 23% and occurred concomitantly in 23% of cases. Patients were treated in 36% of cases (glucocorticoids, surgery…), without improvement of pituitary hormone deficits., Conclusions: A systemic etiology of hypophysitis was found in almost half of the patients. Pituitary disorders preceded the systemic disease in a quarter of the cases. This emphasizes the importance of a systematic repeated workup looking for a secondary etiology of hypophysitis in these patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)
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- 2024
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16. [Role of university hospital doctors specialized in internal medicine in health professions training and institutions in France: Survey of the National College of Teachers of Internal Medicine (CEMI)].
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Rauzy O, Bouillet L, Chevalier K, Cohen-Aubart F, Delacroix I, Hanslik T, Kaplanski G, Lazaro E, Le Moigne E, Pottier P, Riviere E, and Mouthon L
- Abstract
Rationale: On the occasion of the General stage meeting of Internal Medicine, the National College of Internal Medicine Teachers (CEMI) conducted a survey on teaching activity among all French university hospital (HU) internal medicine specialists., Method: The survey was carried out in September 2023 by sending an email to 101 hospital practitioners university professors (PU-PH) and 18 hospital practitioners assistant professors (MCU-PH) of internal medicine in subsection 53-01 of the National council of universities (CNU), as well as to the 11 HU internists working in immunology (subsection 47-01) or therapeutics (subsection 48-04)., Results: Seventy-three HUs (56.1%) responded to the survey, including 65 PU-PH, 7 MCU-PH and 1 university hospital practitioner (PHU). Internal medicine HUs participate in faculty teaching: 80% are responsible for teaching, 30% are responsible for the year or cycle or lead committees and 40% have had or have an elected mandate at the faculty or at university. Internal medicine HU are involved in the teaching of semiology during the first cycle of medical studies, but also in pharmaceutical sciences, dentistry, midwifery and in paramedical training. They are very invested in the implementation of the second cycle reform and 80% are involved in the preparation of Objective Structured Clinical Examinations (ECOS), mainly as examiners (90%). They also participate in teaching using simulation (60%), teaching advanced practice nurses (IPA) (25%), and writing CEMI books (75%). For ECOS, 90% participate as examiners, 60% participate in teaching using simulation, 25% are involved in teaching advanced practice nurses (IPA), 75% participated in the writing of CEMI works. Eight (12%) internal medicine HUs co-facilitate training with patients and 26 (38%) participate in master's courses at the Faculty of Sciences. Finally, 94% are affiliated with a research unit and 48% supervise university theses students., Conclusion: Internal medicine universities teachers have a strong educational commitment, particularly in semiology and in the reform of the second cycle of medical studies with ECOS and simulation., (Copyright © 2024 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)
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- 2024
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17. Tell-tale immune-related neurological syndromes: Should we look for and underlying low-grade B-cell lymphoma? A retrospective study on 12 cases.
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Coen M, Benyamine A, Delmont E, Kaplanski G, Bouabdallah R, Xerri L, Attarian S, and Serratrice J
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- Humans, Retrospective Studies, Male, Female, Middle Aged, Aged, Adult, Lymphoma, B-Cell pathology, Lymphoma, B-Cell immunology
- Abstract
Introduction: Immune-related neurological syndromes (affecting both the central and peripheral nervous system, as well as the neuromuscular junction) can associate with low-grade B-cell lymphomas., Methods: We conducted a retrospective study on the records of patients with miscellaneous immune-related neuropathies followed by the "Referral Centre for Neuromuscular Diseases and ALS" in collaboration with the Services of Internal Medicine and Hematology (La Timone Hospital, and the Paoli Calmettes-Insitute, Marseille, France; Geneva University Hospitals, Geneva, Switzerland). Clinical, biological, immunological and histological work-up was carried out and data collected., Results: We identified 12 patients with neurological syndromes and atypical presentation/course. In all these patients multiple autoantibodies were found. This prompted us to perform thorough hematologic investigations, that led to the diagnosis of different type of Low-Grade B-Cell lymphomas [i.e. marginal zone lymphomas with lymphoplasmacytic differentiation (n=3), splenic marginal area lymphoma with secondary lymph node invasion (n=1), unclassified marginal area lymphomas (n=8)]. Treatment of the underling lymphoma resulted in an improvement (n=8) or stabilization (n=4) of neurological disease., Conclusion: Atypical presentation of immune-related neurological syndromes, as well as the presence of antibodies with different antigenic targets should be regarded as "warning signs" and raise the suspicion of a paraneoplastic origin sustained by an underlying low-grade B-cell lymphoma that should be actively sought and treated. Close collaboration between internists, neurologists and hematologists allows for the appropriate management of each case., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2024. Published by Elsevier GmbH.)
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- 2024
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18. Diagnosis of thrombotic thrombocytopenic purpura: easy-to-use fiber optic surface plasmon resonance immunoassays for automated ADAMTS-13 antigen and conformation evaluation.
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Bonnez Q, Dekimpe C, Bekaert T, Tellier E, Kaplanski G, Joly BS, Veyradier A, Coppo P, Lammertyn J, Tersteeg C, De Meyer SF, and Vanhoorelbeke K
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- Humans, Case-Control Studies, Biomarkers blood, Reproducibility of Results, Protein Conformation, Predictive Value of Tests, Immunoassay methods, Automation, Laboratory, Female, Male, ADAMTS13 Protein blood, ADAMTS13 Protein immunology, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic blood, Purpura, Thrombotic Thrombocytopenic immunology, Surface Plasmon Resonance, Enzyme-Linked Immunosorbent Assay methods
- Abstract
Background: Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS-13 activity ranges between 10% and 20%. To prevent misdiagnosis, open ADAMTS-13 conformation gained clinical attention as a novel biomarker, especially to diagnose acute iTTP in patients with diagnostic undecisive ADAMTS-13 activity. Plasma ADAMTS-13 conformation analysis corrects for ADAMTS-13 antigen, with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians., Objectives: To design ADAMTS-13 antigen and conformation assays on automated, easy-to-use fiber optic surface plasmon resonance (FO-SPR) technology to promote assay accessibility and diagnose challenging iTTP patients., Methods: ADAMTS-13 antigen and conformation assays were designed on FO-SPR technology. Plasma of 20 healthy donors and 20 acute iTTP patients were quantified, and data from FO-SPR and ELISA reference assays were compared., Results: Following assay design, both antigen and conformation FO-SPR assays were optimized and characterized, presenting strong analytical sensitivity (detection limit of 0.001 μg/mL) and repeatability (interassay variation of 14.4%). Comparative analysis suggested positive correlation (Spearman r of 0.92) and good agreement between FO-SPR and ELISA assays. As expected, FO-SPR assays showed a closed or open ADAMTS-13 conformation in healthy donors and acute iTTP patients, respectively., Conclusion: Both ADAMTS-13 antigen and conformation assays were transferred onto automated, easy-to-use FO-SPR technology, displaying potent analytical sensitivity and reproducibility. ADAMTS-13 antigen and conformation were determined for healthy donors and acute iTTP patients showing strong correlation with ELISA reference. Introducing FO-SPR technology in clinical context could support routine diagnosis of acute iTTP patients, notably when ADAMTS-13 activity fluctuates between 10% and 20%., Competing Interests: Declaration of competing interests J.L. is a member of the Board of Directors of FOx Biosystems. Q.B., C.D., T.B., E.T., G.K., B.S.J., A.V., P.C., C.T., S.F.D.M., and K.V. have no conflicts of interest to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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19. Reduction of mortality, cardiac damage, and cerebral damage by IL-1 inhibition in a murine model of TTP.
