RA is currently the most common autoimmune disease, and the risk of cardiovascular events in patients with RA has increased by 48% compared to that of the general population . After excluding traditional cardiovascular risk factors, such as diabetes, hyperlipidemia, hypertension, and obesity, this study found that the indicators of PWV were still higher in patients with RA than in subjects in the control group, indicating that the probability of arteriosclerosis was still higher in patients with RA than in healthy individuals after excluding traditional factors. This is related to the patient’s long-term, high-level, inflammatory accumulation and immune disorder reaction [5, 6]. In a severe chronic inflammatory state, the molecular structure of lipoprotein becomes smaller and more compact. This change induces the production of LDL-C and promotes arteriosclerosis, which reduces nitric oxide production and promotes reactive oxygen species production, leading to vascular endothelium damage . The initial process of arteriosclerosis pathogenesis is usually endothelial injury and dysfunction. This is characterized by decreased vasodilation function, increased adhesion of large numbers of inflammatory cells and platelets, and increased procoagulant activity. The results of this study showed that the CRP, ESR, PLT, and LDL-C levels were higher in patients with RA than in healthy people, and LDL-C was a risk factor for PWV-BS and PWV-ES. This result is consistent with the above-mentioned mechanism. Atherosclerosis in patients with RA is not only closely related to inflammatory factors but also involves platelets. There are a large number of platelets in synovial lesions of patients with RA in the active stage of the disease. This is because synovial cells produce large amounts of pro-inflammatory factors, such as interleukin (IL)-1, IL-2, and IL-6, and these factors promote the proliferation and maturation of macrophages and induce the production of platelets, expand and maintain the inflammatory response, and increase inflammatory damage to the body. Furthermore, thrombocytosis causes patients with RA to be in a hypercoagulable state, and this accelerates arteriosclerosis. This easily results in an increased risk of a series of cardiovascular events, such as rupture and bleeding of atherosclerotic plaques and formation of arterial thromboembolism.
Atherosclerosis in patients with RA is also closely associated with high levels of ESR, CRP, and other indicators. The main mechanism involves action on the adipose tissue, skeletal muscles, liver, vascular endothelium, and other tissues, which results in a series of complex changes, including oxidative stress, insulin resistance, lipid metabolism dysfunction, and endothelial dysfunction, ultimately leading to arteriosclerosis . Even if patients with RA do not have traditional risk factors for arteriosclerosis, they experience endothelial damage and functional changes , which may be associated with specific antibodies, such as RF and anti-CCP antibodies. The results of this study revealed that RF and anti-CCP antibody levels were higher in patients with RA than in healthy people, and the levels of RF and anti-CCP antibodies were higher in the moderate-to-severe activity group than in the mild activity group. Anti-CCP antibodies and RF are risk factors for PWV-BS and ES. This result is consistent with those of previous studies. RF tends to indicate clinical inflammatory activities. The higher the RF titer in patients with RA, the more active their inflammatory response. RF is an antibody against denatured immunoglobulin (Ig)G antigen (produced by bacteria, viruses, and other pathogens in the body), and generally present as IgM-RF. IgM-RF is regarded as the iconic autoantibody of clinical RA and it may interact with the fragment crystallizable fragments of Ig molecules, mainly IgM, IgD, IgE, IgA, and IgG5. Patients with RF-positive RA have a higher risk of cardiovascular events than patients with RF-negative RA. RF is closely associated with a vascular injury in patients with RA. RF can directly produce toxic effects on vascular endothelial cells, resulting in endothelial injury and dysfunction, which is considered to be a risk factor for CVD in patients with RA. A positive anti-CCP antibody is closely correlated with endothelial dysfunction, increased cIMT, and arteriosclerosis. The American College of Rheumatology suggests that combined examinations of RF and anti-CCP antibodies are the best method for diagnosing RA .
Hypertension, diabetes, hyperlipidemia, smoking, and obesity have been proven to be associated with the pathogenesis of central vascular events in the general population [10, 11]. The results of this study revealed that SBP, DBP, BMI, TC, and TG were positively correlated with PWV, and SDP was an influencing factor on PWV, which further confirms the correlation between RA and arteriosclerosis.
Related research has found that vitamin D promotes immunoregulatory activity, and this can inhibit the proliferation and differentiation of T cells, as well as the production of inflammatory cytokines and induction of the differentiation of regulatory T cells . Vitamin D deficiency can increase the risk of autoimmune diseases such as type I diabetes, RA, ankylosing spondylitis, systemic lupus erythematosus, autoimmune thyroid disease, multiple sclerosis, and inflammatory bowel disease [13-15]. The results of a meta-analysis suggested that vitamin D supplementation reduces the positive rate of anti-double-stranded deoxyribonucleic acid in systemic lupus erythematosus and may reduce the recurrence of RA . 25(OH)D3 directly binds to vitamin D receptors to participate in the physiological and pathological regulation of the cardiovascular system, especially in the regulation of endothelial cells and immune cells, which can lead to arteriosclerosis . The results of our study revealed that 25(OH)D3 was negatively correlated with the PWV value, and 25(OH)D3 was a protective factor for PWV-BS; this is consistent with the mechanism described above.
