title: Anticyclic citrullinated protein antibodies are implicated in the development of cardiovascular disease in rheumatoid arthritis.
abstract: OBJECTIVE
  Previous studies have suggested a relationship between anticyclic citrullinated protein (CCP) levels and development of cardiovascular disease in rheumatoid arthritis (RA). However, a limited number of studies have demonstrated an involvement of anti-CCPs in those processes. This study was aimed to define the specific role of these auto-antibodies in the pro-oxidative, inflammatory, and proatherogenic profile observed in leukocytes from RA patients.
  
  
  RESULTS
  Seventy-five RA patients and 31 healthy donors were enrolled. Carotid intima media thickness was evaluated as atherosclerosis marker. Several procoagulant and inflammatory factors, leukocyte activation, and oxidative stress markers were analyzed in plasma and leukocyte subsets. Anti-CCPs were purified from plasma of RA patients, and in vitro treatment of healthy leukocytes was conducted. High titers of anti-CCPs were associated to altered expression of prothrombotic and inflammatory markers, high oxidative stress, and pathological carotid intima media thickness in RA patients. Notably, gene expression analysis showed that lymphocytes were major players in altered inflammatory profile, monocytes were responsible for the protrombotic and atherogenic status, and neutrophils mainly displayed a pro-oxidative feature. In vitro treatment with purified anti-CCPs fully recapitulated that pathogenic profile, promoting the activation of leukocytes.
  
  
  CONCLUSIONS
  Anti-CCPs are key players in the inflammatory and proatherogenic status of RA patients. The effects are specific of the immune cell targeted, promoting overexpression of thrombotic, inflammatory, and pro-oxidative markers in monocytes; pro-oxidative status in neutrophils; and proinflammatory profile in lymphocytes. Targeting these autoantibodies would be an excellent strategy to prevent the development of cardiovascular disease in RA.
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.). nuria.barbarroja.exts@juntadeandalucia.es.
authors.forename: Nuria
authors.initials: N
authors.lastname: Barbarroja
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Sanchez
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz-Limon
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Carmen
authors.initials: C
authors.lastname: Castro-Villegas
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Aguirre
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Rosario
authors.initials: R
authors.lastname: Carretero
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Pedro
authors.initials: P
authors.lastname: Segui
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Jimenez-Gomez
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Manuela
authors.initials: M
authors.lastname: Sanna
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodriguez-Ariza
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Eduardo
authors.initials: E
authors.lastname: Collantes-Estevez
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Alejandro
authors.initials: A
authors.lastname: Escudero
authors.affiliation: From the Rheumatology Service (N.B., C.P.-S., P.R.-L., C.C.-V., M.A.A., R.C., Y.J.-G., M.S., A.R.-A., E.C.-E., A.E., C.L.-P.) and Radiology Service (P.S.), Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital, Cordoba, Spain; and Department of Biomedical Sciences and Centre of Excellence for Biotechnology, Development and Biodiversity Research, University of Sassari, Italy (M.S.).
authors.forename: Chary
authors.initials: C
authors.lastname: López-Pedrera
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D002340:Carotid Artery Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007962:Leukocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010456:Peptides, Cyclic / Q000276:immunology*; D059467:Transcriptome
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D018836:Inflammation Mediators; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide
keywords: cardiovascular disease; inflammation; leukocytes; rheumatoid arthritis