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Muller R, Cauchois R, Lagarde M, Roffino S, Genovesio C, Fernandez S, Hache G, Guillet B, Kara Y, Marlinge M, Lenting P, Poullin P, Dignat-George F, Tellier E, and Kaplanski G
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- Animals, Male, Mice, ADAMTS13 Protein metabolism, Disease Models, Animal, Interleukin-1alpha metabolism, Interleukin-1beta metabolism, Interleukin-1beta blood, Mice, Inbred C57BL, Retrospective Studies, von Willebrand Factor metabolism, von Willebrand Factor antagonists & inhibitors, Interleukin 1 Receptor Antagonist Protein pharmacology, Interleukin 1 Receptor Antagonist Protein therapeutic use, Purpura, Thrombotic Thrombocytopenic drug therapy, Purpura, Thrombotic Thrombocytopenic pathology, Purpura, Thrombotic Thrombocytopenic mortality
- Abstract
Abstract: Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in von Willebrand factor cleavage resulting in capillary microthrombus formation and ischemic organ damage. Interleukin-1 (IL-1) has been shown to drive sterile inflammation after ischemia and could play an essential contribution to postischemic organ damage in TTP. Our objectives were to evaluate IL-1 involvement during TTP and to test the efficacy of the recombinant IL-1 receptor antagonist, anakinra, in a murine TTP model. We retrospectively measured plasma IL-1 concentrations in patients with TTP and controls. Patients with TTP exhibited elevated plasma IL-1α and -1β concentrations, which correlated with disease course and survival. In a mouse model of TTP, we administered anakinra (IL-1 inhibitor) or placebo for 5 days and evaluated the efficacy of this treatment. Anakinra significantly reduced mortality of mice (P < .001). Anakinra significantly decreased TTP-induced cardiac damage as assessed by blood troponin concentrations, evaluation of left ventricular function by echocardiography, [18F]fluorodeoxyglucose positron emission tomography of myocardial glucose metabolism, and cardiac histology. Anakinra also significantly reduced brain TTP-induced damage evaluated through blood PS100b concentrations, nuclear imaging, and histology. We finally showed that IL-1α and -1β trigger endothelial degranulation in vitro, leading to the release of von Willebrand factor. In conclusion, anakinra significantly reduced TTP mortality in a preclinical model of the disease by inhibiting both endothelial degranulation and postischemic inflammation, supporting further evaluations in humans., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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20. Molecular B-cell clonality assay in minor salivary glands as a useful tool for the lymphoma risk assessment in Sjögren's syndrome.
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Benyamine A, Poulet A, Belenotti P, Nihous H, Ene N, Jarrot PA, Swiader L, Mancini J, Beaufils N, Essaydi A, Gabert J, Weiller PJ, and Kaplanski G
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- Humans, Female, Middle Aged, Risk Assessment methods, Male, Aged, Adult, Lymphoma, Non-Hodgkin pathology, Lymphoma, Non-Hodgkin diagnosis, Lymphoma, Non-Hodgkin genetics, Lymphoma, Non-Hodgkin immunology, Salivary Gland Neoplasms genetics, Salivary Gland Neoplasms pathology, Salivary Gland Neoplasms immunology, Aged, 80 and over, Sjogren's Syndrome immunology, Sjogren's Syndrome diagnosis, Sjogren's Syndrome genetics, B-Lymphocytes immunology, Salivary Glands, Minor pathology
- Abstract
Objectives: Non-Hodgkin's lymphoma (NHL) risk assessment is crucial in Sjögren's syndrome (SS). We studied the prevalence of clonal immunoglobulin gene rearrangements in minor salivary glands (MSG) and their correlations with lymphoma occurrence and with previously established NHL predictors., Methods: Molecular B-cell expansion was studied in fresh-frozen MSG of 207 patients with either suspected SS or with suspected lymphoma during SS, using a standardised multiplex PCR assay combined with heteroduplex analysis by microcapillary electrophoresis. The assignation of clonal cases was based on EuroClonality consortium guidelines., Results: Among 207 studied patients, 31 (15%) had MSG monoclonal B-cell infiltration. Monoclonality was significantly more frequent in patients with SS (28/123, 22.8%) compared with patients without SS (3/84, 3.6%, P<0.001). Monoclonal B-cell infiltration in MSG of SS patients correlated significantly with ongoing salivary gland NHL, salivary gland swelling, CD4
+ T-cell lymphopenia, rheumatoid factor (RF) activity, low complement levels and type 2 mixed cryoglobulinemia. The accumulation of biological risk factors was associated with a higher rate of MSG B-cell monoclonality given that patients with only positive RF had no probability of MSG B-cell monoclonality, RF-positive patients with 1 or 2 other risk factors had a 25.0% and 85.7% probability of MSG B-cell monoclonality, respectively., Conclusion: The detection of MSG monoclonal B-cell expansion by this easy-to-perform molecular assay is useful, both at the time of diagnosis and during the course of SS. Monoclonal B-cell expansion is associated with a subset of SS patients presenting either ongoing lymphoma or other established lymphoma predictive factors., (Copyright © 2023 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)- Published
- 2024
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21. [High anti-topoisomerase-1 autoantibodies levels are associated with the extension of skin fibrosis and vascular progression in patients with systemic sclerosis].
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Dol C, Granel B, Resseguier N, Kaplanski G, Reynaud-Gaubert M, Schleinitz N, Grob JJ, Delaporte E, Lafforgue P, Rossi P, Bardin N, and Benyamine A
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- Humans, Female, Male, Sclerosis complications, Prognosis, Fibrosis, Autoantibodies analysis, Scleroderma, Systemic complications, Scleroderma, Systemic diagnosis
- Abstract
Background: Anti-centromere antibodies, anti-topoisomerase-1 antibodies (ATA), and anti-RNA-polymerase III antibodies are three Systemic Sclerosis (SSc)-specific autoantibodies. Their detection is helpful in determining the prognosis. We aimed to evaluate whether ATA levels were associated with disease severity at diagnosis or disease progression during follow-up in ATA positive patients., Methods: We conducted a single-centre French retrospective observational study, between 2014 and 2021. ATA positive patients fulfilling the ACR/EULAR 2013 classification criteria for SSc with a minimal follow-up of 1 year and 2 ATA dosages were included. SSc patients with high IgG ATA levels at baseline (>240IU/mL) were compared with SSc patients with low levels (≤240IU/mL), at inclusion and at 1 and 3 years. A variation of at least 30 % of ATA levels was considered significant., Results: Fifty-nine SSc patients were included and analysed. There was a predominance of women and of patients with diffuse interstitial lung disease. Patients with high ATA levels exhibited a higher skin sclerosis assessed by the modified Rodnan skin score (P=0.0480). They had a lower carbon monoxide transfer coefficient (P=0.0457), a lower forced vital capacity (FVC) (P=0.0427) and more frequently had a FVC under 80 %, when compared to patients with low ATA levels (P=0.0423). Initial high ATA levels were associated with vascular progression at one year (21.95 % vs. 0 %; P=0.0495)., Conclusion: ATA levels are associated with skin sclerosis and vascular progression in SSc. Beyond the detection of ATA, quantifying this autoantibody might be of interest in predicting disease severity and prognosis in SSc., (Copyright © 2023 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)
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- 2024
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22. Macrophage IL-1β-positive microvesicles exhibit thrombo-inflammatory properties and are detectable in patients with active juvenile idiopathic arthritis.
