The association between serum salusin-α and salusin-β levels with subclinical atherosclerosis in rheumatoid arthritis

The association between serum salusin-α and salusin-β levels with subclinical atherosclerosis in rheumatoid arthritis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The association between serum salusin-α and salusin-β levels with subclinical atherosclerosis in rheumatoid arthritis Hamidreza Talari, Roozbeh Esalatmanesh, Kamal Esalatmanesh, Seyed-Vahid Zabihi Hoseini, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7586337/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Cardiovascular disease (CVD) is the leading cause of mortality in rheumatoid arthritis (RA). This study aims to assess the association between serum salusin-α and salusin-β levels with carotid intima media thickness (CIMT) in RA patients. In this cross-sectional study, cases from a prospective cohort of RA were consecutively enrolled. Subclinical atherosclerosis was defined as CIMT > 0.9 mm. The study included 116 RA patients without history of CVD. The median (IQR) serum salusin-α and salusin-β levels were 887 (697, 2165) and 50 (43, 87) pg/ml, respectively. The mean ± SD of CIMT was 0.60 ± 0.25 pg/ml. In 19 (16.4%) patients, CIMT was > 0.9. A significant correlation was observed between serum salusin-β levels with CIMT (r = 0.536, P = 0.001). However, there was no significant correlation between serum salusin-α levels CIMT (r=-0.064, P = 0.485). we constructed three linear regression models to examine the independent effect of serum salusin-β on CIMT. serum salusin-β was significantly associated with higher CIMT (β = 0.003, 95% CI: 0.002–0.003, P-value = 0.001). the R2 value for the CIMT was 0.467. Finaly, ROC curves were plotted. The cut-off values of salusin-α and salusin-𝛽 for detecting high CIMT were 784.40 and 66.75 pg/ml with sensitivities of 52.6% and 75% and specificities of 32% and 78.1%, respectively. In the present study, we found a correlation between serum salusin-β and CIMT in RA patients and demonstrated the possible potential role of this peptide as a biomarker in RA patients. However, further research involving larger numbers of subjects and prospective multicenter studies is needed to explain and clarify this observation. Health sciences/Biomarkers Health sciences/Diseases Biological sciences/Immunology Health sciences/Medical research Health sciences/Rheumatology rheumatoid arthritis salusin-α salusin-β subclinical atherosclerosis Figures Figure 1 Figure 2 Introduction Rheumatoid arthritis (RA) is a chronic, inflammatory systemic rheumatic disease that causes chronic synovitis and erosive polyarthritis. In addition to causing destructive changes in the joints and disability, RA increases mortality by 45–60% in affected individuals, with cardiovascular disease (CVD) being one of the leading causes. 1 – 3 The risk of CVD in RA patients is 1.5 times higher than in the general population. 4 Atherosclerotic plaque formation is the main mechanism in the development of CVD in patients suffering from RA. 4 Although classic CVD risk factors, including diabetes, dyslipidemia, smoking, and hypertension (HTN), are more common in RA patients, they contribute for only 50% of the increased CVD risk in these patients. 4 Systemic inflammation, by causing endothelial dysfunction and increased oxidative stress, is responsible for another 50% of the increased risk of atherosclerosis in these patients. 4 Screening for CVD in patients with RA is recommended in all existing guidelines, and RA is considered an independent CVD risk factor. 4 , 5 However, screening is generally poorly implemented in daily clinical practice. In recent years, numerous biomarkers have been proposed for CVD screening in general population, salusins being one of them. 6 Salusins ​​are endogenous bioactive peptides with hemodynamic and mitogenic activities that consist of two related peptides as salusin-α and salusin-β with 28 and 20 amino acids, respectively. 6 These vasoactive peptides are mainly secreted by vascular smooth muscle cells and endothelial cells and are present in human plasma and urine, and even in atherosclerotic plaques of coronary arteries. 6 It has also been suggested that salusins may play an important role in regulating the immune system function and inflammation, as their increased serum levels have been reported in inflammatory diseases such as RA 7,8 , Behçet's disease (BD) 9 , systemic lupus erythematosus (SLE) 10 , ankylosing spondylitis (AS) 11 and psoriatic arthritis 12 . However, there are very few studies on the serum salusin-α and salusin-β levels in RA patients and its use as a biomarker in the diagnosis of subclinical atherosclerosis. This study aims to assess the association between serum salusin-α and salusin-β levels with carotid intima media thickness (CIMT) in RA patients. Methods In this cross-sectional study, cases from a prospective cohort of RA were consecutively enrolled. Inclusion criteria were meeting the ACR/EULAR 2010 RA classification criteria and age ≥ 18 years. The exclusion criteria were symptomatic CVD (coronary artery disease, stroke and peripheral artery disease), chronic kidney disease, liver disease, pregnancy, malignancy and active infection. The study has been conducted in accordance with the Declaration of Helsinki ethical standards and local ethics committee approved the protocol of study. Written informed consents were obtained from all participants. Demographic, clinical, and laboratory information of the participants was recorded from their records. Participants' height and weight were measured, and body mass index (BMI) was calculated by dividing body weight by the square of height (kilograms per square meter). Disease activity status was determined by calculating the disease activity score-28 with erythrocyte sedimentation rate (DAS-28-ESR). Dyslipidemia was defined as high density lipoprotein 120 mg/dL, triglyceride > 200 mg/dL or treatment with lipid lowering medications. 13 Classic coronary risk factors were defined as HTN, dyslipidemia, diabetes, obesity and smoking. CIMT measurement was performed via B-mode examination using the Samsung UGEO WS80A high-level color Doppler ultrasonography device (Samsung Medison Co., Ltd., Seoul, South Korea) and a linear probe (L3-12A) with a high-resolution central frequency of 7.5 MHz (range 3–12 MHz). Measurements were performed in all participants by a radiologist in the supine position in a quiet and dark room. The probe was placed 1 cm proximal to the common carotid artery bifurcation. CIMT was defined as the distance between the intimal lumen and the media-adventitia interface on the posterior wall in a 5–10 mm plaque-free area, at least 1 cm from the bifurcation CIMT measurements were performed in the right and left carotid arteries, and their average was used in the analysis. Subclinical atherosclerosis was defined as CIMT > 0.9 mm. 14 Fasting blood samples were collected from the subjects after 12 hours’ overnight fasting. Serum levels of salusin-α and salusin-ß were measured using a human salusin-α and salusin-ß enzyme-linked immunosorbent assay (ELISA) kit (ZellBio GmbH, Ulm, Germany). Sensitivity for salusin-α and salusin-β was 9 pg/mL (assay range: 75-2400 pg/mL) and 0.3 pg/mL (assay range: 4-128 pg/mL), respectively. Statistical analysis Statistical analysis was performed using SPSS software version 25.0 (SPSS, Inc., USA). Normally and non-normally distributed continuous variables were reported as mean ± standard deviation (SD) and median (25–75% interquartile range (IQR)), respectively. Statistical differences among the groups were identified with Mann-Whitney u test. Pearson correlation analysis was used to assess correlations between serum salusin-α and salusin-β with CIMT. Furthermore, a multiple linear regression analysis was performed to determine independent predictors of the CIMT levels with including CIMT as dependent variable, serum salusin-β as independent variable and age, sex, BMI, classic coronary risk factor, DAS-28, disease duration and treatment with prednisolone as confounding factors. A receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cut-off points of serum salusins levels for predicting abnormal CIMT. The area under the curve (AUC) value was calculated to determine the accuracy of the test. P-values less than 0.05 were considered as statistically significant. Results The study included 116 RA patients without history of CVD. Demographic, clinical and laboratory