In this study, the Hb level was significantly lower in the RA group than that in the control group, and Hb concentration was a protective factor for PWV-BS and PWV-ES. The possible mechanism is that with the disease progression in patients with RA, macrophages and T cells produce and release large amounts of interferons and tumor destruction factors that aggravate joint injury and bone destruction, inhibit the compensation of bone marrow erythrocytes, block the production of erythropoietin, and ultimately result in anemia . This study revealed a negative correlation between Hb level and PWV value, suggesting that anemia may lead to disease deterioration in patients with RA and could affect their prognosis. Timely correction of anemia may alleviate this condition and delay the development of arteriosclerosis. This study showed that the course of the disease was positively correlated with PWV value and was a risk factor for PWV-BS, suggesting that long-term persistent chronic inflammation was a risk factor for arteriosclerosis. Therefore, patients with RA should be identified and treated as early as possible, as this can effectively prevent and treat the development and progression of arteriosclerosis.
This study showed that the PWV values and cIMT values in both the mild activity group and moderate-to-severe activity group of patients with RA were higher than those of patients in the control group, and the PWV value of those in the moderate-to-severe activity group was significantly higher than that of those in the mild activity group; however, there was no significant difference in the cIMT values between the two groups (P > 0.05), suggesting that arterial elastic function had changed in the mild activity group and the moderate-to-severe activity group. However, as a traditional marker for arteriosclerosis evaluation using ultrasonography, cIMT can rarely identify the difference in arteriosclerosis among patients with RA with different degrees of illness in early stages. cIMT is an important ultrasonic marker of arteriosclerosis and is associated with the degree of carotid artery stiffness [19, 20]. Therefore, detecting changes in arterial function before significant thickening of cIMT has occurred is essential for the prevention and treatment of the disease.
Changes in the arterial elastic function can be examined by different non-invasive modalities. UFPWV is an emerging technology for accurately measuring carotid PWV in recent years. Its most significant characteristics are non-invasiveness, real-time measurement, simple operation, and high accuracy . Because of its good stability and reliability in measuring vascular elasticity, it is considered to be the gold standard for evaluating the degree of arteriosclerosis . UFPWV detects the PWV value using ultrafast imaging technology, with a frame rate of up to 2000 frames/s, and can accurately display and record the movement process of the arterial wall within 2 s and acquires and records the micro-movement speed and direction of the arterial wall by using a tissue Doppler imaging algorithm. It can also automatically calculate the PWV of measured local blood vessels at the beginning and at the end of systole and can obtain the BS and ES values  so as to evaluate changes in arterial elasticity. A larger PWV indicates poorer compliance and represents poorer arterial elastic function . In contrast, traditional PWV measurement technologies, such as carotid-femoral PWV and brachial-ankle PWV, have larger errors in the measured PWV value owing to the complex detection technology and the influence of vascular tortuosity, among other reasons. We assessed the consistency of the findings of this study and found that UFPWV had high reproducibility and good stability; hence, it has great value in clinical application. Scholars from other countries have previously suggested that synovitis and arteriosclerosis in RA have similar immune mechanisms. Under the combined action of these complex factors, cardiovascular events have become the most common cause of death in patients with RA. Because these risk factors in the inflammatory environment change the structure and function of the arterial wall, the assessment of carotid PWV using UFPWV technology can be applied as an independent predictor of future CVD [24-26].
This study has some limitations. The comparison of PWV values among patients with RA of different ages and sexes in this study showed that the PWV values in males were significantly higher than those in females (P < 0.05), and this might be associated with the differences in hormone levels between males and females at different life stages. In this study, we did not analyze the hormone levels in patients of different ages and sexes or their possible effects on PWV. However, we plan to broaden the scope of our research in subsequent studies.
In conclusion, patients with RA should receive calcium supplements, their Hb levels should also be assessed regularly, and anemia should be corrected promptly. This cannot only avoid severe osteoporosis and bone destruction but will also protect their vascular endothelium and delay arteriosclerosis. Traditional risk factors such as hypertension and hyperlipidemia; inflammatory indexes such as ESR, CRP, PLT, and LDL-C; and specific antibody RF (anti-CCP antibody) not only affect the severity of the disease but also cause irreversible damage to blood vessels and increase the risk of cardiovascular events in patients with RA. Therefore, the clinical treatment of patients with RA should involve paying close attention to these related indicators. With disease progression in patients with RA, PWV-BS and PWV-ES values also gradually increase, and arterial elasticity gradually decreases. UFPWV can provide a powerful reference base for the prevention and treatment of early-stage arteriosclerosis in patients with RA and thus should be widely promoted and applied in clinical practice.