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Cambon A, Rebelle C, Bachelier R, Arnaud L, Robert S, Lagarde M, Muller R, Tellier E, Kara Y, Leroyer A, Farnarier C, Vallier L, Chareyre C, Retornaz K, Jurquet AL, Tran TA, Lacroix R, Dignat-George F, and Kaplanski G
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- Humans, Animals, Mice, Inflammasomes metabolism, Lipopolysaccharides pharmacology, Receptors, Purinergic P2X7 metabolism, Macrophages metabolism, Caspase 1 metabolism, Adenosine Triphosphate metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Arthritis, Juvenile metabolism
- Abstract
Objective: IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease such as systemic juvenile idiopathic arthritis (sJIA). Leukocyte microvesicles (MVs) may be a mechanism of IL-1β secretion. The first objective of our study was to characterize IL-1β-positive MVs obtained from macrophage cell culture supernatants and to investigate their biological functions in vitro and in vivo . The second objective was to detect circulating IL-1β-positive MVs in JIA patients., Methods: MVs were purified by serial centrifugations from PBMCs, or THP-1 differentiated into macrophages, then stimulated with LPS ± ATP. MV content was analyzed for the presence of IL-1β, NLRP3 inflammasome, caspase-1, P2X7 receptor, and tissue factor (TF) using ELISA, Western blot, or flow cytometry. MV biological properties were studied in vitro by measuring VCAM-1, ICAM-1, and E-selectin expression after HUVEC co-culture and factor-Xa generation test was realized. In vivo , MVs' ability to recruit leukocytes in a murine model of peritonitis was evaluated. Plasmatic IL-1β-positive MVs were studied ex vivo in 10 active JIA patients using flow cytometry., Results: THP-1-derived macrophages stimulated with LPS and ATP released MVs, which contained NLRP3, caspase-1, and the 33-kDa precursor and 17-kDa mature forms of IL-1β and bioactive TF. IL-1β-positive MVs expressed P2X7 receptor and released soluble IL-1β in response to ATP stimulation in vitro . In mice, MVs induced a leukocyte peritoneal infiltrate, which was reduced by treatment with the IL-1 receptor antagonist. Finally, IL-1β-positive MVs were detectable in plasma from 10 active JIA patients., Conclusion: MVs shed from activated macrophages contain IL-1β, NLRP3 inflammasome components, and TF, and constitute thrombo-inflammatory vectors that can be detected in the plasma from active JIA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cambon, Rebelle, Bachelier, Arnaud, Robert, Lagarde, Muller, Tellier, Kara, Leroyer, Farnarier, Vallier, Chareyre, Retornaz, Jurquet, Tran, Lacroix, Dignat-George and Kaplanski.)
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- 2023
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23. NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.
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Potere N, Garrad E, Kanthi Y, Di Nisio M, Kaplanski G, Bonaventura A, Connors JM, De Caterina R, and Abbate A
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- Humans, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Thromboinflammation, Interleukin-1beta metabolism, Inflammation, Inflammasomes metabolism, COVID-19
- Abstract
Immunothrombosis-immune-mediated activation of coagulation-is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1β and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19., Competing Interests: Conflict of interest: N.P. has received a training fellowship from the International Society on Thrombosis and Haemostasis and research funding from the International Network of VENous Thromboembolism Clinical Research Networks (INVENT), outside of the present work. Y.K. is an inventor on a patent application (US20180369278A1) by the University of Michigan on the use of biogases in vascular disease. M.D.N. reports personal fees as an invited speaker from Bayer, Daiichi Sankyo, and Viatris, personal fees for advisory board membership from LEO Pharma and Pfizer, and institutional funding from LEO Pharma. G.K. has received honorary fees from Swedish Orphan Biovitrum, Chugai-Roche, and Amgen. A.B. received a travel grant from Kiniksa Pharmaceuticals Ltd to attend the 2019 AHA Scientific Sessions and honoraria from Effetti s.r.l. (Milan, Italy) to collaborate on the medical website http://www.inflammology.org, outside the present work. J.M.C. has received personal fees for scientific advisory boards and consulting from Abbott, Anthos, Alnylam, Bristol Myers Squibb, Five Prime Therapeutics, Pfizer, Takeda, and research funding from CSL Behring, outside of the submitted work. R.D.C. has received personal fees from Boehringer-Ingelheim, Bayer, BMS-Pfizer, Daiichi Sankyo, Novartis, Roche, Sanofi, Amgen, Milestone, Menarini, AstraZeneca, and Guidotti, outside the submitted work. A.A. has received research grant funding and has served as a paid scientific advisor to Implicit Biosciences, Kiniksa, Lilly, Merck, Novartis, Novo Nordisk, Olatec, R-Pharm, Serpin Pharma, and Swedish Orphan Biovitrum, outside of the submitted work. E.G. has nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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24. Measuring ADAMTS-13 activity to diagnose thrombotic thrombocytopenic purpura: a novel, fast fiber-optic surface plasmon resonance immunoassay.
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Bonnez Q, Dekimpe C, Tellier E, Kaplanski G, Verhamme P, Tersteeg C, De Meyer SF, Lammertyn J, Joly B, Coppo P, Veyradier A, and Vanhoorelbeke K
- Abstract
Background: Thrombotic thrombocytopenic purpura (TTP) is characterized by severe ADAMTS-13 activity deficiency (<10%). Diagnostic testing is challenging because of unavailability, high cost, and expert technician requirement of ADAMTS-13 enzyme assays. Cost-effective, automated fiber-optic surface plasmon resonance (FO-SPR) platforms show potential for developing diagnostic tests. Yet, FO-SPR has never been explored to measure enzymatic activities., Objectives: To develop an easy-to-use ADAMTS-13 activity assay utilizing optical fibers to rapidly diagnose TTP., Methods: The ADAMTS-13 activity assay was designed and optimized using FO-SPR technology based on a previously described enzyme-linked immunosorbent assay setup. A calibration curve was generated to quantify ADAMTS-13 activity in plasma of healthy donors and patients with acute immune-mediated TTP (iTTP), hemolytic uremic syndrome, or sepsis. ADAMTS-13 activity data from FO-SPR and fluorescence resonance energy transfer-based strategies (FRETS)-VWF73 reference assays were compared., Results: After initial assay development, optimization improved read-out magnitude and signal-to-noise ratio and reduced variation. Further characterization demonstrated a detection limit (6.8%) and inter-assay variation (Coefficient of variation, 7.2%) that showed good analytical sensitivity and repeatability. From diverse plasma samples, only plasma from patients with acute iTTP showed ADAMTS-13 activities below 10%. Strong Pearson correlation ( r = 0.854) between FO-SPR and reference FRETS-VWF73 assays were observed for all measured samples., Conclusions: A fast ADAMTS-13 activity assay was designed onto automated FO-SPR technology. Optimization resulted in sensitive ADAMTS-13 activity measurements with a detection limit enabling clinical diagnosis of TTP within 3 hours. The FO-SPR assay proved strong correlation with the reference FRETS-VWF73 assay. For the first time, this assay demonstrated the capacity of FO-SPR technology to measure enzymatic activity in pre-clinical context., (© 2023 The Author(s).)
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- 2023
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25. Anti-Jo-1 autoantibodies: biomarkers of severity and evolution of the disease in antisynthetase syndrome.
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Arcani R, Rey L, Mazziotto A, Bertin D, Kaplanski G, Jarrot PA, Lafforgue P, Venton G, Heim X, Villani P, Mège JL, Brodovitch A, and Bardin N
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- Humans, Biomarkers, Retrospective Studies, Autoantibodies, Myositis
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Background: Anti-Jo-1 autoantibodies represent essential markers in the diagnosis of antisynthetase syndrome (ASS). In this retrospective study, we aimed to investigate whether their concentrations and fluctuations could both respectively reflect the severity and evolution of ASS., Methods: Between 2015 and 2020, clinical and biological features of ASS patients with at least one positive measure of anti-Jo-1 autoantibody were collected. At each serum sampling, we assessed myositis activity by using the Myositis Intention to Treat Activities Index (MITAX) and compared anti-Jo-1 concentrations with ASS severity, anti-Jo-1 concentrations between patients with and without active disease, and changes in anti-Jo-1 concentrations with disease activity., Results: Forty-eight patients with ASS had at least one positive determination of anti-Jo-1 concentration. Among them, twenty-nine patients had at least two determinations of anti-Jo-1 autoantibody in their follow-up. We showed that these autoantibody concentrations were significantly correlated with MITAX (r = 0.4, p = 0.03) and creatine kinase concentration (r = 0.34, p = 0.002) and that they were significantly higher in patients with active disease than in those with inactive disease (91.7 IU/L vs 44.4 IU/L, p = 0.016). During follow-up, we found a significant correlation between fluctuations of anti-Jo-1 autoantibody concentrations and MITAX score (r = 0.7, p < 0.0001)., Conclusion: Our results suggest that anti-Jo-1 autoantibody concentration could be a predictive marker of the severity and evolution of ASS and show that their quantification could represent a precious tool for disease monitoring and for improving the therapeutic management of ASS patients., (© 2023. The Author(s).)