characteristics of participants has been shown in Table 1 . The median (IQR) serum salusin-α and salusin-β levels were 887 (697, 2165) and 50 (43, 87) pg/ml, respectively. The mean ± SD of CIMT was 0.60 ± 0.25 pg/ml. In 19 (16.4%) patients, CIMT was > 0.9 and carotid plaque was detected in 8 (6.9%) patients. Table 1 Demographics and clinical characteristics of the participants Follow-up duration (months), median (IQR) 87 (36, 151) Female (%) 102 (87.9) Age (years), mean ± SD 51.4 ± 13.1 BMI (kg/m 2 ), mean ± SD 27.4 ± 5.4 Classic coronary risk factors (%) 76 (65.5) Smoking (%) 5 (4.3) Diabetes (%) 4 (3.4) Hypertension (%) 4 (3.4) Dyslipidemia (%) 56 (48.3) TG (mg/dL), mean ± SD 187.2 ± 48.9 LDL (mg/dL), mean ± SD 106.1 ± 26.5 HDL (mg/dL), mean ± SD 47.9 ± 8.7 DAS-28, mean ± SD 3.8 ± 1.9 Extra-articular involvement (%) 22 (19.0) RF (%) 83 (71.6) ACPA (%) 88 (75.9) Medications Prednisolone (%) 77 (66.4) Hydroxychloroquine (%) 99 (85.3) Methotrexate (%) 108 (93.1) Sulfasalazine (%) 44 (37.9) Leflunomide (%) 22 (19.0) Azathioprine (%) 10 (8.6) TNF inhibitors (%) 29 (25.0) Rituximab (%) 1 (0.9) Jack inhibitor (%) 8 (6.9) Number of DMARDs, median (IQR) 2 (1, 3) Serum salusin-α (pg/ml), median (IQR) 887 (697, 2165) Serum salusin-β (pg/ml), median (IQR) 50 (43, 87) CIMT, mean ± SD 0.60 ± 0.25 High CIMT (%) 19 (16.4) Carotid plaque (%) 8 (6.9) SD, standard deviation; IQR, interquartile range; BMI, body mass index; TG, triglyceride; dL, deciliter; LDL, low density lipoprotein; HDL, high density lipoprotein; DAS-28, disease activity score-28; RF, rheumatoid factor; ACPA, anti-citrullinated protein antibodies; DMARDs, disease-modifying antirheumatic drugs; CIMT, carotid intima-media thickness We assessed Pearson correlations between serum salusin-α and salusin-β levels with continuous variables including age, BMI, DAS-28 and CIMT. A significant correlation was observed between serum salusin-β levels with DAS-28 (r = 0.265, P = 0.004) and CIMT (r = 0.536, P = 0.001) (Fig. 1 ). However, there was no significant correlation between serum salusin-α levels with age (r= -0.122, P = 0.193), BMI (r=-0.041, P = 0.663), DAS-28 (r=-0.044, P = 0.622) and CIMT (r=-0.064, P = 0.485), respectively. In addition, there was no significant correlation between serum salusin-β levels with age (r=-0.010, P = 0.919) and BMI (r = 0.002, P = 0.081). In addition, we assessed the association between serum salusin-α and salusin-β levels with categorical variables including classic coronary risk factors, treatment with prednisolone, extra-articular involvement, high CIMT and having coronary plaque (Table 2 ). In patients with high CIMT serum salusin-β was significantly higher (Table 2 ). Table 2 Serum salusin levels in RA patients with various demographic and clinical characteristics Parameters Salusin-α, median (IQR) P-value Salusin-β, median (IQR) P-value Yes No Yes No Females 887 (698, 2268) 891 (603, 1063) 0.351 51 (43, 96) 50 (43, 70) 0.993 Classic coronary risk factors 887 (752, 2195) 873 (580, 2193) 0.482 51 (44, 78) 49 (42, 96) 0.695 Treatment with prednisolone 904 (759, 2241) 843 (656, 975) 0.129 53 (44, 96) 48 (42, 78) 0.244 Extra-articular involvement 895 (715, 1504) 884 (697, 2227) 0.961 54 (45, 142) 50 (43, 68) 0.242 High CIMT 831 (730, 2123) 889 (696, 2165) 0.764 144 (58, 169) 48 (42, 59) 0.001 Coronary plaque 784 (754, 1423) 888 (697, 1407) 0.942 145 (114, 149) 50 (43, 70) 0.073 RA: rheumatoid arthritis; IQR, interquartile range; CIMT, carotid intima media thickness Then, we constructed three linear regression models to examine the independent effect of serum salusin-β on CIMT (Table 3 ). Key assumptions of linear regression were evaluated, including normality of residuals (Shapiro-Wilk test), independence of residuals (Durbin-Watson test), homoscedasticity (residuals vs. predicted values plot), and multicollinearity (variance inflation factor, VIF). All models showed that serum salusin-β levels can predict CIMT (Table 3 ). The results of model 3 showed that serum salusin-β was significantly associated with higher CIMT (β = 0.003, 95% CI: 0.002–0.003, P-value = 0.001). However, the R2 value for the CIMT was 0.467. This result indicated that serum salusin- β level could explain 46.7% of the variance in the CIMT. In addition, longer disease duration and male sex were also associated with higher CIMT (Table 3 ). Finally, we constructed a linear regression model with three independent predictors of CIMT including serum salusin-β, male gender, and disease duration, and obtained the following formula for predicting CIMT. Table 3 Multiple linear regression of association of salusin- β with CIMT in RA patients. Model 1 Model 2 Model 3 Model R 2 R 2 = 0.281 R 2 = 0.436 R 2 = 0.467 Beta (95% CI) P-value Beta (95% CI) P-value Beta (95% CI) P-value Salusin-β 0.002 (0.002–0.003) 0.001 0.002 (0.002–0.003) 0.001 0.003 (0.002–0.003) 0.001 Age, years 0.000 (-0.003-0.003) 0.897 -0.001 (-0.004-0.001) 0.325 Male sex 0.316 (0.208–0.424) 0.001 0.344 (0.234–0.454) 0.001 BMI 0.003 (-0.004-0.001) 0.439 Classic coronary risk factor -0.028 (-0.099-0.043) 0.429 DAS-28 -0.019 (-0.042-0.003) 0.092 Disease duration, months 0.001 (0.000-0.001) 0.012 Treatment with prednisolone -0.086 (-0.175-0.003) 0.058 Model 1: no covariates were adjusted. Model 2: age and sex were adjusted. Model 3: age, sex, BMI, having classic coronary risk factor, DAS-28, disease duration and being under treatment with prednisolone were adjusted. CIMT, carotid intima media thickness; RA, rheumatoid arthritis; CI, confidence interval; BMI: body mass index; DAS-28, disease activity score-28 CIMT (mm) = 0.99 + 0.000406×disease duration (months) + 0.002×salusin-β (pg/ml) – 0.33×sex Male = 1, Female = 2 Finaly, ROC curves were plotted. The cut-off values of salusin-α and salusin-𝛽 for detecting high CIMT were 784.40 and 66.75 pg/ml with sensitivities of 52.6% and 75% and specificities of 32% and 78.1%, respectively (Fig. 2 ). Discussion Salusins are multifunctional peptides that regulate hemodynamics and atherogenesis. 15 Salusin-α has anti-atherogenic effects and its expression is reduced in patients with hypertension and diabetes, while salusin-β has a pro-atherogenic role. 15 It has been shown that macrophage foam cell formation is inhibited by salusin-α and promoted by salusin-β. 16 In addition, there are some reports that continuous infusion of salusin-β aggravates atherosclerotic lesions and chronic infusion of salusin-α alleviates atherosclerotic lesions in apolipoprotein E and LDL receptor deficient mice. 17 , 18 Salusin-β accelerates atherogenesis through several mechanisms, including 1) endothelial dysfunction and oxidative stress by increasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species production, 2) promoting vascular smooth muscle cell (VSMC) proliferation and migration through activation of c-Myc and Fos genes, 3) macrophage foam cell formation by upregulating acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) and stimulating macrophages to take up oxidized LDL, 4) inducing of inflammatory cytokines formation, such as interleukin (IL)-1β, IL-6 and tumor necrosis factor alpha (TNF-α) which perpetuate vascular inflammation. 19 – 23 In contrast, salusin- α inhibits the expression of ACAT-1 and does not have proinflammatory effects. 16 This study showed that higher serum salusin-β level along with male gender and longer disease duration were predictive of higher CIMT in RA patients, but salusin-α was not. Although salusin-α and salusin-β have been proposed as potential biomarkers for predicting atherosclerosis, salusin-β appears to be a better indicator. 24 Wang et al. reported a positive association between salusin-α and salusin-β levels with coronary artery stenosis in a study of 256 patients undergoing coronary angiography for chest pain, however, salusin-β was a better predictor compared to salusin-α. 24 In a study by Ozgen et al. salusin-α level was not associated with the CIMT in RA and BD patients. 8 In another study, salusin-α levels were not associated with CIMT in SLE and systemic sclerosis patients. 