Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is an autoimmune-inflammatory disease that may lead to joint destruction and disability [1]. Genetic factors including class II major histocompatibility complex (MHC) and non-MHC alleles, environmental factors and autoimmune processes are highly involved in the pathogenesis of RA [2]. Early diagnosis and immediate, effective therapy are crucial in order to prevent joint deterioration, functional disability and unfavorable disease outcome [1], [3]. Currently, optimal management of RA is needed within 3–6 months after the onset of disease, therefore a very narrow “window of opportunity” is present to achieve remission [3]. Thus, reliable outcome measures are needed in order to establish prognosis early and to conduct good clinical practice.
Significant amount of data have become available suggesting that genetic factors and autoimmune-inflammatory markers are good indicators of outcome [2], [4]. In this review, we aim to summarize recent data regarding the predictive and prognostic value of genetic and laboratory markers in RA.
Section snippets
Synovial citrullination and production of ACPA
Citrulline is the post-translationally modified, deiminated derivative of arginine [4], [5]. The arginine-to-citrulline transition is catalyzed by the peptidylarginine-deiminase (PAD) enzyme that has five isoforms in mammals, PAD1-4 and PAD6 [5], [6]. Tissue citrullination is a physiological process underlying epithelial keratinization, inflammation and increased apoptosis [4], [5], [6], [7]. Inflammatory leukocytes including RA synovial T and B cells, macrophages, neutrophils and synovial
MHC genes as outcome measures
Certain HLA-DRB1⁎01 (HLA-DR1) and HLA-DRB1⁎04 (HLA-DR4) alleles, also known as “shared epitopes” (SE), has been associated with susceptibility to and/or progression of RA [2], [28], [29], [30]. SE is a risk factor for more severe, destructive RA, as well as for the development of extraarticular manifestations [2], [28]. It is likely, that the SE itself may not be directly responsible for poorer prognosis, but it may rather influence outcome indirectly, via ACPA production [2], [4], [31].
Environmental and lifestyle-associated prognostic factors
Numerous studies have been performed with respect to the role of environmental and lifestyle-related factors, primarily smoking, in susceptibility to the development and progress of RA. At least in some geographical regions, smoking has been associated with the development of extraarticular manifestations, including nodulosis and cardiovascular complications, as well as with more progressive disease course [33], [39], [40]. Yet, smoking may not be related to radiographic progression [39]. It is
Conclusion
In conclusion, RA patients may be classified into ACPA+ and ACPA− subpopulations that may have important prognostic significance. The terms “seropositive” and “seronegative”, originally based on the evaluation of IgM RF, have undergone major transition. The development of ACPA may precede the onset of clinical symptoms by years. ACPA has predictive role in early, undifferentiated arthritis and ACPA+ individuals with UDP may have higher risk to develop RA. ACPA has important prognostic role
Take-home messages
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Synovial citrullination and the production of ACPA are crucial for the pathogenesis and prognosis of rheumatoid arthritis.
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ACPA production has been associated with genetic factors including the shared epitope, PTPN22 polymorphism, as well as with lifestyle-related factors, primarily, smoking.
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The determination of ACPA in association with genetic and environmental factors at the onset of the disease may serve as a complex outcome measure in RA.
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