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- 2023
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26. Predictors of Relapses or Recurrences in Patients With Giant Cell Arteritis: A Medical Records Review Study.
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Gomes de Pinho Q, Daumas A, Benyamine A, Bertolino J, Ebbo M, Schleinitz N, Harlé JR, Jarrot PA, Kaplanski G, Berbis J, Boucekine M, Rossi P, and Granel B
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- Humans, Female, Aged, Aged, 80 and over, Male, Cough chemically induced, Cough complications, Glucocorticoids adverse effects, Pain, Recurrence, Medical Records, Giant Cell Arteritis diagnosis, Giant Cell Arteritis drug therapy, Giant Cell Arteritis epidemiology, Polymyalgia Rheumatica diagnosis, Polymyalgia Rheumatica drug therapy, Polymyalgia Rheumatica epidemiology
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Objective: Giant cell arteritis (GCA) is the most common systemic vasculitis in individuals aged ≥50 years. Its course is marked by a high relapse rate requiring long-term glucocorticoid use with its inherent adverse effects. We aimed to identify factors associated with relapses or recurrences in GCA at diagnosis., Methods: We reviewed the medical records of consecutive patients with GCA diagnosed between 2009 and 2019 and followed for at least 12 months. We recorded their characteristics at onset and during follow-up. Factors associated with relapses or recurrences were identified using multivariable analysis., Results: We included 153 patients, among whom 68% were female with a median age of 73 (47-98) years and a median follow-up of 32 (12-142) months. Seventy-four patients (48.4%) had at least 1 relapse or recurrence. Headache and polymyalgia rheumatica were the most frequent manifestations of relapses. The first relapse occurred at a median time of 13 months after the diagnosis, with a median dose of 5.5 (0-25) mg/d of glucocorticoids.In multivariable analysis, patients with relapses or recurrences had a higher frequency of cough and scalp tenderness at diagnosis (20.3% vs 5.1%; odds ratio [OR], 4.73; 95% confidence interval [CI], 1.25-17.94; p = 0.022; and 41.9% vs 29.1%; OR, 2.4; 95% CI, 1.07-5.39; p = 0.034, respectively). Patients with diabetes mellitus at diagnosis had fewer relapses or recurrences during follow-up (5.4% vs 19%; OR, 0.24; 95% CI, 0.07-0.83; p = 0.024)., Conclusions: Cough and scalp tenderness at diagnosis were associated with relapses or recurrences, whereas patients with diabetes experienced fewer relapses or recurrences., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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27. Tocilizumab versus anakinra in COVID-19: results from propensity score matching.
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Arcani R, Correard F, Suchon P, Kaplanski G, Jean R, Cauchois R, Leprince M, Arcani V, Seguier J, De Sainte Marie B, Andre B, Koubi M, Rossi P, Gayet S, Gobin N, Garrido V, Weiland J, Jouve E, Couderc AL, Villani P, and Daumas A
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- Humans, Male, Aged, SARS-CoV-2, Interleukin 1 Receptor Antagonist Protein therapeutic use, Propensity Score, Retrospective Studies, COVID-19 Drug Treatment, Oxygen, COVID-19
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Background: Tocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra., Methods: Our retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation., Results: Among 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44)., Conclusion: Our study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19., Competing Interests: GK has received from ROCHE-CHUGAI Research Grants <€20,000 and fees from Sobi France for scientific presentations <€4,000 and participated in a SOBI Advisory Board on COVID unpaid and an OLATEC Monitoring Board unpaid. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Arcani, Correard, Suchon, Kaplanski, Jean, Cauchois, Leprince, Arcani, Seguier, De Sainte Marie, Andre, Koubi, Rossi, Gayet, Gobin, Garrido, Weiland, Jouve, Couderc, Villani and Daumas.)
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- 2023
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28. [Hospitalization for infection in patients treated for giant cell arteritis: A single-centre retrospective study].
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Lavrard-Meyer P, Gomes De Pinho Q, Daumas A, Benyamine A, Ebbo M, Schleinitz N, Harlé JR, Jarrot PA, Kaplanski G, Berbis J, and Granel B
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- Humans, Retrospective Studies, Glucocorticoids therapeutic use, Adrenal Cortex Hormones therapeutic use, Hospitalization, Giant Cell Arteritis complications, Giant Cell Arteritis diagnosis, Giant Cell Arteritis epidemiology
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Introduction: Infections are associated with morbimortality of patients with giant cell arteritis (GCA). The aim of this work was twofold: the identification of factors predisposing to the risk of infection and the description of patients hospitalized with an infection occurring during the treatment period of CAG., Methods: A monocentric retrospective study was conducted in GCA patients, comparing patients hospitalized for infection with patients without infection. The analysis included 21/144 (14.6%) patients with 26 infections (cases) and 42 control matched on sex, age, and diagnosis of GCA., Results: Both groups were similar except for a higher frequency of seritis in cases (15% vs. 0%, p=0.03). Relapses of GCA were less common in cases (23.8% vs 50.0%, p=0.041). Hypogammaglobulinemia was present during infection. More than half of the infections (53.8%) occurred in the first year of follow-up with an average dose of 15mg/day of corticosteroids. Infections were mainly pulmonary (46.2%) and cutaneous (26.9%)., Conclusion: Factors associated with infectious risk were identified. This preliminary monocentric work will continue with a national multicentre study., (Copyright © 2023 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)
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- 2023
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29. Characteristics of ANCA-associated vasculitis with aneurysms: Case series and review of the literature.
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Hankard A, Puéchal X, Martin Silva N, Deshayes S, Lorcy N, Le Gallou T, Carron PL, Daugas E, Kaplanski G, Boutemy J, Maigné G, Galimard C, Terrier B, Aouba A, and de Boysson H
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- Humans, Antibodies, Antineutrophil Cytoplasmic, Arteries, Retrospective Studies, Aneurysm complications, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis complications, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis therapy, Granulomatosis with Polyangiitis complications
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Introduction: ANCA-associated vasculitis (AAV) is an exceptional cause of small and large vascular aneurysms. Here, we present the phenotypic characteristics of patients with AAV associated with the presence of aneurysms., Methods: We conducted a retrospective multicenter study and a systematic review of the literature. Only AAV patients with positive ANCA results and > 1 aneurysm(s) were enrolled. Patients were recruited through a call of observations among the French Vasculitis Study Group (FVSG) and the French Internal Medicine Network. Patients with aneurysm rupture were compared to those without., Results: We enrolled 51 patients in the cohort, including 31 (67%) with granulomatosis with polyangiitis. The median Birmingham Vasculitis Activity Score was 18 [6-41]. A total of 92 aneurysms were noted, 74% of which involved medium-sized arteries, particularly the renal artery. During a follow-up of 24 [6-56] months, 22 (43%) patients experienced aneurysmal rupture, 91% of which involved medium-sized vessels. Patients with aneurysmal rupture showed significantly more pulmonary infiltrates and higher creatinine levels at baseline than patients without rupture. Initial treatments did not differ between the two groups. Ten (20%) patients died during the follow-up, including three from an aneurysmal rupture., Conclusion: Aneurysms were more frequently observed in GPA patients and predominantly affected medium-sized vessels, especially the renal arteries. The risk of rupture was high and occurred in >40% of patients. Because of their increased mortality, further studies are required to better manage this subset of patients., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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30. Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity.
