Vascular pathology as a systemic factor in synovitis development

Aim: to systematize current data on the role of vascular comorbidity as a systemic factor in the pathogenesis, diagnosis, and treatment of synovitis to optimize management of patients with combined pathology.

Materials and methods. Publications from PubMed/MEDLINE, Cochrane Library, and Google Scholar databases for 2000–2025 were analyzed, systematizing epidemiological data, molecular mechanisms of pathogenesis, diagnostic algorithms, and therapeutic strategies for synovitis with vascular comorbidity, with emphasis on Eastern European specificity.

Results. Epidemiological studies confirm bidirectional associations: in women, arterial hypertension is associated with knee osteoarthritis (OR 2.27; 95% CI 1.17–4.39), while in inflammatory arthritis, overall cardiovascular risk increases by 35% (RR 1.35; 95% CI 1.12–1.63) and myocardial infarction risk by 43% (RR 1.43; 95% CI 1.29–1.57). The molecular basis involves convergence of pathogenic pathways: endothelial dysfunction with reduced nitric oxide bioavailability, NF-κB signaling activation with adhesion molecule expression (ICAM-1, VCAM-1), and pathological VEGF-dependent angiogenesis. Integrated diagnostic approaches include biomarkers (VEGF with activity correlation r=0.72, soluble adhesion molecules) and imaging modalities (MRI using RAMRIS system with 95% sensitivity and histological correlation r=0.85). The therapeutic paradox of nonsteroidal anti-inflammatory drugs involves 10–50% cardiovascular risk elevation even with short-term use, justifying patient stratification by risk level. Colchicine demonstrates dual benefit, reducing cardiovascular events by 49–67% in coronary artery disease. Subclinical synovitis persists in 45–50% of patients with vascular comorbidity compared to 27–31% without.

Conclusion. Vascular comorbidity fundamentally modifies synovitis pathogenesis, diagnosis, and therapeutic response through molecular mechanism convergence. Personalization of treatment strategies considering cardiovascular profile and integration of vascular protection into treatment protocols should become standard clinical practice, especially for the high-risk Eastern European population.

