title: Tocilizumab improves the proatherothrombotic profile of rheumatoid arthritis patients modulating endothelial dysfunction, NETosis, and inflammation.
abstract: Tocilizumab (TCZ) is an effective treatment for rheumatoid arthritis (RA). However, the changes that occurred after TCZ therapy on endothelial dysfunction, monocyte activity, NETosis, and oxidative stress, the principal effectors of atherosclerosis and cardiovascular disease, have not been analyzed yet. A total of 20 RA patients received 162 mg per week subcutaneous TCZ for 6 months. Endothelial function was measured through postocclusive hyperemia using Laser Doppler. Oxidative stress markers in monocytes and neutrophils were analyzed by flow cytometry. NETosis was measured through SYTOX staining of DNA fibers and the expression of myeloperoxidase and neutrophil elastase. Percentage of low-density granulocytes was analyzed through flow cytometry. Gene expression and phosphorylation of intracellular pathways was analyzed in monocytes. TCZ improved endothelial function and decreased oxidative stress in RA leukocytes. Percentage of low-density granulocytes and NETosis generation were reduced. The proinflammatory and prothrombotic status of RA monocytes was also reversed through a modulation of specific intracellular pathways. All these results were recapitulated after in vitro treatment with TCZ of monocytes and neutrophils purified from RA patients and cocultured with endothelial cells. TCZ might reduce the proatherothrombotic profile in RA patients through the restoration of the endothelial function, oxidative stress reduction, inhibition of monocytes' prothrombotic and inflammatory profile, and abridged NETosis generation.
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz-Limón
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Ortega
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Arias de la Rosa
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Maria Del Carmen
authors.initials: MDC
authors.lastname: Abalos-Aguilera
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Sanchez
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Jimenez-Gomez
authors.affiliation: Microscopy, cytomics and scientific imaging unit, IMIBIC, Cordoba, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Peralbo-Santaella
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Font
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Desiree
authors.initials: D
authors.lastname: Ruiz-Vilches
authors.affiliation: Biomedical Research Centre Network, Digestive and Liver Diseases (CIBEREHD), Instituto de Salud Carlos III, Córdoba, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ferrin
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Collantes-Estevez
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Escudero-Contreras
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain.
authors.forename: Chary
authors.initials: C
authors.lastname: López-Pedrera
authors.affiliation: Rheumatology Service, Maimonides Institute for biomedical research in Cordoba (IMIBIC)/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain. Electronic address: nuria.barbarroja.exts@juntadeandalucia.es.
authors.forename: Nuria
authors.initials: N
authors.lastname: Barbarroja
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006098:Granulocytes; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D012313:RNA / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013927:Thrombosis / Q000517:prevention & control*; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D012313:RNA; C502936:tocilizumab