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Tellier E, Widemann A, Cauchois R, Faccini J, Lagarde M, Brun M, Robert P, Robert S, Bachelier R, Poullin P, Roose E, Vanhoorelbeke K, Coppo P, Dignat-George F, and Kaplanski G
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- Animals, Humans, Calcium, von Willebrand Factor metabolism, Immunoglobulin G, ADAMTS13 Protein, Patient Acuity, Purpura, Thrombotic Thrombocytopenic
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Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) multimers. The role of endothelial cell activation as a trigger of the disease has been suggested in animal models but remains to be demonstrated in humans. We prospectively obtained plasma from the first plasma exchange of 25 patients during iTTP acute phase. iTTP but not control plasma, induced a rapid VWF release and P-selectin exposure on the surface of dermal human micro-vascular endothelial cell (HMVEC-d), associated with angiopoietin-2 and endothelin-1 secretion, consistent with Weibel-Palade bodies exocytosis. Calcium (Ca2+) blockade significantly decreased VWF release, whereas iTTP plasma induced a rapid and sustained Ca2+ flux in HMVEC-d which correlated in retrospect, with disease severity and survival in 62 iTTP patients. F(ab)'2 fragments purified from the immunoglobulin G fraction of iTTP plasma mainly induced endothelial cell activation with additional minor roles for circulating free heme and nucleosomes, but not for complement. Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patients' B cells, but not serum from hereditary TTP, induced endothelial Ca2+ flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small intering RNA, significantly decreased the stimulating effects of iTTP immunoglobulin G. In conclusion, Ca2+-mediated endothelial cell activation constitutes a "second hit" of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target.
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- 2023
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31. BIOMARKERS: CAN THEY REALLY GUIDE OUR DAILY PRACTICE?
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Tsangaris I, Antonakos N, Fantoni M, Kaplanski G, Kyriazopoulou E, Veas F, and Clemens M
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- Humans, Biomarkers, Ferritins, Procalcitonin, C-Reactive Protein, Bacteremia
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Abstract: Optimal management of septic patients requires accurate assessment of both current severity status and prognosis. Since the 1990s, substantial advances have been made in the use of circulating biomarkers for such assessments. This summary of the session on "Biomarkers: can they really use guide our daily practice?" presented at the 2021 WEB-CONFERENCE OF THE EUROPEAN SHOCK SOCIETY, 6 November 2021. These biomarkers include ultrasensitive detection of bacteremia, circulating soluble urokina-type plasminogen activator receptor (suPAR), C-reactive protein (CRP) and ferritin and procalcitonin. In addition, the potential application of novel multiwavelength optical biosensor technology allows noninvasive monitoring of multiple metabolites that can be used to assess severity and prognosis in septic patients. The application these biomarkers and improved technologies provide the potential for improved personalized management of septic patients., Competing Interests: M.F. served as advisor for SOBI and Menarini and as both advisor and speaker for GSK. F.V. is cofounder and Chie Scientific Officer of ApoH-Technologies; He acknowledges ApoH-Technologies’ team as well as the European Commission for the European Projects: EDCTP “PANDORA-ID-NET” (grant no. RIA2016E-1609) and Horizon Europe “EPIC-Crown 2” (grant no. 101046084). The rest of the authors report no conflict of interests., (Copyright © 2023 by the Shock Society.)
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- 2023
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32. "True" Antiphospholipid Syndrome in COVID-19: Contribution of the Follow-up of Antiphospholipid Autoantibodies.
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Arcani R, Cauchois R, Suchon P, Weber S, Jean R, Jarrot PA, Rey L, Venton G, Koubi M, Muller R, Bertin D, Mège JL, Kaplanski G, and Bardin N
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- Humans, Antibodies, Antiphospholipid, Follow-Up Studies, beta 2-Glycoprotein I, Autoantibodies, Antiphospholipid Syndrome complications, COVID-19
- Abstract
Competing Interests: None declared.
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- 2023
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33. Is Endothelial Activation a Critical Event in Thrombotic Thrombocytopenic Purpura?
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Cauchois R, Muller R, Lagarde M, Dignat-George F, Tellier E, and Kaplanski G
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Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy. The current pathophysiologic paradigm suggests that the ADAMTS13 deficiency leads to Ultra Large-Von Willebrand Factor multimers accumulation with generation of disseminated microthrombi. Nevertheless, the role of endothelial cells in this pathology remains an issue. In this review, we discuss the various clinical, in vitro and in vivo experimental data that support the important role of the endothelium in this pathology, suggesting that ADAMTS13 deficiency may be a necessary but not sufficient condition to induce TTP. The "second hit" model suggests that in TTP, in addition to ADAMTS13 deficiency, endogenous or exogenous factors induce endothelial activation affecting mainly microvascular cells. This leads to Weibel-Palade bodies degranulation, resulting in UL-VWF accumulation in microcirculation. This endothelial activation seems to be worsened by various amplification loops, such as the complement system, nucleosomes and free heme.
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- 2023
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34. Eosinopenia as Predictor of Poor Outcome in Hospitalized COVID-19 Adult Patients from Waves 1 and 2 of 2020 Pandemic.
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Cauchois R, Pietri L, Dalmas JB, Koubi M, Capron T, Cassir N, Potere N, Polidoro I, Jean R, Jarrot PA, Andre B, Veit V, Carvelli J, Pauly V, Chanez P, Papazian L, and Kaplanski G
- Abstract
During SARS-CoV-2 infection, eosinopenia may reflect a hyperactive immune response. In this study of hospitalized COVID-19 patients, we aimed to better understand the prognostic value of severe eosinopenia (absolute eosinophil count = 0 G/L) and decipher its underlying mechanisms. We retrospectively analyzed the records of COVID-19 patients hospitalized from March to June 2020 in three university hospitals in Marseille, France. We assessed the association between severe eosinopenia and a composite poor outcome in these patients, including the need for oxygen supplementation at >6 L/min, ICU admission, and in-hospital death. Among the 551 COVID-19 patients included in this study, severe eosinopenia was found in 228 (51%) of them on admission to hospital and was associated with a composite poor outcome using multivariate analysis (OR = 2.58; CI95 [1.77−3.75]; p < 0.0001). We found a significant association between the presence of severe eosinopenia on admission and the elevation in C-reactive protein, ferritin, IP-10, and suPAR. The histological findings in a series of 37 autopsies from patients who died from severe COVID-19 and presented with severe eosinopenia showed no pulmonary eosinophil trapping. Severe eosinopenia can be a reliable biomarker associated with a composite poor outcome in hospitalized COVID-19 adult patients. It may reflect the magnitude of immune hyperactivation during severe-to-critical COVID-19.
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- 2022
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35. Pericardial effusion in giant cell arteritis is associated with increased inflammatory markers: a retrospective cohort study.
