Assessment of laboratory indicators of inflammatory, infection and indicators of subclinical atherosclerosis in patients with systemic lupus erythematosus

The aim of the study was to reveal the relationship between the activity of inflammation, the infectious component, platelet function and dyslipidemia, in the development of subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE).

Material and methods. Fifty women with SLE at the age of 52.0 [48.0–58.0] years and disease duration – 11.5 [6.0– 22.0] years were examined. The control group consisted of 21 healthy women. The concentration of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), IgG antibodies to Chlamydia pneumonia (at IgG CP), the level of Toll-like receptor (TLR2), platelet factor 4 (PF4) and antibodies to oxidized high-density lipoproteins (at oxLDL) were determined by enzyme immunoassay. Platelet aggregation indices, lipid spectrum, intima-media thickness (IMT) of common carotid arteries were investigated.

Results. A significant increase in IMT of the common carotid artery (1.00 [0.80–1.10] and 0.80 [0.70–0.90] mm, respectively; p<0.01) and TKIM of the carotid bifurcation (1.10 [1.00–1.20] and 0.80 [0.70–1.10] mm, respectively; p<0.01), increased hsCRP concentration (3.67 [2.17–5.92] and 0.74 [0.30–1.26] mg/L, respectively; p<0.01), IL-6 (1.72 [1.39–2.68] and 0.60 [0.22–0.75] pg/mL, respectively; p<0.01). Significant platelet activation was noted in SLE: significant increase in TF4 concentration (21.5 [19.80–23.28] and 18.30 [13.88–20.46] ng/mL, respectively; p<0.01), marked dyslipidemia, increased concentration of oxLDL (3.16 [1.45–4.60] and 1.39 [1.26–2.04] kp, respectively; p<0.01). At IgG CP concentration and TLR2 values in patients with SLE did not differ from controls.

Conclusion. In addition to traditional risk factors for the development of cardiovascular disease, the association between SLE and subclinical atherosclerotic lesions of the vascular wall can be explained by additional risk factors – inflammation and autoimmune processes. The role of the infectious component is for further study.

1. Nasonov EL, Popkova TV, Panafidina TA. Problems of early diagnosis of systemic lupus erythematosus during the COVID-19 pandemic. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2021;59(2):119-128 (In Russ.). doi:10.47360/1995-4484-2021-119-128

2. Drosos GC, Konstantonis G, Sfikakis PP, Tektonidou MG. Lipid management in systemic lupus erythematosus according to risk classifiers suggested by the European Society of Cardiology and diseaserelated risk factors reported by the EULAR recommendations. RMD Open. 2023;9(1):e002767. doi: 10.1136/rmdopen-2022-002767

3. Drosos GC, Vedder D, Houben E, Boekel L, Atzeni F, Badreh S, et al. EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome. Ann Rheum Dis. 2022;81(6):768-779. doi: 10.1136/annrheumdis-2021-221733

4. Guzmán-Martínez G, Marañón C. Immune mechanisms associated with cardiovascular disease in systemic lupus erythematosus: A path to potential biomarkers. Front Immunol. 2022;(13):974826. doi: 10.3389/fimmu.2022.974826

5. Reiss AB, Jacob B, Ahmed S, Carsons SE, DeLeon J. Understanding accelerated atherosclerosis in systemic lupus erythematosus: Toward better treatment and prevention. Inflammation. 2021;44(5):1663-1682. doi: 10.1007/s10753-021-01455-6

6. Yazdany J, Pooley N, Langham J, Nicholson L, Langham S, Embleton N, et al. Systemic lupus erythematosus; stroke and myocardial infarction risk: A systematic review and meta-analysis. RMD Open. 2020;6(2):e001247. doi: 10.1136/rmdopen-2020-001247

7. Gerasimova EV, Popkova TV, Gerasimova DA, Kirichenko TV. Macrophage dysfunction in autoimmune rheumatic diseases and atherosclerosis. Int J Mol Sci. 2022;23(9):4513. doi: 10.3390/ijms23094513

8. Насонова ВА. Системная красная волчанка. М.:Медицина; 972. [Nasonova VA. Systemic lupus erythematosus. Moscow: Meditsina;1972 (In Russ.)].

9. Aseeva EA, Solovyev SK, Nasonov EL. Current methods for evaluating the activity of systemic lupus erythematosus. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2013;51(2): 186-200 (In Russ.). doi: 10.14412/1995-4484-2013-648

10. Johri AM, Nambi V, Naqvi TZ, Feinstein SB, Kim ESH, Park MM, et al. Recommendations for the assessment of carotid arterial plaque by ultrasound for the characterization of atherosclerosis and evaluation of cardiovascular risk: From the American Society of Echocardiography. J Am Soc Echocardiogr. 2020;33(8):917-933. doi: 10.1016/j.echo.2020.04.021

11. Chen C, Li T, Zhu X, Yuan Y, Wang Y. Haemoglobin A1c variability is independently associated with carotid intima media thickness and plaque in type 2 diabetes: A retrospective, crosssectional study. Endocr J. 2023;70(9):891-900. doi: 10.1507/endocrj.EJ23-0134

12. López P, Rodríguez-Carrio J, Martínez-Zapico A, Pérez-Álvarez ÁI, Suárez-Díaz S, Mozo L, et al. Low-density granulocytes and monocytes as biomarkers of cardiovascular risk in systemic lupus erythematosus. Rheumatology (Oxford). 2020;59(7):1752- 1764. doi: 10.1093/rheumatology/keaa016

13. Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res. 2021;128:1728-1746. doi: 10.1161/CIRCRESAHA.121.319077