References

1. Lo K., Au M., Ni J., Wen C. (2022) Association between hypertension and osteoarthritis: A systematic review and meta-analysis of observational studies. J. Orthop. Translat., 32: 12–20. doi: 10.1016/j.jot.2021.05.003.
2. Semb A.G., Ikdahl E., Kerola A.M. et al. (2022) A Clinical Audit of Cardiovascular Risk Factors and Disease in Patients with Rheumatoid Arthritis — SURF-RA. Mediterr. J. Rheumatol., 33(2): 201–217. doi: 10.31138/mjr.33.2.201.
3. Hall A.J., Stubbs B., Mamas M.A. et al. (2016) Association between osteoarthritis and cardiovascular disease: Systematic review and meta-analysis. Eur. J. Prev. Cardiol., 23(9): 938–946. doi: 10.1177/2047487315610663.
4. Baghdadi L.R., Woodman R.J., Shanahan E.M., Mangoni A.A. (2015) The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One, 10(2): e0117952. doi: 10.1371/journal.pone.0117952.
5. Steyers C.M. 3rd, Miller F.J. Jr. (2014) Endothelial dysfunction in chronic inflammatory diseases. Int. J. Mol. Sci., 15(7): 11324–11349. doi: 10.3390/ijms150711324.
6. Aymon R., Mongin D., Guemara R. et al. (2025) Incidence of Major Adverse Cardiovascular Events in Patients With Rheumatoid Arthritis Treated With JAK Inhibitors Compared With Biologic Disease-Modifying Antirheumatic Drugs: Data From an International Collaboration of Registries. Arthritis Rheumatol., 77(9): 1194–1204. doi: 10.1002/art.43188.
7. Hansildaar R., Vedder D., Baniaamam M. et al. (2021) Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol., 3(1): e58–e70. doi: 10.1016/S2665-9913(20)30221-6.
8. Pepine C.J., Gurbel P.A. (2017) Cardiovascular safety of NSAIDs: Additional insights after PRECISION and point of view. Clin. Cardiol., 40(12): 1352–1356. doi: 10.1002/clc.22814.
9. Kerola A.M., Rollefstad S., Semb A.G. (2021) Atherosclerotic Cardiovascular Disease in Rheumatoid Arthritis: Impact of Inflammation and Antirheumatic Treatment. Eur. Cardiol., 16: e18. doi: 10.15420/ecr.2020.44.
10. Barkhane Z., Zaree A., Zulfiqar S. et al. (2023) Comparison of Cardiovascular Outcomes in Patients With and Without Rheumatoid Arthritis: A Meta-Analysis of Observational Studies. Cureus, 15(6): e40348. doi: 10.7759/cureus.40348.
11. Dijkshoorn B., Raadsen R., Nurmohamed M.T. (2022) Cardiovascular Disease Risk in Rheumatoid Arthritis Anno 2022. J. Clin. Med., 11(10). doi: 10.3390/jcm11102704.
12. Jagpal A., Navarro-Millan I. (2018) Cardiovascular co-morbidity in patients with rheumatoid arthritis: a narrative review of risk factors, cardiovascular risk assessment and treatment. BMC Rheumatol., 2: 10. doi: 10.1186/s41927-018-0014-y.
13. Middleton J., Americh L., Gayon R. et al. (2004) Endothelial cell phenotypes in the rheumatoid synovium: activated, angiogenic, apoptotic and leaky. Arthritis Res. Ther., 6(2): 60–72. doi: 10.1186/ar1156.
14. Dimitroglou Y., Aggeli C., Theofilis P. et al. (2023) Novel Anti-Inflammatory Therapies in Coronary Artery Disease and Acute Coronary Syndromes. Life (Basel), 13(8).
15. Totoson P., Maguin-Gate K., Prati C. et al. (2014) Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies. Arthritis Res. Ther., 16(1): 202. doi: 10.1186/ar4450.
16. Ma J., Chen X. (2022) Advances in pathogenesis and treatment of essential hypertension. Front. Cardiovasc. Med., 9: 1003852. doi: 10.3389/fcvm.2022.1003852.
17. Navarro-Hernandez R.E., Oregon-Romero E., Vazquez-Del Mercado M. et al. (2009) Expression of ICAM1 and VCAM1 serum levels in rheumatoid arthritis clinical activity. Association with genetic polymorphisms. Dis. Markers, 26(3): 119–126.
18. Carter R.A., Campbell I.K., O’Donnel K.L., Wicks I.P. (2002) Vascular cell adhesion molecule-1 (VCAM-1) blockade in collagen-induced arthritis reduces joint involvement and alters B cell trafficking. Clin. Exp. Immunol., 128(1): 44–51.
19. Szekanecz Z., Koch A.E. (2000) Cell-cell interactions in synovitis. Endothelial cells and immune cell migration. Arthritis Res., 2(5): 368–373. doi: 10.1186/ar114.
20. Carter M.M., Birmingham T.B., Philpott H.T. et al. (2022) Angiogenesis and Endothelial Dysfunction: Synovial Vascular Pathology Is Associated with Surrogate Measures of Knee Load during Walking. Osteoarthritis and Cartilage, 30: S36–S37.
