The dynamics of extracellular DNA associates with treatment response in patients with rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) as a chronic autoimmune inflammatory disease increases extracellular DNA (ecDNA). Our previous study has shown that anti-inflammatory treatment reduces ecDNA, but it is unclear whether there is an association with treatment response. The aim of this study was to analyze the changes of ecDNA induced by biological disease-modifying antirheumatic drugs (bDMARDs) in RA patients with an emphasis on the subcellular origin of ecDNA. Plasma samples from 40 RA patients were collected in three different time-points: before treatment with bDMARDs as well as 3 and 12 months following treatment initiation. Total, nuclear and mitochondrial ecDNA was quantified using fluorometry and real-time PCR. Disease activity score (DAS28) and C-reactive protein (CRP) were used to monitor the clinical status and the response to treatment. Treatment with bDMARDs elicited an overall improvement of the clinical status: DAS28 and CRP showed a significant decrease by 54% and 43%, respectively, after 3 months of treatment. A significant decrease of total ecDNA by 60% and nuclear ecDNA by 58% was detected only in good responders after 3 months of bDMARDs treatment. No significant changes of plasma ecDNA concentration were observed in moderate and non-responders. Deoxyribonuclease activity was not affected by the treatment. None of the analyzed biomarkers differed between the groups at baseline. Plasma ecDNA especially of nuclear origin could potentially be useful to monitor the treatment response in RA. Further studies should shed light on disease-treatment interplay implicated in ecDNA origin potentially linked to neutrophil extracellular traps.

Plasma mtDNA as a possible contributor to and biomarker of inflammation in rheumatoid arthritis

“…In systemic lupus erythematosus (SLE), impaired degradation of extracellular DNA by deoxyribonuclease (DNase) 1 was shown to contribute to the upregulation of mtDNA in the plasma of some patients [ 42 , 43 ]. The one study investigating the activity of DNase1 in RA, however, did not find an impairment [ 44 ].…”

“…We cannot exclude the possibility that the latter lack of significance results from the high number of patients in remission and the small number of patients with high activity in our study. Other investigators have suggested a significant correlation between elevated plasma cfDNA levels and DAS28 [6,44]. It must be determined in further studies, if mtDNA quantification has a potential in the monitoring of longitudinal changes in RA activity, as demonstrated for SLE [32] and anti-citrullinated protein antibodies (ANCA)-associated vasculitis [45].…”

Metabolic Effects of Anti-TNF-α Treatment in Rheumatoid Arthritis

“…We have described how the application of the biological treatment led to a decrease in thiobarbituric acid-reacting substances as a marker of lipid peroxidation [6]. We have also observed a decrease in extracellular DNA, which can cause a decrease in inflammation or be its consequence [24][25][26]. Given that RA also causes cartilage and bone damage that ultimately has a major effect on quality of life, the administration of anti-TNF also leads to functional benefits such as cartilage remodeling and periodontal status, as RA and periodontitis share similarities in the pathomechanism of the disease, like the production of interleukins [27,28].…”