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Circulating DNA in rheumatoid arthritis: pathological changes and association with clinically used serological markers.

ABSTRACT: Early diagnosis of rheumatoid arthritis (RA) is crucial to providing effective therapy and often hampered by unspecific clinical manifestations. Elevated levels of extracellular circulating DNA (cirDNA) in patients with autoimmune disease were found to be associated with etiopathogenesis. To our knowledge, this is the first study to investigate the putative diagnostic use of cirDNA in RA and its association with disease activity.Blood samples were taken from 63 healthy subjects (HS) and 74 patients with RA. cirDNA was extracted from plasma and cell surface-bound cirDNA fractions (csbDNA). cirDNA concentration was measured by quantitative real-time polymerase chain reaction. Rheumatoid factor was analyzed by immunonephelometry, whereas C-reactive protein and anticitrullinated protein/peptide antibodies (ACPA) were detected by enzyme-linked immunosorbent assay.Plasma cirDNA was significantly elevated in patients with RA compared with HS (12.0 versus 8.4 ng/ml, p?

SUBMITTER: Rykova E

PROVIDER: S-EPMC5414163 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Circulating DNA in rheumatoid arthritis: pathological changes and association with clinically used serological markers.

Rykova Elena E Sizikov Aleksey A Roggenbuck Dirk D Antonenko Oksana O Bryzgalov Leonid L Morozkin Evgeniy E Skvortsova Kseniya K Vlassov Valentin V Laktionov Pavel P Kozlov Vladimir V

Arthritis research & therapy 20170502 1

<h4>Background</h4>Early diagnosis of rheumatoid arthritis (RA) is crucial to providing effective therapy and often hampered by unspecific clinical manifestations. Elevated levels of extracellular circulating DNA (cirDNA) in patients with autoimmune disease were found to be associated with etiopathogenesis. To our knowledge, this is the first study to investigate the putative diagnostic use of cirDNA in RA and its association with disease activity.<h4>Methods</h4>Blood samples were taken from 63 ...[more]

PMID: 28464939

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Project description:Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and presence of systemic autoantibodies, with a great clinical and molecular heterogeneity. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are routinely used for the diagnosis of RA. However, additional serological markers are needed to improve the clinical management of this disease, allowing for better patient stratification and the desirable application of precision medicine strategies. In the present study, we investigated those systemic molecular changes that are associated with the RF and ACPA status of RA patients. To achieve this objective, we followed a proteomic biomarker pipeline from the discovery phase to validation. First, we performed an iTRAQ-based quantitative proteomic experiment on serum samples from the RA cohort of the Hospital of Santiago de Compostela (CHUS). In this discovery phase, serum samples from the CHUS cohort were pooled according to their RF/ACPA status. Shotgun analysis revealed that, in comparison with the double negative group (RF-/ACPA-), the abundance of 12 proteins was altered in the RF+/ACPA+ pool, 16 in the RF+/ACPA- pool and 10 in the RF-/ACPA+ pool. Vitamin D binding protein and haptoglobin were the unique proteins increased in all the comparisons. For the verification phase, 80 samples from the same cohort were analyzed individually. To this end, we developed a Multiple Reaction Monitoring (MRM) method that was employed in a comprehensive targeted analysis with the aim of verifying the results obtained in the discovery phase. Thirty-one peptides belonging to 12 proteins associated with RF and/or ACPA status were quantified by MRM. In a final validation phase, the serum levels of alpha-1-acid glycoprotein 1 (A1AG1), haptoglobin (HPT) and retinol-binding protein 4 (RET4) were measured by immunoassays in the RA cohort of the Hospital of A Coruña (HUAC). The increase of two of these putative biomarkers in the double seropositive group was validated in 260 patients from this cohort (p = 0.009 A1AG1; p = 0.003 HPT). The increased level of A1AG1 showed association with RF rather than ACPA (p = 0.023), whereas HPT showed association with ACPA rather than RF (p = 0.013). Altogether, this study has allowed a further classification of the RA seropositive patients into two novel clusters: RF+A1AG+ and ACPA+HPT+. The determination of A1AG1 and HPT in serum would provide novel information useful for RA patient stratification, which could facilitate the effective implementation of personalized medicine in routine clinical practice.

Project description:Commensal bacteria and their pathogenic components in the gastrointestinal tract and oral cavity may play pathological roles in autoimmune diseases. To study the possible involvement of bacterial pathogens in autoimmune diseases, IgG and IgA antibodies against pathogenic components produced by three strains of commensal bacteria, Escherichia coli-lipopolysaccharide (E. coli-LPS), Porphyromonas gingivalis-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from Streptococcus pyogenes, were determined by an improved ELISA system for sera from two groups of patients with rheumatoid arthritis (RA), who met rapid radiographic progression (RRP) criteria and non-RRP, and compared to normal (NL) controls. Antibody responses to these bacterial pathogens are unique and consistent in individuals, and no fundamental difference was observed between RA and NL controls. Despite the similar antibody responses to pathogens, lower IgG or higher IgA and consequent higher IgA/IgG antibody ratio among the patients with RA related to disease marker levels and disease activity. Peculiarly, the IgA/IgG anti-Pg-LPS antibody ratio resulted from lower IgG and higher IgA antibody responses to Pg-LPS strongly correlated not only with rheumatoid factor (RF), but also correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score of 28 joints with ESR (DAS28-ESR) in the RRP group. In contrast, the IgA/IgG anti-E. coli-LPS and anti-PG-PS antibody ratio correlated or tended to correlate with RF, ESR, CRP, and DAS28-ESR in the non-RRP group, whereas either the IgG or IgA anti-Pg-LPS antibody levels and consequent IgA/IgG anti-Pg-LPS antibody ratio did not correlate with any clinical marker levels in this group. Notably, anti-circular-citrullinated peptide (CCP) antibody levels, which did not correlate with either IgG or IgA antibody levels to any pathogens, did not correlate with severity of arthritis in both RRP and non-RRP. Taken together, we propose that multiple environmental pathogens, which overwhelm the host antibody defense function, contribute independently or concomitantly to evoking disease makers and aggravating disease activity, and affect disease outcomes.Trial registrationUMIN CTR UMIN000012200.

Dataset Information

Circulating DNA in rheumatoid arthritis: pathological changes and association with clinically used serological markers.

Publications

Circulating DNA in rheumatoid arthritis: pathological changes and association with clinically used serological markers.

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