25 In a study on AS patients, there was no relationship between Sal-α, Sal-β levels and CIMT. 26 This study showed a moderately strong correlation between serum salusin-β levels and CIMT (r = 0.623) and serum salusin-β levels were predictive of subclinical atherosclerosis, independent of age, sex, and classical coronary risk factors. Furthermore, we found that serum salusin-β levels > 66.75 pg/ml had a sensitivity of 75% and a specificity of 88.1% for the detection of subclinical atherosclerosis. All these findings suggest that although salusin-β is a relatively strong predictor of CIMT, it is not sufficient for use as a single biomarker for the diagnosis of subclinical atherosclerosis. Although this study is, to our knowledge, the first to evaluate the correlation between salusins and CIMT in RA patients, there are also limitations. Our sample size was relatively small and the study was cross-sectional. A longitudinal study with long-term follow-up and examination of the incidence of symptomatic atherosclerosis could better evaluate the potential of salusin-β in predicting atherosclerosis. Conclusion In the present study, we found a correlation between serum salusin- β and CIMT in RA patients and demonstrated the possible potential role of this peptide as a biomarker in RA patients. However, further research involving larger numbers of subjects and prospective multicenter studies is needed to explain and clarify this observation. Declarations Funding Information This research was supported by the Kashan University of Medical Sciences (awarded to A.T.; Grant KUOMS‐1401.2). Conflicts of interest We declare, we have no potential conflict of interest. We declare that no part of the review is copied or published elsewhere. Acknowledgments We would like to thank Kashan University of Medical Sciences for funding this study. Ethics Statement The study has been conducted in accordance with the Declaration of Helsinki ethical standards (Ethics code: IR.KAUMS.MEDNT.REC.1403.171) and local ethics committee approved the protocol of study Contributions Conceptualization and designing the study: H.T., K.E. Data acquisition: R.E., SV.ZH, MJ.A Data analysis: A.K. Drafting the manuscript: R.E., A.K. Supervision: H.T., A.K. Data Availability Statements Data available on request. The data underlying this article will be shared on reasonable request to the corresponding author. References Aviña-Zubieta, J.A., Choi, H.K., Sadatsafavi, M., Etminan, M., Esdaile, J.M. & Lacaille, D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 59, 1690–1697. https://doi.org/10.1002/art.24092 (2008). Meune, C., Touzé, E., Trinquart, L. & Allanore, Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 48, 1309–1313. https://doi.org/10.1093/rheumatology/kep252 (2009). Sparks, J.A., Chang, S.C., Liao, K.P., Lu, B., Fine, A.R., Solomon, D.H., Costenbader, K.H., Karlson, E.W. Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: results from the Nurses’ Health Study. Arthritis Care Res. (Hoboken). 68, 753–762. https://doi.org/10.1002/acr.22752 (2016). Dijkshoorn, B., Raadsen, R. & Nurmohamed, M.T. Cardiovascular disease risk in rheumatoid arthritis anno 2022. J. Clin. Med. 11, 2704. https://doi.org/10.3390/jcm11102704 (2022). Agca, R., Heslinga, S.C., Rollefstad, S., Heslinga, M., McInnes, I.B., Peters, M.J., et al. 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, 17–28. https://doi.org/10.1136/annrheumdis-2016-209775 (2017). van Breukelen-van der Stoep, D.F., van Zeben, D., Klop, B., van de Geijn, G.J.M., Janssen, H.J., van der Meulen, N.V., et al. Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis. Rheumatology (Oxford). 55, 1210–1216. https://doi.org/10.1093/rheumatology/kew039 (2016). Niepolski, L. & Grzegorzewska, A.E. Salusins and adropin: new peptides potentially involved in lipid metabolism and atherosclerosis. Adv. Med. Sci. 61, 282–287 (2016). Ozgen, M., Koca, S.S., Dagli, N., Balin, M., Ustundag, B. & Isik, A. Serum salusin-α level in rheumatoid arthritis. Regul. Pept. 167, 125–128. https://doi.org/10.1016/j.regpep.2010.12.003 (2011). Erden, I., Demir, B., Uçak, H., Cicek, D., Bakar Dertlioğlu, S. & Aydin, S. Serum salusin-α and salusin-β levels in patients with Behcet’s disease. Eur. J. Dermatol. 24, 577–582. https://doi.org/10.1684/ejd.2014.2397 (2014). Hajialilo, M., Jorjani, R., Rahimi, M., Ghorbanihaghjo, A., Malek Mahdavi, A., Ghojazadeh, M. & Khabbazi, A. Serum salusin-β levels in patients with systemic lupus erythematosus. Clin. Rheumatol. 42, 2097–2103. https://doi.org/10.1007/s10067-023-06610-y (2023). Tocoglu, A.G. et al. The relationship between salusin-α, salusin-β, and Klotho levels with subclinical atherosclerosis in ankylosing spondylitis. Eur. Rev. Med. Pharmacol. Sci. 27, 9838–9845. https://doi.org/10.26355/eurrev_202310_34160 (2023). Kobak, S., Atabay, T., Akyildiz, M., Gokduman, A. & Vural, H. Serum salusin-α and salusin-β levels in patients with psoriatic arthritis. Reumatologia. 60, 306–310. https://doi.org/10.5114/reum.2022.120753 (2022). Rhee, E.J. et al. 2018 guidelines for the management of dyslipidemia. Korean J. Intern. Med. 34, 723–771. https://doi.org/10.3904/kjim.2019.188 (2019). Visseren, F.L.J., Mach, F., Smulders, Y.M., Carballo, D., Koskinas, K.C., et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur. Heart J. 42, 3227–3337. https://doi.org/10.1093/eurheartj/ehab484 (2021). Watanabe, T. et al. The roles of salusins in atherosclerosis and related cardiovascular diseases. J. Am. Soc. Hypertens. 5, 359–365. https://doi.org/10.1016/j.jash.2011.06.003 (2011). Watanabe, T. et al. Impact of salusin-α and -β on human macrophage foam cell formation and coronary atherosclerosis. Circulation. 117, 638–648. https://doi.org/10.1161/CIRCULATIONAHA.107.712539 (2008). Nagashima, M. et al. Salusin-β promotes atherosclerosis. Atherosclerosis. 212, 70–77. https://doi.org/10.1016/j.atherosclerosis.2010.04.027 (2010). Zhou, C.H., Liu, L.L., Wu, Y.Q., Song, Z. & Xing, S.H. Enhanced expression of salusin-β contributes to progression of atherosclerosis in LDL receptor deficient mice. Can. J. Physiol. Pharmacol. 90, 463–471. https://doi.org/10.1139/y2012-022 (2012). Watanabe, T. et al. The roles of salusins in atherosclerosis and related cardiovascular diseases. J. Am. Soc. Hypertens. 5, 359–365. https://doi.org/10.1016/j.jash.2011.06.003 (2011). Wu, L.L. et al. Salusin-β in intermediate dorsal motor nucleus of the vagus regulates sympathetic–parasympathetic balance and blood pressure. Biomedicines. 9, 1118. https://doi.org/10.3390/biomedicines9091118 (2021). Zhu, X., Zhou, Y., Cai, W., Sun, H. & Qiu, L. Salusin-β mediates high glucose-induced endothelial injury via disruption of AMPK signaling pathway. Biochem. Biophys. Res. Commun. 491, 515–521. https://doi.org/10.1016/j.bbrc.2017.06.126 (2017). Fujimoto, K. et al. Circulating levels of human salusin-β, a potent hemodynamic and atherogenesis regulator. PLoS One. 8, e76714. https://doi.org/10.1371/journal.pone.0076714 (2013). Zhao, M.X., Zhou, B., Ling, L., Xiong, X.Q., Zhang, F., Chen, Q., et al. Salusin-β contributes to oxidative stress and inflammation in diabetic cardiomyopathy. Cell Death Dis. 8, e2690. https://doi.org/10.1038/cddis.2017.106 (2017). Wang, Y., Wang, S., Zhang, J., Zhang, M., Zhang, H., Gonget, G., et al. Salusin-β is superior to salusin-α as a marker for evaluating coronary atherosclerosis. J. Int. Med. Res. 48, 30006052090386. https://doi.org/10.1177/0300060520903868 (2020). Koca, S.S., Özgen, M., Işık, B., Dağlı, M.N., Üstündağ, B. & Işık, A. Serum salusin-α levels in systemic lupus erythematosus and systemic sclerosis. Eur. J. Rheumatol. 1, 14–17. https://doi.org/10.5152/eurjrheum.2014.004 (2014). Tocoglu, A.G., Dogan, B., Tuzun, S., Akcay, E.U., Altas, A.E., Ayhan, L.T., et al. The relationship between salusin-α, salusin-β, and Klotho levels with subclinical atherosclerosis in ankylosing spondylitis. Eur. Rev. Med. Pharmacol. Sci. 27, 9838–9845. https://doi.org/10.26355/eurrev_202310_34160 (2023). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7586337","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":526298953,"identity":"d0593c9f-133a-4ba2-8fad-b8d47c55f7e7","order_by":0,"name":"Hamidreza Talari","email":"","orcid":"","institution":"Kashan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Hamidreza","middleName":"","lastName":"Talari","suffix":""},{"id":526298955,"identity":"fcaa67e5-1576-40c0-94df-1aa28c79d0ca","order_by":1,"name":"Roozbeh Esalatmanesh","email":"","orcid":"","institution":"Kashan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Roozbeh","middleName":"","lastName":"Esalatmanesh","suffix":""},{"id":526298958,"identity":"6c3cdaf7-f706-4b4c-aa36-ae6ebe059241","order_by":2,"name":"Kamal Esalatmanesh","email":"","orcid":"","institution":"Kashan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Kamal","middleName":"","lastName":"Esalatmanesh","suffix":""},{"id":526298961,"identity":"ddbb6829-b380-40ce-9e56-ca73e56179b7","order_by":3,"name":"Seyed-Vahid Zabihi Hoseini","email":"","orcid":"","institution":"Kashan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Seyed-Vahid","middleName":"Zabihi","lastName":"Hoseini","suffix":""},{"id":526298962,"identity":"ae36ffbd-a7b5-49cb-97b0-ba7a79191679","order_by":4,"name":"Mohammad Javad Azadchehr","email":"","orcid":"","institution":"Kashan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Javad","lastName":"Azadchehr","suffix":""},{"id":526298964,"identity":"c64b07be-d62b-4314-b022-797ab5858c27","order_by":5,"name":"Alireza Khabbazi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYDCCAwzMzCASSAEJBgkZUrSwJYC08JCghYHHAMQnrIXv9gFm44KaO/Ly7TyfX92oseBhYD98dAM+LZLnEpiTZxx7ZtjYzLvNOucY0GE8aWk38GkxOMPAfJiH7TBjMzPvNuMcNqAWCR4zIrT8O2zfxszzzDjnH5FaknnbDif2MPMwP85tI0KL5BnGZmPevmfJM5jZzJhz+yR42Aj5he8M82Fpnm93bOf3H378OedbnRw/++FjeLUwMDA2wFhsEmASv3JUwPyBFNWjYBSMglEwcgAAdgFDjLlj0ToAAAAASUVORK5CYII=","orcid":"","institution":"Tabriz University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Alireza","middleName":"","lastName":"Khabbazi","suffix":""}],"badges":[],"createdAt":"2025-09-10 23:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7586337/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7586337/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93243372,"identity":"f21850ab-2045-441e-9dfa-ec1121c0b5e0","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"jpg","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":528849,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/e688818edb090bbd4f915eb4.jpg"},{"id":93243371,"identity":"82abdede-c923-4262-86b1-582ee8f460e6","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43942,"visible":true,"origin":"","legend":"","description":"","filename":"Paper.docx","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/b0514d2931730312146ee94b.docx"},{"id":93246550,"identity":"0bc3d827-984e-4262-8bef-8a076246594e","added_by":"auto","created_at":"2025-10-10 15:14:31","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":328601,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/a876e30b9b87c8c8ca605656.jpg"},{"id":93247013,"identity":"cdcb9b7e-ac79-4cb0-8a3d-efddd69d04b6","added_by":"auto","created_at":"2025-10-10 15:22:31","extension":"json","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7645,"visible":true,"origin":"","legend":"","description":"","filename":"96044ab6407c402bbfa9544f181e384e.json","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/6c9f27542397a5989e8af1b6.json"},{"id":93243375,"identity":"aeae8b16-b471-4684-9040-e99240cfccb6","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":83167,"visible":true,"origin":"","legend":"","description":"","filename":"96044ab6407c402bbfa9544f181e384e1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/73b69071c081f6e04f6e3966.xml"},{"id":93246549,"identity":"903a31cf-c8b5-4116-8b71-5cd73ae8fbda","added_by":"auto","created_at":"2025-10-10 15:14:31","extension":"jpg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":528849,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/caeeb960d7b18a45414f5a7e.jpg"},{"id":93244366,"identity":"ccd5190a-eb35-4d79-812c-2fe335ff9253","added_by":"auto","created_at":"2025-10-10 15:06:31","extension":"jpg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":328601,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/0fbd728390ab58c0f66ce3fe.jpg"},{"id":93243374,"identity":"dad9937f-0c07-4ee6-b7ce-827fb6c3a0ef","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":115811,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/b597c4f0fdb2c2b25582c117.png"},{"id":93243383,"identity":"0f2c822c-d887-4ba1-9020-b0a94663b7c7","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":74047,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/0580d51b5887edfdf19ef510.png"},{"id":93244364,"identity":"bfad8d65-1742-4af4-9295-45ba1b7eeed5","added_by":"auto","created_at":"2025-10-10 15:06:31","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":81991,"visible":true,"origin":"","legend":"","description":"","filename":"96044ab6407c402bbfa9544f181e384e1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/e41aad38b469e4bdb634ecb1.xml"},{"id":93243382,"identity":"630f32a3-fb25-4e78-9a1f-e7bf0e644552","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":92808,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/55b795e7fb51466a7af14a86.html"},{"id":93243373,"identity":"2f5fad33-8bba-4dee-a50f-3df9439c5d45","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":528849,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between serum salusin salusin-α (1A) and salusin-β (1B) levels and CIMT in RA patients\u003c/p\u003e\n\u003cp\u003eCIMT, carotid intima media thickness; RA, rheumatoid arthritis\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/1f9d849dc7d61508f2a9f286.jpg"},{"id":93243377,"identity":"c43ffa92-7f92-43c8-98ec-8c523afb4aac","added_by":"auto","created_at":"2025-10-10 14:58:31","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":328601,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve analysis of sensitivity and specifity of salusin-α and salusin-β for diagnosis of subclinical atherosclerosis in RA\u003c/p\u003e\n\u003cp\u003eRA, rheumatoid arthritis\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/c008aeb54a58536082818dd3.jpg"},{"id":98774578,"identity":"fe180457-b743-4a06-a000-d233c84983a8","added_by":"auto","created_at":"2025-12-22 12:01:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1645673,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7586337/v1/8455d570-1735-485d-9a17-d3e50ec89bef.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The association between serum salusin-α and salusin-β levels with subclinical atherosclerosis in rheumatoid arthritis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic, inflammatory systemic rheumatic disease that causes chronic synovitis and erosive polyarthritis. In addition to causing destructive changes in the joints and disability, RA increases mortality by 45\u0026ndash;60% in affected individuals, with cardiovascular disease (CVD) being one of the leading causes.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e The risk of CVD in RA patients is 1.5 times higher than in the general population.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Atherosclerotic plaque formation is the main mechanism in the development of CVD in patients suffering from RA.\u003csup\u003e4\u003c/sup\u003e Although classic CVD risk factors, including diabetes, dyslipidemia, smoking, and hypertension (HTN), are more common in RA patients, they contribute for only 50% of the increased CVD risk in these patients.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Systemic inflammation, by causing endothelial dysfunction and increased oxidative stress, is responsible for another 50% of the increased risk of atherosclerosis in these patients.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eScreening for CVD in patients with RA is recommended in all existing guidelines, and RA is considered an independent CVD risk factor.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e However, screening is generally poorly implemented in daily clinical practice. In recent years, numerous biomarkers have been proposed for CVD screening in general population, salusins being one of them.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Salusins ​​are endogenous bioactive peptides with hemodynamic and mitogenic activities that consist of two related peptides as salusin-α and salusin-β with 28 and 20 amino acids, respectively.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e These vasoactive peptides are mainly secreted by vascular smooth muscle cells and endothelial cells and are present in human plasma and urine, and even in atherosclerotic plaques of coronary arteries.