14. Tanhapour M, Miri A, Vaisi-Raygani A. Synergism between apolipoprotein E Ɛ4 allele and paraoxonase (PON1) 55-M allele is associated with risk of systemic lupus erythematosus. Clin Rheumatol. 2018;37:971-977. doi: 10.1007/s10067-017-3859-3

15. Khatana C, Saini NK, Chakrabarti S, Saini V, Sharma A, Saini RV, et al. Mechanistic insights into the oxidized low-density lipoprotein-induced atherosclerosis. Oxid Med Cell Longev. 2020;2020:5245308. doi: 10.1155/2020/5245308

16. Ye Y, Wu T, Zhang T, Han J, Habazi D, Saxena R, et al. Elevated oxidized lipids, anti-lipid autoantibodies and oxidized lipid immune complexes in active SLE. Clin Immunol. 2019;205:43-48. doi: 10.1016/j.clim.2019.05.004

17. Wirestam L, Jönsson F, Enocsson H, Svensson C, Weiner M, Wetterö J, et al. Limited association between antibodies to oxidized low-density lipoprotein and vascular affection in patients with established systemic lupus erythematosus. Int J Mol Sci. 2023;24(10):8987. doi: 10.3390/ijms24108987

18. Blachut D, Przywara-Chowaniec B, Tomasik A, Kukulski T, Morawiec B. Update of potential biomarkers in risk prediction and monitoring of atherosclerosis in systemic lupus erythematosus to prevent cardiovascular disease. Biomedicines. 2023;11(10):2814. doi: 10.3390/biomedicines11102814

19. Obermayer G, Afonyushkin T, Binder CJ. Oxidized low-density lipoprotein in inflammation-driven thrombosis. J Thromb Haemost. 2018;16(3):418-428. doi: 10.1111/jth.13925

20. Theofilis P, Sagris M, Antonopoulos AS, Oikonomou E, Tsioufis C, Tousoulis D. Inflammatory mediators of platelet activation: Focus on atherosclerosis and COVID-19. Int J Mol Sci. 2021;22(20):11170. doi: 10.3390/ijms222011170

21. Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal Transduct Target Ther. 2022;7(1):131. doi: 10.1038/s41392-022-00955-7

22. Gremmel T, Ay C, Riedl J, Kopp CW, Eichelberger B, Koppensteiner R, et al. Platelet-specific markers are associated with monocyte-platelet aggregate formation and thrombin generation potential in advanced atherosclerosis. Thromb Haemost. 2016;115(3):615-621. doi: 10.1160/TH15-07-0598

23. Badrnya S, Schrottmaier WC, Kral JB, Yaiw KC, Volf I, Schabbauer G, et al. Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation. Arterioscler Thromb Vasc Biol. 2014;34(3):571-580. doi: 10.1161/ATVBAHA.113.302919

24. Reshetnyak T, Nurbaeva K. The role of neutrophil extracellular traps (NETs) in the pathogenesis of systemic lupus erythematosus and antiphospholipid syndrome. Int J Mol Sci. 2023;24(17):13581. doi: 10.3390/ijms241713581

25. Hally KE, La Flamme AC, Larsen PD, Harding SA. Platelet Tolllike receptor (TLR) expression and TLR-mediated platelet activation in acute myocardial infarction. Thromb Res. 2017;158:8-15. doi: 10.1016/j.thromres.2017.07.031

26. Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal Transduct Target Ther. 2022;7(1):131. doi: 10.1038/s41392-022-00955-7

27. Li B, Xia Y, Hu B. Infection and atherosclerosis: TLR-dependent pathways. Cell Mol Life Sci. 2020;77(14):2751-2769. doi: 10.1007/s00018-020-03453-7

28. Xue L, Liang YH, Gao YY, Wang XJ. Clinical study of Chlamydia pneumoniae infection in patients with coronary heart disease. BMC Cardiovasc Disord. 2019;19(1):110. doi: 10.1186/s12872-019-1099-y

29. Miao G, Zhao X, Wang B, Zhang L, Wang G, Zheng N, et al. TLR2/CXCR4 coassociation facilitates Chlamydia pneumoniae infection-induced atherosclerosis. Am J Physiol Heart Circ Physiol. 2020;318(6):H1420-H1435. doi: 10.1152/ajpheart.00011.2020

30. Boytsov SA, Kukharchuk VV, Karpov YuA, Sergienko IV, Drapkina OM, Semenova AE, et al. Subclinical atherosclerosis as a risk factor of cardiovascular events. Cardiovasc Ther Prev. 2012;11(3):82-86 (In Russ.). doi: 10.15829/1728-8800-2012-3-82-86

31. Peng J, Dönnes P, Ardoin SP, Schanberg LE, Lewandowski L. Atherosclerosis progression in the APPLE trial can be predicted in young people with juvenile-onset systemic lupus erythematosus using a novel lipid metabolomic signature. Arthritis Rheumatol. 2024;76(3):455-468. doi: 10.1002/art.42722

32. Popkova TV, Panafidina TA, Novikova DS, Aleksandrova EN, Novikov AA, Novoselova TE, et al. Role of inflammation markers in development of atherosclerosis and its compications in patients with systemic lupus erythematosus. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2013;51(6): 646-653 (In Russ.). doi: 10.14412/1995-4484-2013-646-53

33. Oliveira CB, Mariana JK. Cardiovascular disease risk and pathogenesis in systemic lupus erythematosus. Semin Immunopathol. 2022;44(3):309-324. doi: 10.1007/s00281-022-00922-y