Abstract
BackgroundEarly 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.MethodsBlood 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.ResultsPlasma cirDNA was significantly elevated in patients with RA compared with HS (12.0 versus 8.4 ng/ml, p < 0.01). In contrast, nuclear csbDNA (n-csbDNA) was significantly decreased (24.0 versus 50.8 ng/ml, p < 0.01), whereas mitochondrial csbDNA (m-csbDNA) was elevated (1.44 × 106 copies/ml versus 0.58 × 106 copies/ml, p < 0.05) in RA. The combination of csbDNA (mitochondrial + nuclear) with ACPA reveals the best positive/negative likelihood ratios (LRs) for the discrimination RA from HS (LR+ 61.00, LR− 0.03) in contrast to ACPA (LR+ 9.00, LR− 0.19) or csbDNA (LR+ 8.00, LR− 0.18) alone.ConclusionsNuclear and mitochondrial cirDNA levels in plasma and on the surface of blood cells are modulated in RA. Combination of cirDNA values with ACPA can improve the serological diagnosis of RA.
Highlights
Diagnosis of rheumatoid arthritis (RA) is crucial to providing effective therapy and often hampered by unspecific clinical manifestations
Creactive protein (CRP) is a sensitive but unspecific inflammation marker that is widely used for the 28-joint Disease Activity Score (DAS28) based on C-reactive protein definition in patients with RA and is in good agreement with DAS28 based on erythrocyte sedimentation rate [6]
Circulating nuclear RA Rheumatoid arthritis (DNA), mitochondrial DNA, anticitrullinated protein/peptide antibodies (ACPA), rheumatoid factor (RF), and CRP concentrations in healthy subjects and patients with RA A significant increase of the plasma n-circulating DNA (cirDNA) concentration was found for patients with RA compared with age- and sex-matched HS, whereas levels of n-cell surface-bound DNA (csbDNA) in patients with RA were found to be significantly decreased (24.0 versus 50.8 ng/ ml, p < 0.01) (Table 2). m-cirDNA concentration was not changed in patients with RA compared with HS, whereas the m-csbDNA level was different (1.44 × 106 copies/ml versus 0.58 × 106 copies/ml, p < 0.05)
Summary
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. Creactive protein (CRP) is a sensitive but unspecific inflammation marker that is widely used for the 28-joint Disease Activity Score (DAS28) based on C-reactive protein definition in patients with RA and is in good agreement with DAS28 based on erythrocyte sedimentation rate [6]
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