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e It has also been suggested that salusins may play an important role in regulating the immune system function and inflammation, as their increased serum levels have been reported in inflammatory diseases such as RA\u003csup\u003e7,8\u003c/sup\u003e, Beh\u0026ccedil;et's disease (BD)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, systemic lupus erythematosus (SLE)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, ankylosing spondylitis (AS)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e and psoriatic arthritis\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, there are very few studies on the serum salusin-α and salusin-β levels in RA patients and its use as a biomarker in the diagnosis of subclinical atherosclerosis. This study aims to assess the association between serum salusin-α and salusin-β levels with carotid intima media thickness (CIMT) in RA patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eIn this cross-sectional study, cases from a prospective cohort of RA were consecutively enrolled. Inclusion criteria were meeting the ACR/EULAR 2010 RA classification criteria and age\u0026thinsp;\u0026ge;\u0026thinsp;18 years. The exclusion criteria were symptomatic CVD (coronary artery disease, stroke and peripheral artery disease), chronic kidney disease, liver disease, pregnancy, malignancy and active infection. The study has been conducted in accordance with the Declaration of Helsinki ethical standards and local ethics committee approved the protocol of study. Written informed consents were obtained from all participants.\u003c/p\u003e\u003cp\u003eDemographic, clinical, and laboratory information of the participants was recorded from their records. Participants' height and weight were measured, and body mass index (BMI) was calculated by dividing body weight by the square of height (kilograms per square meter). Disease activity status was determined by calculating the disease activity score-28 with erythrocyte sedimentation rate (DAS-28-ESR).\u003c/p\u003e\u003cp\u003eDyslipidemia was defined as high density lipoprotein\u0026thinsp;\u0026lt;\u0026thinsp;40 mg/dL, low density lipoprotein (LDL)\u0026thinsp;\u0026gt;\u0026thinsp;120 mg/dL, triglyceride\u0026thinsp;\u0026gt;\u0026thinsp;200 mg/dL or treatment with lipid lowering medications.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Classic coronary risk factors were defined as HTN, dyslipidemia, diabetes, obesity and smoking.\u003c/p\u003e\u003cp\u003eCIMT measurement was performed via B-mode examination using the Samsung UGEO WS80A high-level color Doppler ultrasonography device (Samsung Medison Co., Ltd., Seoul, South Korea) and a linear probe (L3-12A) with a high-resolution central frequency of 7.5 MHz (range 3\u0026ndash;12 MHz). Measurements were performed in all participants by a radiologist in the supine position in a quiet and dark room. The probe was placed 1 cm proximal to the common carotid artery bifurcation. CIMT was defined as the distance between the intimal lumen and the media-adventitia interface on the posterior wall in a 5\u0026ndash;10 mm plaque-free area, at least 1 cm from the bifurcation CIMT measurements were performed in the right and left carotid arteries, and their average was used in the analysis. Subclinical atherosclerosis was defined as CIMT\u0026thinsp;\u0026gt;\u0026thinsp;0.9 mm.\u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eFasting blood samples were collected from the subjects after 12 hours\u0026rsquo; overnight fasting. Serum levels of salusin-α and salusin-\u0026szlig; were measured using a human salusin-α and salusin-\u0026szlig; enzyme-linked immunosorbent assay (ELISA) kit (ZellBio GmbH, Ulm, Germany). Sensitivity for salusin-α and salusin-β was 9 pg/mL (assay range: 75-2400 pg/mL) and 0.3 pg/mL (assay range: 4-128 pg/mL), respectively.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed using SPSS software version 25.0 (SPSS, Inc., USA). Normally and non-normally distributed continuous variables were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and median (25\u0026ndash;75% interquartile range (IQR)), respectively. Statistical differences among the groups were identified with Mann-Whitney u test.\u003c/p\u003e\u003cp\u003ePearson correlation analysis was used to assess correlations between serum salusin-α and salusin-β with CIMT. Furthermore, a multiple linear regression analysis was performed to determine independent predictors of the CIMT levels with including CIMT as dependent variable, serum salusin-β as independent variable and age, sex, BMI, classic coronary risk factor, DAS-28, disease duration and treatment with prednisolone as confounding factors. A receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cut-off points of serum salusins levels for predicting abnormal CIMT. The area under the curve (AUC) value was calculated to determine the accuracy of the test. P-values less than 0.05 were considered as statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe study included 116 RA patients without history of CVD. Demographic, clinical and laboratory characteristics of participants has been shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median (IQR) serum salusin-α and salusin-β levels were 887 (697, 2165) and 50 (43, 87) pg/ml, respectively. The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of CIMT was 0.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 pg/ml. In 19 (16.4%) patients, CIMT was \u0026gt;\u0026thinsp;0.9 and carotid plaque was detected in 8 (6.9%) patients.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographics and clinical characteristics of the participants\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow-up duration (months), median (IQR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87 (36, 151)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e102 (87.9)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e51.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e27.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eClassic coronary risk factors (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e76 (65.5)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoking (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (4.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (3.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (3.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDyslipidemia (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56 (48.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTG (mg/dL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e187.2\u0026thinsp;\u0026plusmn;\u0026thinsp;48.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLDL (mg/dL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e106.1\u0026thinsp;\u0026plusmn;\u0026thinsp;26.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHDL (mg/dL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDAS-28, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eExtra-articular involvement (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (19.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRF (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e83 (71.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eACPA (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88 (75.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMedications\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrednisolone (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77 (66.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHydroxychloroquine (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99 (85.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMethotrexate (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e108 (93.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSulfasalazine (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44 (37.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLeflunomide (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (19.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAzathioprine (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (8.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTNF inhibitors (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29 (25.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRituximab (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJack inhibitor (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (6.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of DMARDs, median (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1, 3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum salusin-α (pg/ml), median (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e887 (697, 2165)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSerum salusin-β (pg/ml), median (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50 (43, 87)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCIMT, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHigh CIMT (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (16.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCarotid plaque (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (6.