Elsevier

Autoimmunity Reviews

Volume 9, Issue 3, January 2010, Pages 140-143
Autoimmunity Reviews

Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis

https://doi.org/10.1016/j.autrev.2009.04.006Get rights and content

Abstract

Anti-citrullinated protein/peptide antibodies (ACPA) have recently emerged as sensitive and specific serological markers of rheumatoid arthritis (RA), providing superior alternative of the rheumatoid factor (RF) test in the laboratory diagnostics of RA. Citrullination is a post-translational modification of arginine by deimination, physiologically occurring during apoptosis, inflammation or keratinization. The presence of several citrullinated proteins has been demonstrated in the RA synovium. The identification of citrullinated epitopes as targets led to the development of the first and later second-generation anti-cyclic citrullinated peptide (anti-CCP) antibody assays. The anti-Sa antibody has been identified a decade ago; however, recent studies confirmed that anti-Sa is directed against citrullinated vimentin. The determination of ACPA may have important prognostic significance, since ACPA production can precede the onset of clinical RA symptoms by years. ACPA+ individuals with early, undifferentiated arthritis may have higher risk to develop RA. ACPA has important prognostic role during the progression of RA and it has also been associated with pronounced radiographic progression. ACPA production has been associated with several genetic predisposing factors, including HLA-DRB1 and PTPN22 1858T alleles, as well as with environmental and lifestyle-related factors, primarily smoking and possibly, the use of oral contraceptives and excessive caffeine intake. Thus, the assessment of ACPA, in addition to clinical, radiographic and genetic outcome measures may be important to assess disease prognosis and aids to design effective, early therapeutic strategies.

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

  • Synovial citrullination and the production of ACPA are crucial for the pathogenesis and prognosis of rheumatoid arthritis.

  • ACPA production has been associated with genetic factors including the shared epitope, PTPN22 polymorphism, as well as with lifestyle-related factors, primarily, smoking.

  • 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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