Abstract
Background
Extracellular DNA (ecDNA) is increased in inflammation and it also induces inflammation. In patients with rheumatoid arthritis (RA), plasma ecDNA is higher than in healthy controls. Due to low specificity, it cannot be used for screening, but it might be useful for monitoring and prognosis of therapy success. The effect of treatment with biological disease-modifying antirheumatic drugs (bDMARDs) on plasma ecDNA in RA patients with regards to its subcellular origin has not been analyzed yet. The aim of this study was to describe the effects of bDMARDs on plasma ecDNA and its nuclear (nDNA) and mitochondrial (mtDNA) fractions in patients with RA.
Methods
Plasma samples of 32 patients with RA were collected before, as well as 3 and 6 months after starting the treatment with bDMARDs. Total plasma ecDNA was quantified fluorometrically. The subcellular origin of ecDNA was assessed using real time PCR. Treatment success was monitored using DAS28 and C-reactive protein (CRP).
Results
The clinical status of patients improved. Both DAS28 and CRP decreased by 52 and 73% after 3 months of treatment. Plasma ecDNA decreased significantly only after 6 months (by 26%). Real-time PCR showed that both, nDNA and mtDNA decreased by 63 and by 45% after 6 months.
Conclusion
Treatment with bDMARDs decreases plasma ecDNA of both nuclear and mitochondrial origin. Dynamics of ecDNA is slower than dynamics of standard clinical markers. Therefore, it is likely to be not useful for monitoring of the disease progress, at least for RA.
References
Zhong X-Y, von Mühlenen I, Li Y et al (2007) Increased concentrations of antibody-bound circulatory cell-free DNA in rheumatoid arthritis. Clin Chem 53:1609–1614. https://doi.org/10.1373/clinchem.2006.084509
Dwivedi DJ, Toltl LJ, Swystun LL et al (2012) Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care 16:R151. https://doi.org/10.1186/cc11466
Kostjuk S, Loseva P, Chvartatskaya O et al (2012) Extracellular GC-rich DNA activates TLR9- and NF-kB-dependent signaling pathways in human adipose-derived mesenchymal stem cells (haMSCs). Expert Opin Biol Ther 12:S99–S111. https://doi.org/10.1517/14712598.2012.690028
Miyake K, Onji M (2013) Endocytosis-free DNA sensing by cell surface TLR9 in neutrophils: Rapid defense with autoimmune risks. Eur J Immunol 43:2006–2009. https://doi.org/10.1002/eji.201343882
Sur Chowdhury C, Giaglis S, Walker UA et al (2014) Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res Ther 16:R122. https://doi.org/10.1186/ar4579
Singh JA, Hossain A, Tanjong Ghogomu E et al (2016) Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database Syst Rev 13:CD012183. https://doi.org/10.1002/14651858.CD012183
Hashimoto T, Yoshida K, Hashimoto N et al (2017) Circulating cell free DNA: a marker to predict the therapeutic response for biological DMARDs in rheumatoid arthritis. Int J Rheum Dis 20:722–730. https://doi.org/10.1111/1756-185X.12959
Fransen J, van Riel PLCM. (2009) The Disease Activity Score and the EULAR response criteria. Rheum Dis Clin North Am 35:745–757. https://doi.org/10.1016/j.rdc.2009.10.001
Tsuji N, Tsuji T, Ohashi N et al (2016) Role of mitochondrial DNA in septic AKI via toll-Like receptor 9. J Am Soc Nephrol 27:2009–2020. https://doi.org/10.1681/ASN.2015040376
Rykova E, Sizikov A, Roggenbuck D et al (2017) Circulating DNA in rheumatoid arthritis: pathological changes and association with clinically used serological markers. Arthritis Res Ther 19:85. https://doi.org/10.1186/s13075-017-1295-z
Pratesi F, Dioni I, Tommasi C et al (2014) Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps. Ann Rheum Dis 73:1414–1422. https://doi.org/10.1136/annrheumdis-2012-202765
Szekanecz Z, Soós L, Szabó Z et al (2008) Anti-citrullinated protein antibodies in rheumatoid arthritis: as good as it gets? Clin Rev Allergy Immunol 34:26–31. https://doi.org/10.1007/s12016-007-8022-5
Dunaeva M, Buddingh’ BC, Toes REM et al (2015) Decreased serum cell-free DNA levels in rheumatoid arthritis. Auto Immun Highlights 6:23–30. https://doi.org/10.1007/s13317-015-0066-6
Sun K, Jiang P, Chan KCA et al (2015) Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci 112:E5503–E5512. https://doi.org/10.1073/pnas.1508736112
Jiménez-Alcázar M, Napirei M, Panda R et al (2015) Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J Thromb Haemost 13:732–742. https://doi.org/10.1111/jth.12796
Acknowledgements
This study was supported by the Ministry of Education of the Slovak Republic (VEGA 1/0156/17, VEGA 1/0092/17 and APVV-16-0273).
Funding
This study was funded by the Ministry of Education of the Slovak Republic (VEGA 1/0156/17).
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PC, BV, EŠ and VM designed and directed the study; LL, BV, and BK isolated and quantified DNA from plasma samples; LL analyzed the data; PC and LL wrote the article.
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Lucia Lauková declares that there is no conflict of interest regarding the publication of this article. Barbora Konečná declares that there is no conflict of interest regarding the publication of this article. Barbora Vlková declares that there is no conflict of interest regarding the publication of this article. Vanda Mlynáriková declares that there is no conflict of interest regarding the publication of this article. Peter Celec declares that there is no conflict of interest regarding the publication of this article. Emőke Šteňová declares that there is no conflict of interest regarding the publication of this article.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Number of ethical approval: ICH GCP 135/95, date: 13.06.2016. Name of approving institution: Ethics Committee of University Hospital and Faculty of Medicine in Bratislava.
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Informed consent was obtained from all individual participants included in the study.
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Lauková, L., Konečná, B., Vlková, B. et al. Anti-cytokine therapy and plasma DNA in patients with rheumatoid arthritis. Rheumatol Int 38, 1449–1454 (2018). https://doi.org/10.1007/s00296-018-4055-8
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DOI: https://doi.org/10.1007/s00296-018-4055-8