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Gomes de Pinho Q, Daumas A, Benyamine A, Bertolino J, Rossi P, Schleinitz N, Harlé JR, Jarrot PA, Kaplanski G, Berbis J, and Granel B
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- Biomarkers, Hemoglobins, Humans, Retrospective Studies, Giant Cell Arteritis complications, Giant Cell Arteritis diagnostic imaging, Pericardial Effusion diagnostic imaging, Pericardial Effusion etiology, Pericarditis complications, Polymyalgia Rheumatica diagnosis
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Objective: Giant cell arteritis (GCA) is the most frequent vasculitis affecting adults aged > 50 years. Cardiac involvement in GCA is considered rare, and only a few cases of pericarditis have been reported. The aim of this study was to determine the characteristics and prognosis of GCA patients suffering from pericardial involvement at diagnosis., Methods: We conducted a single-centre, retrospective chart review of patients with GCA in internal medicine departments (from 2000 to 2020). Patients were identified through a centralized hospital database. We retrospectively collected demographic, clinicobiological, histological, imaging, treatment and outcome data. Patients with pericardial effusion, defined as an effusion visible on the CT-scan performed at GCA diagnosis were compared to those without pericardial involvement., Results: Among the 250 patients with GCA, 23 patients (9.2%) had pericardial effusion on CT-scan. The comparison between the groups revealed similar distribution of age, gender, cranial symptoms and ocular ischaemic complications. Patients with pericardial effusion had a higher frequency of weight loss. They also had lower haemoglobin levels and higher platelet levels (p = 0.006 and p = 0.002, respectively), and they more frequently had positive temporal artery biopsy. There were no differences concerning the treatment, relapses, follow-up duration or deaths., Conclusions: This case series sheds light on GCA as a cause of unexplained pericardial effusion or symptomatic pericarditis among adults aged > 50 years and elevated inflammatory biological markers. Fortunately, pericardial involvement is a benign GCA manifestation. In that context, the search for constitutional symptoms, cranial symptoms and associated signs of polymyalgia rheumatica is crucial for rapidly guiding GCA diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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36. Factors associated with dexamethasone efficacy in COVID-19. A retrospective investigative cohort study.
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Arcani R, Cauchois R, Suchon P, Jean R, Jarrot PA, Gomes De Pinho Q, Dalmas JB, Jean E, Andre B, Veit V, Koubi M, and Kaplanski G
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- Anti-Bacterial Agents therapeutic use, Cohort Studies, Dexamethasone therapeutic use, Humans, Retrospective Studies, SARS-CoV-2, COVID-19 Drug Treatment
- Abstract
Dexamethasone has demonstrated efficacy in reducing mortality in COVID-19. However, its practical use is badly defined. We aimed to investigate factors associated with dexamethasone efficacy in real life. Our retrospective study was conducted in two university hospitals between September and November 2020 and included all the consecutive hospitalized patients with a laboratory-confirmed SARS-CoV-2 infection assessed by RT-PCR, treated with intravenous dexamethasone (6 mg/day). Among 111 patients, 10.6% necessitated a transfer into the intensive care unit (ICU) and the 28-day mortality rate was 17.1%. The 28-day mortality rate was significantly lower in patients who demonstrated improvement at 48 h (hazard ratio [HR]: 0.17, 95% confidence interval [CI]: 0.04-0.78, p = 0.02) and 96 h (HR: 0.07, 95% CI: 0.02-0.31, p = 0.0005) after dexamethasone initiation. Apart from well-known risk factors (age, hypertension, active cancer, severe lesions on chest computed tomography [CT] scan), we found that a high viral load in nasopharyngeal swab (Cycle threshold <30) at dexamethasone initiation was associated with higher 28-day mortality (66.6% vs. 36.7%, p = 0.03). Patients who did not receive antibiotics at dexamethasone initiation had a higher rate of transfer into the ICU (55.6% vs. 23.5%, p = 0.045) with a trend towards higher mortality in case of severe or critical lesions on CT scan (75.0% vs. 25.0%, p = 0.053). Patients who did not improve within 2-4 days after steroid initiation have a bad prognosis and should receive additional anti-inflammatory drugs. Our data suggest better efficacy of dexamethasone in patients with a low or negative viral load, receiving broad-spectrum antibiotics., (© 2022 Wiley Periodicals LLC.)
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- 2022
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37. Herpetic encephalitis: which treatment for which body weight?
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Mulatero M, Boucekine M, Felician O, Boussen S, Kaplanski G, Rossi P, Parola P, Stein A, Brouqui P, Lagier JC, Leone M, and Kaphan E
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- Acyclovir therapeutic use, Antiviral Agents therapeutic use, Body Weight, Disease Progression, Humans, Retrospective Studies, Encephalitis, Herpes Simplex diagnostic imaging, Encephalitis, Herpes Simplex drug therapy
- Abstract
Background: Prognosis of herpetic encephalitis remains severe, with a high proportion of deaths and sequelae. Its treatment is based on acyclovir, but the precise and most effective modalities of this treatment are not established. The objective of this study was to determine them., Methods: For this, we carried out a descriptive, retrospective, monocentric study, using the current coding database at Marseille University Hospitals. Cohort was intended to be exhaustive for the disease, from January 2000 to June 2019, including patients hospitalized in intensive care and conventional hospitalization sector. Patients (n = 76) included were at least 16 years of age and had a clinical presentation, cerebral Magnetic Resonance Imaging, and/or electroencephalogram abnormalities consistent with herpetic encephalitis confirmed by a positive HSV-PCR in the CSF. Clinical data and treatment, including the doses actually administered to the patient, were compared according to patient's outcome., Results: The mortality rate was 12%, whereas 49% had complete recovery and 39% sequelae impeding independence. Poor outcome was statistically associated with persistence of confusion, aphasia, and impaired consciousness lasting more than 5 days, superinfection, status epilepticus, and length of stay in intensive care unit. A statistical decision tree, constructed using the Classification And Regression Tree model, to prioritize treatment management, showed two main factors that influence the outcome: the patient's weight, and the average daily acyclovir dose actually administered., Conclusion: These results suggest to modify acyclovir management in herpetic encephalitis, for low-weight patients (< 79 kg) with a minimum dosage of 2550 mg/day (850 mg/ 8 h), when possible., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
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- 2022
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38. Immune-mediated thrombotic thrombocytopenic purpura prognosis is affected by blood pressure.
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Joseph A, Eloit M, Azoulay E, Kaplanski G, Provot F, Presne C, Wynckel A, Grangé S, Rondeau É, Pène F, Delmas Y, Lautrette A, Barbet C, Mousson C, Coindre JP, Perez P, Jamme M, Augusto JF, Poullin P, Jacobs F, El Karoui K, Vigneau C, Ulrich M, Kanouni T, Le Quintrec M, Hamidou M, Ville S, Charvet-Rumpler A, Ojeda-Uribe M, Godmer P, Fremeaux-Bacchi V, Veyradier A, Halimi JM, and Coppo P
- Abstract
Background: The prevalence, prognostic role, and diagnostic value of blood pressure in immune-mediated thrombotic thrombocytopenic purpura (iTTP) and other thrombotic microangiopathies (TMAs) remain unclear., Methods: Using a national cohort of iTTP ( n = 368), Shigatoxin-induced hemolytic uremic syndrome ( n = 86), atypical hemolytic uremic syndrome ( n = 84), and hypertension-related thrombotic microangiopathy ( n = 25), we sought to compare the cohort's blood pressure profile to assess its impact on prognosis and diagnostic performances., Results: Patients with iTTP had lower blood pressure than patients with other TMAs, systolic (130 [interquartile range (IQR) 118-143] vs 161 [IQR 142-180] mmHg) and diastolic (76 [IQR 69-83] vs 92 [IQR 79-105] mmHg, both p < 0.001). The best threshold for iTTP diagnosis corresponded to a systolic blood pressure <150 mmHg. iTTP patients presenting with hypertension had a significantly poorer survival (hazard ratio 1.80, 95% confidence interval 1.07-3.04), and this effect remained significant after multivariable adjustment (hazard ratio = 1.14, 95% confidence interval 1.00-1.30). Addition of a blood pressure criterion modestly improved the French clinical score to predict a severe A disintegrin and metalloprotease with thrombospondin type 1 deficiency in patients with an intermediate score (i.e., either platelet count <30 × 10
9 /L or serum creatinine <200 µM)., Conclusions: Elevated blood pressure at admission affects the prognosis of iTTP patients and may help discriminate them from other TMA patients. Particular attention should be paid to blood pressure and its management in these patients., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)- Published
- 2022
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39. Aortitis is an under-recognized manifestation of antiphospholipid syndrome: A case report and literature review.
