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      Increased levels of peptidylarginine deiminase 2 in synovial fluid from anti-CCP-positive rheumatoid arthritis patients: Association with disease activity and inflammatory markers

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          Abstract

          Objective. To quantify peptidylarginine deiminase 2 (PAD2) in SF of RA patients and OA patients, and to determine the association between PAD2 levels, disease activity and inflammatory markers in RA.

          Methods. Blood and SF samples were obtained from 39 RA patients and 40 patients with OA. PAD2 content and PAD activity were measured by means of in-house assays. TNF-α, IL-1β, IL-6, IL-8, IL-10 and IL-12 were measured using flow cytometry.

          Results. PAD2 levels and PAD activity were higher in SF from RA than OA patients (P < 0.0001 and P = 0.03, respectively), as were all cytokine levels (P < 0.0001–0.05). SF PAD2 levels were higher among anti-CCP-positive patients than among anti-CCP-negative patients (P = 0.005). PAD2 levels in SF from RA patients correlated with disease activity, as assessed by DAS28 (P < 0.005). Moreover, SF PAD2 levels correlated with circulating CRP and anti-CCP levels (P < 0.0006), as well as with leucocyte count, IL-6, IL-8 and IL-10 levels in SF (P < 0.0001–0.02). PAD activity in SF was higher in RA patients than in OA patients, and correlated with PAD2 concentration.

          Conclusion. Extracellular PAD2 levels in SF correlate with disease activity in RA patients. Anti-CCP-positive RA patients have higher PAD2 levels in SF than anti-CCP-negative RA patients and OA patients. Since we could demonstrate enzymatically active PADs in SF, we propose that free, extracellular PAD is of pathogenic relevance.

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          Most cited references 44

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          The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

          The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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            Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies.

            Only a few autoantibodies that are more or less specific for RA have been described so far. The rheumatoid factor most often tested for is not very specific for RA, while the more specific antiperinuclear factor for several reasons is not routinely used as a serological parameter. Here we show that autoantibodies reactive with synthetic peptides containing the unusual amino acid citrulline, a posttranslationally modified arginine residue, are specifically present in the sera of RA patients. Using several citrulline-containing peptide variants in ELISA, antibodies could be detected in 76% of RA sera with a specificity of 96%. Sera showed a remarkable variety in the reactivity pattern towards different citrulline-containing peptides. Affinity-purified antibodies were shown to be positive in the immunofluorescence-based antiperinuclear factor test, and in the so-called antikeratin antibody test, and were reactive towards filaggrin extracted from human epidermis. The specific nature of these antibodies and the presence of these antibodies early in disease, even before other disease manifestations occur, are indicative for a possible role of citrulline-containing epitopes in the pathogenesis of RA.
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              The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.

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                Author and article information

                Journal
                Rheumatology (Oxford)
                Rheumatology (Oxford)
                brheum
                Rheumatology (Oxford, England)
                Oxford University Press
                1462-0324
                1462-0332
                May 2016
                15 February 2016
                15 February 2016
                : 55
                : 5
                : 918-927
                Affiliations
                [1 ]Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet,
                [2 ]Section for Periodontology, Microbiology and Community Dentistry, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark and
                [3 ]Institute of Rheumatology and Department of Rheumatology, 1 [st ] Faculty of Medicine, Charles University in Prague, Czech Republic
                Author notes
                Correspondence to: Claus H. Nielsen, Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, section 7521, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: claus.henrik.nielsen@ 123456rh.regionh.dk
                Article
                kev440
                10.1093/rheumatology/kev440
                5854038
                26880831
                © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                Page count
                Pages: 10
                Product
                Funding
                Funded by: Novo Nordisk Foundation and the Ministry of Health of the Czech Republic
                Award ID: 00023728
                Categories
                Clinical Science
                53

                Rheumatology

                cytokines, peptidylarginine deiminase, citrullination, rheumatoid arthritis

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