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      Different Clinical Relevance of Anti-Citrullinated Protein Antibodies in RA Patients

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          Abstract

          The objective of the study was to find a potential relationship between ACPAs and disease activity, bone destruction, and ACPA responses to various therapeutic regimens. The study included 232 patients with rheumatoid arthritis (RA); 90 patients had early RA, and 142 patients had an advanced stage of the disease. 77 (85.6%) patients with early RA were highly positive for anti-CCP, and 29 (70.7%) patients were highly positive for anti-MCV. A positive correlation was found between anti-MCV and DAS28 ( r = 0.4; p = 0.04). As for advanced RA, 78 (80.4%) patients were high-positive for anti-CCP, and 70 (79.5%) were high-positive for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI ( r = 0.4; p = 0.02), as well as CDAI ( r = 0.4; p = 0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0–122.0)) were found in pts highl-positive for anti-MCV ( n = 79), compared to low-positive/negative ( n = 27) patients (57.0 (31.0–88.0); p < 0.05). Anti-MCV levels dropped significantly in pts on rituximab and tocilizumab therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment. Anti-MCV levels correlated with inflammatory activity and development of bone destruction and decreased in pts on treatment. Anti-CCP was less responsive and showed minor changes during treatment; therefore, its thorough monitoring was not feasible.

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          NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.

          Ritika Khandpur, Carmelo Carmona-Rivera, Anuradha Vivekanandan-Giri … (2013)
          The early events leading to the development of rheumatoid arthritis (RA) remain unclear, but formation of autoantibodies to citrullinated protein antigens (ACPAs) is considered a key pathogenic event. Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophil extracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context of immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers, and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and from patients with osteoarthritis (OA). Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules, and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. Indeed, during NETosis, neutrophils externalized the citrullinated autoantigens implicated in RA pathogenesis, and anti-citrullinated vimentin antibodies potently induced NET formation. Moreover, the inflammatory cytokines interleukin-17A (IL-17A) and tumor necrosis factor-α (TNF-α) induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease.
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            Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin.

            Ulrike Harre, Dan Georgess, Holger Bang … (2012)
            Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.
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              Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.

              Kunihiro Nishimura, Daisuke Sugiyama, Yoshinori Kogata … (2007)
              Rheumatoid factor (RF) and autoantibodies against cyclic citrullinated peptide (CCP) are markers that might help physicians diagnose rheumatoid arthritis. To determine whether anti-CCP antibody more accurately identifies patients with rheumatoid arthritis and better predicts radiographic progression than does RF. MEDLINE through September 2006 and reference lists of retrieved studies and review articles. Studies in any language that enrolled at least 10 participants and that examined the role of anti-CCP antibody and RF in the diagnosis or prognosis of known or suspected rheumatoid arthritis. Two authors independently evaluated studies for inclusion, rated methodological quality, and abstracted relevant data. The DerSimonian-Laird random-effects method was used to summarize sensitivities, specificities, and positive and negative likelihood ratios from 37 studies of anti-CCP antibody and 50 studies of RF. The pooled sensitivity, specificity, and positive and negative likelihood ratios for anti-CCP antibody were 67% (95% CI, 62% to 72%), 95% (CI, 94% to 97%), 12.46 (CI, 9.72 to 15.98), and 0.36 (CI, 0.31 to 0.42), respectively. For IgM RF, the values were 69% (CI, 65% to 73%), 85% (CI, 82% to 88%), 4.86 (CI, 3.95 to 5.97), and 0.38 (CI, 0.33 to 0.44). Likelihood ratios among IgM RF, IgG RF, and IgA RF seemed to be similar. Results from studies of patients with early rheumatoid arthritis were similar to those from all studies. Three of 4 studies found that risk for radiographic progression was greater with anti-CCP antibody positivity than with IgM RF positivity. Many studies had methodological limitations. Studies of RF were heterogeneous and had wide ranges of sensitivity and specificity. Anti-CCP antibodies are more specific than RF for diagnosing rheumatoid arthritis and may better predict erosivedisease.
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                Author and article information

                Contributors
                A. S. Avdeeva: 9056249400@mail.ru
                Journal
                Journal ID (nlm-ta): Dokl Biochem Biophys
                Journal ID (iso-abbrev): Dokl Biochem Biophys
                Title: Doklady. Biochemistry and Biophysics
                Publisher: Pleiades Publishing (Moscow )
                ISSN (Print): 1607-6729
                ISSN (Electronic): 1608-3091
                Publication date (Electronic): 13 October 2023
                Publication date PMC-release: 13 October 2023
                Publication date (Print): 2023
                Volume: 511
                Issue: 1
                Pages: 187-194
                Affiliations
                [1 ]GRID grid.488825.b, Nasonova Research Institute of Rheumatology, ; Moscow, Russia
                [2 ]GRID grid.448878.f, ISNI 0000 0001 2288 8774, Department of Rheumatology, Institute of Professional Education, Sechenov First Moscow State Medical University (Sechenov University), ; Moscow, Russia
                Article
                Publisher ID: 7410
                DOI: 10.1134/S160767292370031X
                PMC ID: 10739558
                PubMed ID: 37833605
                SO-VID: 4902a4d3-0788-4c7d-ba5b-790f34f459fb
                Copyright © © The Author(s) 2023, ISSN 1607-6729, Doklady Biochemistry and Biophysics, 2023, Vol. 511, pp. 187–194. © The Author(s), 2023. This article is an open access publication, corrected publication 2023.Russian Text © The Author(s), 2022, published in Nauchno-Prakticheskaya Revmatologiya, 2022, Vol. 60, No. 2, pp. 181–187.
                License:

                Open Access.This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 29 March 2023
                Date revision received : 17 April 2023
                Date accepted : 20 April 2023
                Categories
                Subject: Biochemistry, Biophysics, and Molecular Biology
                Custom metadata
                issue-copyright-statement © Pleiades Publishing, Ltd. 2023

                Keywords: rheumatoid arthritis,disease activity,bone destruction,anti-citrullinated proteins antibodies
                Data availability:
                Keywords: rheumatoid arthritis, disease activity, bone destruction, anti-citrullinated proteins antibodies

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