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eSD, standard deviation; IQR, interquartile range; BMI, body mass index; TG, triglyceride;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003edL, deciliter; LDL, low density lipoprotein; HDL, high density lipoprotein; DAS-28, disease activity score-28; RF, rheumatoid factor; ACPA, anti-citrullinated protein antibodies; DMARDs, disease-modifying antirheumatic drugs; CIMT, carotid intima-media thickness\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWe assessed Pearson correlations between serum salusin-α and salusin-β levels with continuous variables including age, BMI, DAS-28 and CIMT. A significant correlation was observed between serum salusin-β levels with DAS-28 (r\u0026thinsp;=\u0026thinsp;0.265, P\u0026thinsp;=\u0026thinsp;0.004) and CIMT (r\u0026thinsp;=\u0026thinsp;0.536, P\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, there was no significant correlation between serum salusin-α levels with age (r= -0.122, P\u0026thinsp;=\u0026thinsp;0.193), BMI (r=-0.041, P\u0026thinsp;=\u0026thinsp;0.663), DAS-28 (r=-0.044, P\u0026thinsp;=\u0026thinsp;0.622) and CIMT (r=-0.064, P\u0026thinsp;=\u0026thinsp;0.485), respectively. In addition, there was no significant correlation between serum salusin-β levels with age (r=-0.010, P\u0026thinsp;=\u0026thinsp;0.919) and BMI (r\u0026thinsp;=\u0026thinsp;0.002, P\u0026thinsp;=\u0026thinsp;0.081).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn addition, we assessed the association between serum salusin-α and salusin-β levels with categorical variables including classic coronary risk factors, treatment with prednisolone, extra-articular involvement, high CIMT and having coronary plaque (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In patients with high CIMT serum salusin-β was significantly higher (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSerum salusin levels in RA patients with various demographic and clinical characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eSalusin-α, median (IQR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eSalusin-β, median (IQR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemales\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e887 (698, 2268)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e891 (603, 1063)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.351\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e51 (43, 96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50 (43, 70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.993\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClassic coronary risk factors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e887 (752, 2195)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e873 (580, 2193)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.482\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e51 (44, 78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e49 (42, 96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.695\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment with prednisolone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e904 (759, 2241)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e843 (656, 975)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e53 (44, 96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e48 (42, 78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.244\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExtra-articular involvement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e895 (715, 1504)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e884 (697, 2227)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.961\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e54 (45, 142)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50 (43, 68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.242\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHigh CIMT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e831 (730, 2123)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e889 (696, 2165)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.764\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e144 (58, 169)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e48 (42, 59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCoronary plaque\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e784 (754, 1423)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e888 (697, 1407)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.942\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e145 (114, 149)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50 (43, 70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.073\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eRA: rheumatoid arthritis; IQR, interquartile range; CIMT, carotid intima media thickness\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThen, we constructed three linear regression models to examine the independent effect of serum salusin-β on CIMT (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Key assumptions of linear regression were evaluated, including normality of residuals (Shapiro-Wilk test), independence of residuals (Durbin-Watson test), homoscedasticity (residuals vs. predicted values plot), and multicollinearity (variance inflation factor, VIF). All models showed that serum salusin-β levels can predict CIMT (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The results of model 3 showed that serum salusin-β was significantly associated with higher CIMT (β\u0026thinsp;=\u0026thinsp;0.003, 95% CI: 0.002\u0026ndash;0.003, P-value\u0026thinsp;=\u0026thinsp;0.001). However, the R2 value for the CIMT was 0.467. This result indicated that serum salusin- β level could explain 46.7% of the variance in the CIMT. In addition, longer disease duration and male sex were also associated with higher CIMT (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Finally, we constructed a linear regression model with three independent predictors of CIMT including serum salusin-β, male gender, and disease duration, and obtained the following formula for predicting CIMT.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMultiple linear regression of association of salusin- β with CIMT in RA patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eModel 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eModel 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eModel 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModel R\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.281\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.436\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.467\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBeta (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBeta (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eBeta (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSalusin-β\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.002 (0.002\u0026ndash;0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.002 (0.002\u0026ndash;0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.003 (0.002\u0026ndash;0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.000 (-0.003-0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.897\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.001 (-0.004-0.001)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.325\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.316 (0.208\u0026ndash;0.424)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.344 (0.234\u0026ndash;0.454)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.003 (-0.004-0.001)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.439\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClassic coronary risk factor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.028 (-0.099-0.043)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.429\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDAS-28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.019 (-0.042-0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.092\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease duration, months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.001 (0.000-0.001)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment with prednisolone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.086 (-0.175-0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.058\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eModel 1: no covariates were adjusted.