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Escoda T, George J, Jarrot PA, Jean R, Mazodier K, Sanderson F, Poullin P, Saby L, Jourde-Chiche N, Kaplanski G, and Chiche L
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- Adult, Antibodies, Antiphospholipid, Female, Humans, Microcirculation, Pregnancy, Antiphospholipid Syndrome complications, Antiphospholipid Syndrome diagnosis, Aortitis complications, Aortitis etiology, Lupus Erythematosus, Systemic complications, Lupus Erythematosus, Systemic diagnosis, Thrombosis
- Abstract
Aortitis is a classic manifestation of large vessel vasculitis. Antiphospholipid syndrome (APS), sometimes known as Hughes syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent venous or arterial thrombosis. Patients with APS may also suffer from various underlying diseases, most frequently systemic lupus erythematosus (SLE). Catastrophic antiphospholipid syndrome (CAPS) is a rare but serious complication of APS characterized by failure of several organs due to diffuse microcirculatory thrombi. Its main manifestations involve the kidneys, lungs, heart and central nervous system, and require early diagnosis and rapid therapeutic management. While APS can affect virtually any blood vessel, aortitis is not a known symptom of APS. We report the case of a 36-year-old patient with APS and SLE who presented with CAPS during pregnancy, with no concomitant SLE flare. The first manifestation of CAPS was aortitis, preceding renal, cardiac and haematological manifestations. The outcome was favourable with combined treatment including corticosteroids, anticoagulants, plasma exchange and rituximab. We then carried out a literature search for papers describing the presence of aortitis in APS and/or SLE. In the cases of aortic involvement identified in the literature, including another case of CAPS, the occurrence of aortitis in SLE, often associated with the presence of antiphospholipid antibodies/APS, suggests that aortitis should be considered as an under-recognized manifestation and potential non-criterion feature of APS.
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- 2022
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40. Hydroxychloroquine-related hyperpigmentation.
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Muller R, Jarrot PA, and Kaplanski G
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- Adult, Antirheumatic Agents therapeutic use, Cheek, Female, Humans, Hydroxychloroquine therapeutic use, Leg, Lupus Erythematosus, Systemic drug therapy, Antirheumatic Agents adverse effects, Hydroxychloroquine adverse effects, Hyperpigmentation chemically induced
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- 2022
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41. Considering the level of myositis-specific autoantibodies could improve the precision of multiplex assay : lesson from patients with multiple positive results.
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Briantais A, De Sainte Marie B, Campana-Salort E, Kaplanski G, Durand JM, Bertin D, Bardin N, Ebbo M, and Schleinitz N
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- Humans, Autoantibodies, Myositis diagnosis, Myositis immunology
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- 2022
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42. Mast cells drive pathologic vascular lesions in Takayasu arteritis.
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Le Joncour A, Desbois AC, Leroyer AS, Tellier E, Régnier P, Maciejewski-Duval A, Comarmond C, Barete S, Arock M, Bruneval P, Launay JM, Fouret P, Blank U, Rosenzwajg M, Klatzmann D, Jarraya M, Chiche L, Koskas F, Cacoub P, Kaplanski G, and Saadoun D
- Subjects
- Actins metabolism, Adult, Animals, Aorta, Cells, Cultured, Collagen Type I metabolism, Female, Fibroblasts metabolism, Fibronectins metabolism, Fibrosis, Human Umbilical Vein Endothelial Cells, Humans, Interleukin-33 blood, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Middle Aged, Neovascularization, Physiologic, Takayasu Arteritis blood, Mice, Capillary Permeability, Mast Cells metabolism, Takayasu Arteritis metabolism
- Abstract
Background: Takayasu arteritis (TAK) is a large vessel vasculitis resulting in artery wall remodeling with segmental stenosis and/or aneurysm formation. Mast cells (MCs) are instrumental in bridging cell injury and inflammatory response., Objectives: This study sought to investigate the contribution of MCs on vessel permeability, angiogenesis, and fibrosis in patients with TAK., Methods: MC activation and their tissue expression were assessed in sera and in aorta from patients with TAK and from healthy donors (HDs). In vivo permeability was assessed using a modified Miles assay. Subconfluent cultured human umbilic vein endothelial cells and fibroblasts were used in vitro to investigate the effects of MC mediators on angiogenesis and fibrogenesis., Results: This study found increased levels of MC activation markers (histamine and indoleamine 2,3-dioxygenase) in sera of patients with TAK compared with in sera of HDs. Marked expression of MCs was shown in aortic lesions of patients with TAK compared with in those of noninflammatory aorta controls. Using Miles assay, this study showed that sera of patients with TAK significantly increased vascular permeability in vivo as compared with that of HDs. Vessel permeability was abrogated in MC-deficient mice. MCs stimulated by sera of patients with TAK supported neoangiogenesis (increased human umbilic vein endothelial cell proliferation and branches) and fibrosis by inducing increased production of fibronectin, type 1 collagen, and α-smooth muscle actin by fibroblasts as compared to MCs stimulated by sera of HD., Conclusions: MCs are a key regulator of vascular lesions in patients with TAK and may represent a new therapeutic target in large vessel vasculitis., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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- 2022
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43. Anti-cysteine/spacer antibodies that open ADAMTS13 are a common feature in iTTP.
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De Waele L, Curie A, Kangro K, Tellier E, Kaplanski G, Männik A, Tersteeg C, Joly BS, Coppo P, Veyradier A, De Meyer SF, Roose E, and Vanhoorelbeke K
- Subjects
- ADAMTS13 Protein, Autoantibodies, Cysteine, Humans, Immunoglobulin G, Purpura, Thrombocytopenic, Idiopathic, Purpura, Thrombotic Thrombocytopenic
- Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency in ADAMTS13. In healthy individuals, ADAMTS13 has a folded conformation in which the central spacer (S) domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G antibodies (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in patients with iTTP are directed against the different ADAMTS13 domains, but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13, thereby opening ADAMTS13. To this end, we purified anti-CS and anti-CUB autoantibodies from 13 patients with acute iTTP by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were tested further in our ADAMTS13 conformation enzyme-linked immunosorbent assay to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2021
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44. COVID-19 as a potential trigger of complement-mediated atypical HUS.
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El Sissy C, Saldman A, Zanetta G, Martins PV, Poulain C, Cauchois R, Kaplanski G, Venetz JP, Bobot M, Dobosziewicz H, Daniel L, Koubi M, Sadallah S, Rotman S, Mousson C, Pascual M, Frémeaux-Bacchi V, and Fakhouri F
- Subjects
- Adult, Aged, Atypical Hemolytic Uremic Syndrome etiology, COVID-19 transmission, COVID-19 virology, Female, Humans, Male, Atypical Hemolytic Uremic Syndrome pathology, COVID-19 complications, Complement System Proteins adverse effects, SARS-CoV-2 isolation & purification
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- 2021
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45. Clinical characteristics and outcomes of patients with haematologic malignancies and COVID-19 suggest that prolonged SARS-CoV-2 carriage is an important issue.