21. Kim J.W., Kong J.S., Lee S. et al. (2020) Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis. Exp. Mol. Med., 52(5): 8430853. doi: 10.1038/s12276-020-0443-8.
22. Guo D., Wang Q., Li C. et al. (2017) VEGF stimulated the angiogenesis by promoting the mitochondrial functions. Oncotarget., 8(44): 77020-7.
23. Sokolove J., Lepus C.M. (2013) Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther. Adv. Musculoskelet. Dis., 5(2): 77–94. doi: 10.1177/1759720X12467868.
24. Taylor P.C. (2002) VEGF and imaging of vessels in rheumatoid arthritis. Arthritis Res., 4 Suppl 3(Suppl. 3): S99–S107. doi: 10.1186/ar582.
25. Haraden C.A., Huebner J.L., Hsueh M.F. et al. (2019) Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation. Arthritis Res. Ther., 21(1): 146. doi: 10.1186/s13075-019-1923-x.
26. Leblond A., Pezet S., Trouvin A.P. et al. (2018) Linking systemic angiogenic markers to synovial vascularization in rheumatoid arthritis. PLoS One, 13(9): e0203607.
27. Thoenen J., MacKay J.W., Sandford H.J.C. et al. (2022) Imaging of Synovial Inflammation in Osteoarthritis, From the AJR Special Series on Inflammation. AJR Am. J. Roentgenol., 218(3): 405–417. doi: 10.2214/AJR.21.26170.
28. Vasanth L.C., Foo L.F., Potter H.G. et al. (2010) Using magnetic resonance angiography to measure abnormal synovial blood vessels in early inflammatory arthritis: a new imaging biomarker? J. Rheumatol., 37(6): 1129–1135.
29. Frenken M., Schleich C., Brinks R. et al. (2019) The value of the simplified RAMRIS-5 in early RA patients under methotrexate therapy using high-field MRI. Arthritis Res. Ther., 21(1): 21. doi: 10.1186/s13075-018-1789-3.
30. Fukae J., Tanimura K., Atsumi T., Koike T. (2014) Sonographic synovial vascularity of synovitis in rheumatoid arthritis. Rheumatology (Oxford), 53(4): 586–591.
31. Cupek R., Ziebinski A. (2016) Automated assessment of joint synovitis activity from medical ultrasound and power doppler examinations using image processing and machine learning methods. Reumatologia, 54(5): 239–242.
32. Gislason G.H. (2009) NSAIDs and cardiovascular risk. Am. Fam. Physician, 80(12): 1366.
33. Ikdahl E., Kerola A., Sollerud E., Semb A.G. (2024) Cardiovascular Implications of Non-steroidal Anti-inflammatory Drugs: A Comprehensive Review, with Emphasis on Patients with Rheumatoid Arthritis. Eur. Cardiol., 19: e27.
34. Baoqi Y., Dan M., Xingxing Z. et al. (2021) Effect of Anti-Rheumatic Drugs on Cardiovascular Disease Events in Rheumatoid Arthritis. Front. Cardiovasc. Med., 8: 812631. doi: 10.3389/fcvm.2021.812631.
35. Taubert K.A. (2008) Cardiology patient pages. Can patients with cardiovascular disease take nonsteroidal antiinflammatory drugs? Circulation, 117(17): e322–e324.
36. Pello Lazaro A.M., Blanco-Colio L.M., Franco Pelaez J.A., Tunon J. (2021) Anti-Inflammatory Drugs in Patients with Ischemic Heart Disease. J. Clin. Med., 10(13).
37. Smolen J.S., Landewe R.B.M., Bergstra S.A. et al. (2023) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann. Rheum. Dis., 82(1): 3–18.
38. Waksman R., Merdler I., Case B.C. et al. (2024) Targeting inflammation in atherosclerosis: overview, strategy and directions. EuroIntervention, 20(1): 32–44.
39. Kosmas C.E., Silverio D., Sourlas A. et al. (2019) Anti-inflammatory therapy for cardiovascular disease. Ann. Transl. Med., 7(7): 147. doi: 10.21037/atm.2019.02.34.
40. Agca R., Heslinga S.C., Rollefstad S. et al. (2017) EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann. Rheum. Dis., 76(1): 17–28. doi: 10.1136/annrheumdis-2016-209775.
41. Sun A.R., Panchal S.K., Friis T. et al. (2017) Obesity-associated metabolic syndrome spontaneously induces infiltration of pro-inflammatory macrophage in synovium and promotes osteoarthritis. PLoS One, 12(8): e0183693.
42. Hulander E., Barebring L., Turesson Wadell A. et al. (2021) Diet intervention improves cardiovascular profile in patients with rheumatoid arthritis: results from the randomized controlled cross-over trial ADIRA. Nutr J., 20(1): 9.
43. Dickson B.M., Roelofs A.J., Rochford J.J. et al. (2019) The burden of metabolic syndrome on osteoarthritic joints. Arthritis Res. Ther., 21(1): 289.
44. Zhang F., Wei K., Slowikowski K. et al. (2019) Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol., 20(7): 928–942.