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eModel 2: age and sex were adjusted.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eModel 3: age, sex, BMI, having classic coronary risk factor, DAS-28, disease duration and being under treatment with prednisolone were adjusted.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eCIMT, carotid intima media thickness; RA, rheumatoid arthritis; CI, confidence interval; BMI: body mass index; DAS-28, disease activity score-28\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eCIMT (mm)\u0026thinsp;=\u0026thinsp;0.99\u0026thinsp;+\u0026thinsp;0.000406\u0026times;disease duration (months)\u0026thinsp;+\u0026thinsp;0.002\u0026times;salusin-β (pg/ml) \u0026ndash; 0.33\u0026times;sex Male\u0026thinsp;=\u0026thinsp;1, Female\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e\u003cp\u003eFinaly, ROC curves were plotted. The cut-off values of salusin-α and salusin-\u0026#120573; for detecting high CIMT were 784.40 and 66.75 pg/ml with sensitivities of 52.6% and 75% and specificities of 32% and 78.1%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSalusins are multifunctional peptides that regulate hemodynamics and atherogenesis.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Salusin-α has anti-atherogenic effects and its expression is reduced in patients with hypertension and diabetes, while salusin-β has a pro-atherogenic role.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e It has been shown that macrophage foam cell formation is inhibited by salusin-α and promoted by salusin-β.\u003csup\u003e16\u003c/sup\u003e In addition, there are some reports that continuous infusion of salusin-β aggravates atherosclerotic lesions and chronic infusion of salusin-α alleviates atherosclerotic lesions in apolipoprotein E and LDL receptor deficient mice.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Salusin-β accelerates atherogenesis through several mechanisms, including 1) endothelial dysfunction and oxidative stress by increasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species production, 2) promoting vascular smooth muscle cell (VSMC) proliferation and migration through activation of c-Myc and Fos genes, 3) macrophage foam cell formation by upregulating acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) and stimulating macrophages to take up oxidized LDL, 4) inducing of inflammatory cytokines formation, such as interleukin (IL)-1β, IL-6 and tumor necrosis factor alpha (TNF-α) which perpetuate vascular inflammation.\u003csup\u003e\u003cspan additionalcitationids=\"CR20 CR21 CR22\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e In contrast, salusin- α inhibits the expression of ACAT-1 and does not have proinflammatory effects.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis study showed that higher serum salusin-β level along with male gender and longer disease duration were predictive of higher CIMT in RA patients, but salusin-α was not. Although salusin-α and salusin-β have been proposed as potential biomarkers for predicting atherosclerosis, salusin-β appears to be a better indicator.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Wang et al. reported a positive association between salusin-α and salusin-β levels with coronary artery stenosis in a study of 256 patients undergoing coronary angiography for chest pain, however, salusin-β was a better predictor compared to salusin-α.\u003csup\u003e24\u003c/sup\u003e In a study by Ozgen et al. salusin-α level was not associated with the CIMT in RA and BD patients.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In another study, salusin-α levels were not associated with CIMT in SLE and systemic sclerosis patients.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e In a study on AS patients, there was no relationship between Sal-α, Sal-β levels and CIMT.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis study showed a moderately strong correlation between serum salusin-β levels and CIMT (r\u0026thinsp;=\u0026thinsp;0.623) and serum salusin-β levels were predictive of subclinical atherosclerosis, independent of age, sex, and classical coronary risk factors. Furthermore, we found that serum salusin-β levels\u0026thinsp;\u0026gt;\u0026thinsp;66.75 pg/ml had a sensitivity of 75% and a specificity of 88.1% for the detection of subclinical atherosclerosis. All these findings suggest that although salusin-β is a relatively strong predictor of CIMT, it is not sufficient for use as a single biomarker for the diagnosis of subclinical atherosclerosis.\u003c/p\u003e\u003cp\u003eAlthough this study is, to our knowledge, the first to evaluate the correlation between salusins and CIMT in RA patients, there are also limitations. Our sample size was relatively small and the study was cross-sectional. A longitudinal study with long-term follow-up and examination of the incidence of symptomatic atherosclerosis could better evaluate the potential of salusin-β in predicting atherosclerosis.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn the present study, we found a correlation between serum salusin- β and CIMT in RA patients and demonstrated the possible potential role of this peptide as a biomarker in RA patients. However, further research involving larger numbers of subjects and prospective multicenter studies is needed to explain and clarify this observation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Kashan University of Medical Sciences\u0026nbsp;(awarded to A.T.; Grant KUOMS‐1401.2).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe declare, we have no potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eWe declare that no part of the review is copied or published elsewhere.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Kashan University of Medical Sciences for funding this study.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study has been conducted in accordance with the Declaration of Helsinki ethical standards (Ethics code: IR.KAUMS.MEDNT.REC.1403.171) and local ethics committee approved the protocol of study \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization and designing the study: H.T., K.E.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData acquisition: R.E., SV.ZH, MJ.A\u003c/p\u003e\n\u003cp\u003eData analysis: A.K.\u003c/p\u003e\n\u003cp\u003eDrafting the manuscript: R.E., A.K.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSupervision: H.T., A.K.\u003cstrong\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData available on request.\u003c/p\u003e\n\u003cp\u003eThe data underlying this article will be shared on reasonable request to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAvi\u0026ntilde;a-Zubieta, J.A., Choi, H.K., Sadatsafavi, M., Etminan, M., Esdaile, J.M. \u0026amp; Lacaille, D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 59, 1690\u0026ndash;1697. https://doi.org/10.1002/art.24092 (2008).\u003c/li\u003e\n\u003cli\u003eMeune, C., Touz\u0026eacute;, E., Trinquart, L. \u0026amp; Allanore, Y. Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 48, 1309\u0026ndash;1313. https://doi.org/10.1093/rheumatology/kep252 (2009).\u003c/li\u003e\n\u003cli\u003eSparks, J.A., Chang, S.C., Liao, K.P., Lu, B., Fine, A.R., Solomon, D.H., Costenbader, K.H., Karlson, E.W. Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: results from the Nurses\u0026rsquo; Health Study. Arthritis Care Res. (Hoboken). 68, 753\u0026ndash;762. https://doi.org/10.1002/acr.22752 (2016).\u003c/li\u003e\n\u003cli\u003eDijkshoorn, B., Raadsen, R. \u0026amp; Nurmohamed, M.T. Cardiovascular disease risk in rheumatoid arthritis anno 2022. J. Clin. Med. 11, 2704. https://doi.org/10.3390/jcm11102704 (2022).\u003c/li\u003e\n\u003cli\u003eAgca, R., Heslinga, S.C., Rollefstad, S., Heslinga, M., McInnes, I.B., Peters, M.J., et al. 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, 17\u0026ndash;28. https://doi.org/10.1136/annrheumdis-2016-209775 (2017).\u003c/li\u003e\n\u003cli\u003evan Breukelen-van der Stoep, D.F., van Zeben, D., Klop, B., van de Geijn, G.J.M., Janssen, H.J., van der Meulen, N.V., et al. Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis. Rheumatology (Oxford). 55, 1210\u0026ndash;1216. https://doi.org/10.1093/rheumatology/kew039 (2016).\u003c/li\u003e\n\u003cli\u003eNiepolski, L. \u0026amp; Grzegorzewska, A.E. Salusins and adropin: new peptides potentially involved in lipid metabolism and atherosclerosis. Adv. Med. Sci. 61, 282\u0026ndash;287 (2016).