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Arcani R, Colle J, Cauchois R, Koubi M, Jarrot PA, Jean R, Boyer A, Lachamp J, Tichadou A, Couderc AL, Farnault L, Costello R, Venton G, and Kaplanski G
- Subjects
- Adult, Aged, Aged, 80 and over, COVID-19 therapy, COVID-19 virology, Cardiovascular Diseases epidemiology, Comorbidity, Diabetes Mellitus epidemiology, Female, Hospital Mortality, Humans, Male, Malnutrition epidemiology, Middle Aged, SARS-CoV-2 isolation & purification, Smoking epidemiology, Treatment Outcome, Viral Load, COVID-19 epidemiology, Hematologic Neoplasms epidemiology, Leukemia epidemiology, Lymphoma epidemiology, Multiple Myeloma epidemiology, SARS-CoV-2 pathogenicity
- Abstract
Specificities of COVID-19 disease course in patients with haematologic malignancies are still poorly studied. So, we aimed to compare patients with haematologic malignancies to patients without malignancies, matched by sex and age and hospitalised for COVID-19 at the same time and in the same centre. Among 25 patients with haematologic malignancies, we found that mortality (40% versus 4%, p < 0.01), number of days with RT-PCR positivity (21.2 ± 15.9 days [range, 3-57] versus 7.4 ± 5.6 days [range, 1-24], p < 0.01), maximal viral load (mean minimal Ct, 17.2 ± 5.2 [range, 10-30] versus 26.5 ± 5.1 [range, 15-33], p < 0.0001) and the delay between symptom onset and clinical worsening (mean time duration between symptom onset and first day of maximum requirement in inspired oxygen fraction, 14.3 ± 10.7 days versus 9.6 ± 3.7 days, p = 0.0485) were higher than in other patients. COVID-19 course in patients with haematologic malignancies has a delayed onset and is more severe with a higher mortality, and patients may be considered as super-spreaders. Clinicians and intensivists need to be trained to understand the specificity of COVID-19 courses in patients with haematological malignancies., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2021
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46. High Mortality of HLH in ICU Regardless Etiology or Treatment.
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Bichon A, Bourenne J, Allardet-Servent J, Papazian L, Hraiech S, Guervilly C, Pauly V, Kaplanski G, Mokart D, Gainnier M, and Carvelli J
- Abstract
Background: Adult hemophagocytic lymphohistiocytosis (HLH) is highly lethal in the ICU. The diagnostic and therapeutic emergency that HLH represents is compounded by its unknown pathophysiological mechanisms. Here, we report on a large cohort of adult HLH in the ICU (ICU-HLH). We analyzed prognostic factors associated with mortality to define the diagnostic and therapeutic challenges in this specific population. Methods: This retrospective study included adult patients diagnosed with HLH in four ICUs in Marseille, France between 2010 and 2020. Patients who fulfilled the HLH-2004 criteria (≥ 4/8) and/or had an HScore ≥ 169 were diagnosed with HLH. HLH was categorized into four groups according to etiology: sepsis-associated HLH, intracellular infection-associated HLH, malignancy-associated HLH, and idiopathic HLH. Results: Two hundred and sixty patients were included: 121 sepsis-associated HLH (47%), 84 intracellular infection-associated HLH (32%), 28 malignancy-associated HLH (11%), and 27 idiopathic HLH (10%). The ICU mortality rate reached 57% ( n = 147/260) without a statistical difference between etiological groups. Independent factors associated with mortality in multivariate analysis included age (OR (5 years) = 1.31 [1.16-1.48], p < 0.0001), SOFA score at ICU admission (OR = 1.37 [1.21-1.56], p < 0.0001), degradation of the SOFA score between ICU arrival and HLH diagnosis (Delta SOFA) (OR = 1.47 [1.28-1.70], p < 0.0001), the presence of bone-marrow hemophagocytosis (OR = 5.27 [1.11-24.97], p = 0.04), highly severe anemia (OR = 1.44 [1.09-1.91], p = 0.01), and hypofibrinogenemia (OR = 1.21 [1.04-1.41], p = 0.02). Conclusions: In this large retrospective cohort study of critically ill patients, ICU-HLH in adults was associated with a 57% mortality rate, regardless of HLH etiology or specific treatment. Factors independently associated with prognosis included age, presence of hemophagocytosis in bone-marrow aspirates, organ failure at admission, and worsening organ failure during the ICU stay. Whether a rapid diagnosis and the efficacy of specific therapy improve outcome is yet to be prospectively investigated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bichon, Bourenne, Allardet-Servent, Papazian, Hraiech, Guervilly, Pauly, Kaplanski, Mokart, Gainnier and Carvelli.)
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- 2021
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47. Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.
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Kyriazopoulou E, Huet T, Cavalli G, Gori A, Kyprianou M, Pickkers P, Eugen-Olsen J, Clerici M, Veas F, Chatellier G, Kaplanski G, Netea MG, Pontali E, Gattorno M, Cauchois R, Kooistra E, Kox M, Bandera A, Beaussier H, Mangioni D, Dagna L, van der Meer JWM, Giamarellos-Bourboulis EJ, and Hayem G
- Abstract
Background: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19., Methods: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491)., Findings: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO
2 /FiO2 ), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO2 /FiO2 . In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10])., Interpretation: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L., Funding: Sobi., Competing Interests: EJG-B has received honoraria from AbbVie USA, Abbott CH, Biotest Germany, Brahms, InflaRx, MSD Greece, XBiotech, and Angelini Italy; independent educational grants from AbbVie, Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux, InflaRx, the Medicines Company and XBiotech; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). MG has received speakers' fees and unrestricted grants from Novartis and Sobi. PP, MKo, and EKo are funded by a COVID-19 grant paid to the Radboud University Medical Center (Radboudumc). JE-O is a co-founder, shareholder, and CSO of ViroGates, Denmark, and named inventor on patents on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark. GK has received from ROCHE-CHUGAI Research Grants (<€20 000), fees from Sobi France for scientific presentations (<€4000) and participated in a SOBI Advisory Board on COVID (unpaid) and in an OLATEC Monitoring Board (unpaid). GCa has received speakers' and consulting fees from Novartis and Sobi. LD has received grants (paid to LD's institution outside the current work) from AbbVie, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Kiniksa, Merk Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi Genzyme, and Sobi; and consulting fees from AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Galapagos, GlaxoSmithKline, Kiniksa, Novartis, Pfizer, Roche, Sanofi-Genzyme, and Sobi. GH reports consultancy fees from Bristol-Myers Squibb, Lilly, Novartis; speakers' fees from AbbVie, Bristol-Myers-Squibb, Celgene, Lilly, Novartis, Pfizer, Roche, Sanofi-Aventis; support for attending meetings from Bristol-Myers-Squibb, Fresenius-Kabi, Janssen-Cilag, Lilly, Mylan, Roche, UCB; and participation on advisory boards for Bristol-Myers-Squibb and Lilly. FV has received (via the Institut de Recherche pour le Développement) Horizon 2020-EDCTP-European Grants: PANDORA and ITAIL-COVID. All other authors declare no competing interests., (© 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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48. Discrimination of COVID-19 From Inflammation-Induced Cytokine Storm Syndromes Using Disease-Related Blood Biomarkers.
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Kessel C, Vollenberg R, Masjosthusmann K, Hinze C, Wittkowski H, Debaugnies F, Nagant C, Corazza F, Vély F, Kaplanski G, Girard-Guyonvarc'h C, Gabay C, Schmidt H, Foell D, and Tepasse PR
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers blood, COVID-19 blood, COVID-19 complications, Cytokine Release Syndrome blood, Diagnosis, Differential, Female, Humans, Lymphohistiocytosis, Hemophagocytic blood, Lymphohistiocytosis, Hemophagocytic complications, Macrophage Activation Syndrome blood, Macrophage Activation Syndrome complications, Male, Middle Aged, Young Adult, COVID-19 diagnosis, Cytokine Release Syndrome etiology, Interleukin-18 blood, Interleukin-8 blood, Lymphohistiocytosis, Hemophagocytic diagnosis, Macrophage Activation Syndrome diagnosis
- Abstract
Objective: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes., Methods: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome., Results: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes., Conclusion: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
- Published
- 2021
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