\u003c/li\u003e\n\u003cli\u003eOzgen, M., Koca, S.S., Dagli, N., Balin, M., Ustundag, B. \u0026amp; Isik, A. Serum salusin-\u0026alpha; level in rheumatoid arthritis. Regul. Pept. 167, 125\u0026ndash;128. https://doi.org/10.1016/j.regpep.2010.12.003 (2011).\u003c/li\u003e\n\u003cli\u003eErden, I., Demir, B., U\u0026ccedil;ak, H., Cicek, D., Bakar Dertlioğlu, S. \u0026amp; Aydin, S. Serum salusin-\u0026alpha; and salusin-\u0026beta; levels in patients with Behcet\u0026rsquo;s disease. Eur. J. Dermatol. 24, 577\u0026ndash;582. https://doi.org/10.1684/ejd.2014.2397 (2014).\u003c/li\u003e\n\u003cli\u003eHajialilo, M., Jorjani, R., Rahimi, M., Ghorbanihaghjo, A., Malek Mahdavi, A., Ghojazadeh, M. \u0026amp; Khabbazi, A. Serum salusin-\u0026beta; levels in patients with systemic lupus erythematosus. Clin. Rheumatol. 42, 2097\u0026ndash;2103. https://doi.org/10.1007/s10067-023-06610-y (2023).\u003c/li\u003e\n\u003cli\u003eTocoglu, A.G. et al. The relationship between salusin-\u0026alpha;, salusin-\u0026beta;, and Klotho levels with subclinical atherosclerosis in ankylosing spondylitis. Eur. Rev. Med. Pharmacol. Sci. 27, 9838\u0026ndash;9845. https://doi.org/10.26355/eurrev_202310_34160 (2023).\u003c/li\u003e\n\u003cli\u003eKobak, S., Atabay, T., Akyildiz, M., Gokduman, A. \u0026amp; Vural, H. Serum salusin-\u0026alpha; and salusin-\u0026beta; levels in patients with psoriatic arthritis. Reumatologia. 60, 306\u0026ndash;310. https://doi.org/10.5114/reum.2022.120753 (2022).\u003c/li\u003e\n\u003cli\u003eRhee, E.J. et al. 2018 guidelines for the management of dyslipidemia. Korean J. Intern. Med. 34, 723\u0026ndash;771. https://doi.org/10.3904/kjim.2019.188 (2019).\u003c/li\u003e\n\u003cli\u003eVisseren, F.L.J., Mach, F., Smulders, Y.M., Carballo, D., Koskinas, K.C., et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur. Heart J. 42, 3227\u0026ndash;3337. https://doi.org/10.1093/eurheartj/ehab484 (2021).\u003c/li\u003e\n\u003cli\u003eWatanabe, T. et al. The roles of salusins in atherosclerosis and related cardiovascular diseases. J. Am. Soc. Hypertens. 5, 359\u0026ndash;365. https://doi.org/10.1016/j.jash.2011.06.003 (2011).\u003c/li\u003e\n\u003cli\u003eWatanabe, T. et al. Impact of salusin-\u0026alpha; and -\u0026beta; on human macrophage foam cell formation and coronary atherosclerosis. Circulation. 117, 638\u0026ndash;648. https://doi.org/10.1161/CIRCULATIONAHA.107.712539 (2008).\u003c/li\u003e\n\u003cli\u003eNagashima, M. et al. Salusin-\u0026beta; promotes atherosclerosis. Atherosclerosis. 212, 70\u0026ndash;77. https://doi.org/10.1016/j.atherosclerosis.2010.04.027 (2010).\u003c/li\u003e\n\u003cli\u003eZhou, C.H., Liu, L.L., Wu, Y.Q., Song, Z. \u0026amp; Xing, S.H. Enhanced expression of salusin-\u0026beta; contributes to progression of atherosclerosis in LDL receptor deficient mice. Can. J. Physiol. Pharmacol. 90, 463\u0026ndash;471. https://doi.org/10.1139/y2012-022 (2012).\u003c/li\u003e\n\u003cli\u003eWatanabe, T. et al. The roles of salusins in atherosclerosis and related cardiovascular diseases. J. Am. Soc. Hypertens. 5, 359\u0026ndash;365. https://doi.org/10.1016/j.jash.2011.06.003 (2011).\u003c/li\u003e\n\u003cli\u003eWu, L.L. et al. Salusin-\u0026beta; in intermediate dorsal motor nucleus of the vagus regulates sympathetic\u0026ndash;parasympathetic balance and blood pressure. Biomedicines. 9, 1118. https://doi.org/10.3390/biomedicines9091118 (2021).\u003c/li\u003e\n\u003cli\u003eZhu, X., Zhou, Y., Cai, W., Sun, H. \u0026amp; Qiu, L. Salusin-\u0026beta; mediates high glucose-induced endothelial injury via disruption of AMPK signaling pathway. Biochem. Biophys. Res. Commun. 491, 515\u0026ndash;521. https://doi.org/10.1016/j.bbrc.2017.06.126 (2017).\u003c/li\u003e\n\u003cli\u003eFujimoto, K. et al. Circulating levels of human salusin-\u0026beta;, a potent hemodynamic and atherogenesis regulator. PLoS One. 8, e76714. https://doi.org/10.1371/journal.pone.0076714 (2013).\u003c/li\u003e\n\u003cli\u003eZhao, M.X., Zhou, B., Ling, L., Xiong, X.Q., Zhang, F., Chen, Q., et al. Salusin-\u0026beta; contributes to oxidative stress and inflammation in diabetic cardiomyopathy. Cell Death Dis. 8, e2690. https://doi.org/10.1038/cddis.2017.106 (2017).\u003c/li\u003e\n\u003cli\u003eWang, Y., Wang, S., Zhang, J., Zhang, M., Zhang, H., Gonget, G., et al. Salusin-\u0026beta; is superior to salusin-\u0026alpha; as a marker for evaluating coronary atherosclerosis. J. Int. Med. Res. 48, 30006052090386. https://doi.org/10.1177/0300060520903868 (2020).\u003c/li\u003e\n\u003cli\u003eKoca, S.S., \u0026Ouml;zgen, M., Işık, B., Dağlı, M.N., \u0026Uuml;st\u0026uuml;ndağ, B. \u0026amp; Işık, A. Serum salusin-\u0026alpha; levels in systemic lupus erythematosus and systemic sclerosis. Eur. J. Rheumatol. 1, 14\u0026ndash;17. https://doi.org/10.5152/eurjrheum.2014.004 (2014).\u003c/li\u003e\n\u003cli\u003eTocoglu, A.G., Dogan, B., Tuzun, S., Akcay, E.U., Altas, A.E., Ayhan, L.T., et al. The relationship between salusin-\u0026alpha;, salusin-\u0026beta;, and Klotho levels with subclinical atherosclerosis in ankylosing spondylitis. Eur. Rev. Med. Pharmacol. Sci. 27, 9838\u0026ndash;9845. https://doi.org/10.26355/eurrev_202310_34160 (2023).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"rheumatoid arthritis, salusin-α, salusin-β, subclinical atherosclerosis","lastPublishedDoi":"10.21203/rs.3.rs-7586337/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7586337/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCardiovascular disease (CVD) is the leading cause of mortality in rheumatoid arthritis (RA). This study aims to assess the association between serum salusin-α and salusin-β levels with carotid intima media thickness (CIMT) in RA patients. In this cross-sectional study, cases from a prospective cohort of RA were consecutively enrolled. Subclinical atherosclerosis was defined as CIMT\u0026thinsp;\u0026gt;\u0026thinsp;0.9 mm. The study included 116 RA patients without history of CVD. The median (IQR) serum salusin-α and salusin-β levels were 887 (697, 2165) and 50 (43, 87) pg/ml, respectively. The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of CIMT was 0.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 pg/ml. In 19 (16.4%) patients, CIMT was \u0026gt;\u0026thinsp;0.9. A significant correlation was observed between serum salusin-β levels with CIMT (r\u0026thinsp;=\u0026thinsp;0.536, P\u0026thinsp;=\u0026thinsp;0.001). However, there was no significant correlation between serum salusin-α levels CIMT (r=-0.064, P\u0026thinsp;=\u0026thinsp;0.485). we constructed three linear regression models to examine the independent effect of serum salusin-β on CIMT. serum salusin-β was significantly associated with higher CIMT (β\u0026thinsp;=\u0026thinsp;0.003, 95% CI: 0.002\u0026ndash;0.003, P-value\u0026thinsp;=\u0026thinsp;0.001). the R2 value for the CIMT was 0.467. Finaly, ROC curves were plotted. The cut-off values of salusin-α and salusin-\u0026#120573; for detecting high CIMT were 784.40 and 66.75 pg/ml with sensitivities of 52.6% and 75% and specificities of 32% and 78.1%, respectively. In the present study, we found a correlation between serum salusin-β and CIMT in RA patients and demonstrated the possible potential role of this peptide as a biomarker in RA patients. However, further research involving larger numbers of subjects and prospective multicenter studies is needed to explain and clarify this observation.\u003c/p\u003e","manuscriptTitle":"The association between serum salusin-α and salusin-β levels with subclinical atherosclerosis in rheumatoid arthritis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-10 14:58:27","doi":"10.21203/rs.3.rs-7586337/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"147dd056-8e60-4e30-a812-5a6e6296da95","owner":[],"postedDate":"October 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55936427,"name":"Health sciences/Biomarkers"},{"id":55936428,"name":"Health sciences/Diseases"},{"id":55936429,"name":"Biological sciences/Immunology"},{"id":55936430,"name":"Health sciences/Medical research"},{"id":55936431,"name":"Health sciences/Rheumatology"}],"tags":[],"updatedAt":"2025-12-19T11:40:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-10 14:58:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7586337","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7586337","identity":"rs-7586337","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}