Ambulatory Blood Pressure in Patients With Rheumatoid Arthritis: Association With Immune Activation.

OBJECTIVE: The prevalence of hypertension, a major cardiovascular risk factor, is increased in patients with rheumatoid arthritis (RA) and may be driven by immune activation. The purpose of this study was to determine if ambulatory 24-hour blood pressure (BP) is elevated in RA vs control participants and whether it is associated with immune activation. METHODS: We conducted a cross-sectional study of 46 patients with RA and 23 control participants. Participants wore an ambulatory BP monitor that obtained diurnal BP every 15-30 minutes and nocturnal BP every 30 minutes. Inflammatory mediators in plasma were measured using an inflammation proteomics panel. Differences in BP measurements were assessed by Mann-Whitney U test, and association with inflammatory mediators was assessed by Spearman correlation. RESULTS: Patients with RA and control participants had similar office BP, but median ambulatory systolic BP (SBP) measurements (24-hour [RA 121 mmHg vs control 116 mmHg; P = 0.01], diurnal [RA 128 mmHg vs control 120 mmHg; P = 0.003], and nocturnal [RA 112 mmHg vs control 103 mmHg; P = 0.002]) were higher in patients with RA. Patients with RA also had higher nocturnal diastolic BP (DBP; RA 63 mmHg vs control 57 mmHg; P = 0.02), but other DBP measurements were similar. Nocturnal BP dipping was less in patients with RA (12%) compared to control participants (16%; P = 0.02). In patients with RA, higher 24-hour and nocturnal SBPs and less nocturnal dipping were strongly correlated with a wide range of inflammatory mediators. CONCLUSION: Despite similar office measurements, 24-hour and nocturnal SBP measurements were higher in patients with RA than in control participants and were strongly associated with inflammation.

Ambulatory blood pressure in patients with systemic lupus erythematosus: Association with markers of immune activation.

Objectives: Ambulatory blood pressure monitoring measures 24-hour blood pressure, night-time blood pressure, and impaired dipping of nocturnal blood pressure, parameters that better predict cardiovascular risk than standard office blood pressure measurements. Systemic lupus erythematosus is characterized by immune system hyperactivity, elevated cardiovascular risk and high prevalence of hypertension; however, little is known about ambulatory blood pressure in lupus patients and its relationship to immune activation. Methods: We studied 26 patients with lupus and 26 control subjects. We obtained ambulatory 24-hour blood pressure measurements and report plasma concentrations of 77 markers of immune activation using a multiplex immunoassay and assessed their association with blood pressure measurements. Results: Despite similar office blood pressure measurements in patients with lupus and controls, lupus patients had higher 24-hour systolic [median (interquartile range) 129 (113 - 140) vs. 116 (111 - 121) mmHg, p = 0.03] and diastolic blood pressure [80 (69 - 86) vs. 72 (64 - 75) mmHg, p = 0.006] as well as less nocturnal dipping [7.8% (5.1 - 14.2%) vs. 12.0% (8.1 20.0%)] p = 0.03], compared to controls. In patients with lupus, markers of the innate (monocyte chemotactic protein-3) and adaptive immune systems [CUB domain-containing protein-1 and Interleukin-15 receptor subunit-α,] were associated with nocturnal blood pressure measurements and attenuated nocturnal dipping. In conclusion, 24-hour systolic and diastolic blood pressure was higher and nocturnal blood pressure dipping was attenuated in patients with lupus compared to control subjects. Conclusion: In patients with SLE, nocturnal blood pressure and attenuated nocturnal blood pressure dipping were significantly associated with several innate and adaptive immune system biomarkers.

Exercise is Associated With Increased Small HDL Particle Concentration and Decreased Vascular Stiffness in Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) risk. In the general population, exercise improves several CV risk factors. In a cross-sectional study, we examined the hypothesis that more exercise is associated with protective traditional and non-traditional CV risk factor profile in patients with RA. METHODS: Patient-reported exercise outside of daily activities was quantified by time and metabolic equivalents per week (METmin/week) and CV risk factors including blood pressure, standard lipid profiles, lipoprotein particle concentrations (NMR spectroscopy), and vascular indices were measured in 165 patients with RA. The relationship between exercise and CV risk factors was assessed according to whether patients exercised or not, and after adjustment for age, race and sex. RESULTS: Over half (54%) of RA patients did not exercise. Among those who did exercise, median value for exercise duration was 113 min/week [IQR: 60, 210], and exercise metabolic equivalent expenditure was 484 METmin/week [IQR: 258, 990]. Disease activity (measured by DAS28 score), C-reactive protein, waist-hip ratio, and prevalence of hypertension were lower in patients who exercised compared to those who did not (all p-values < 0.05) but standard lipid profile and body mass index were not significantly different. Patients who exercised had significantly higher concentrations of HDL particles (p = 0.004) and lower vascular stiffness as measured by pulse wave velocity (p = 0.005). CONCLUSIONS: More self-reported exercise in patients with RA was associated with a protective CV risk factor profile including lower waist-hip ratio, higher HDL particle concentration, lower vascular stiffness, and a lower prevalence of hypertension.

A variant in the osteoprotegerin gene is associated with coronary atherosclerosis in patients with rheumatoid arthritis: results from a candidate gene study.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis, but there is limited information about the genetic contribution to atherosclerosis in this population. Therefore, we examined the association between selected genetic polymorphisms and coronary atherosclerosis in patients with RA. METHODS: Genotypes for single-nucleotide polymorphisms (SNPs) in 152 candidate genes linked with autoimmune or cardiovascular risk were measured in 140 patients with RA. The association between the presence of coronary artery calcium (CAC) and SNP allele frequency was assessed by logistic regression with adjustment for age, sex, and race. To adjust for multiple comparisons, a false discovery rate (FDR) threshold was set at 20%. RESULTS: Patients with RA were 54±11 years old and predominantly Caucasian (89%) and female (69%). CAC was present in 70 patients (50%). A variant in rs2073618 that encodes an Asn3Lys missense substitution in the osteoprotegerin gene (OPG, TNFRSF11B) was significantly associated with the presence of CAC (OR=4.09, p<0.00026) and withstands FDR correction. CONCLUSION: Our results suggest that a polymorphism of the TNFRSF11B gene, which encodes osteoprotegerin, is associated with the presence of coronary atherosclerosis in patients with RA. Replication of this finding in independent validation cohorts will be of interest.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study.

Background: Two risk variants in the apolipoprotein L1 gene ( APOL1 ) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. Methods: A retrospective cohort study of 2,242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality and organ failure related to sepsis. Results: Of 2,242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR=1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR=0.99 [95% CI, 0.70-1.39; p=0.95]. APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR=1.64 [95% CI, 1.21-2.22; p=0.001], but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR=1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR=1.16 [95% CI, 0.74-1.81; p=0.52]). Conclusion: APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. Funding: This study was supported by R01GM120523 (Q.F.), R01HL163854 (Q.F.), R35GM131770 (C.M.S.), HL133786 (W.Q.W.), and Vanderbilt Faculty Research Scholar Fund (Q.F.). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126).The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The relationship between high density lipoprotein cholesterol and sepsis: A clinical and genetic approach.

Sepsis accounts for one in three hospital deaths. Higher concentrations of high-density lipoprotein cholesterol (HDL-C) are associated with apparent protection from sepsis, suggesting a potential therapeutic role for HDL-C or drugs, such as cholesteryl ester transport protein (CETP) inhibitors that increase HDL-C. However, these beneficial clinical associations might be due to confounding; genetic approaches can address this possibility. We identified 73,406 White adults admitted to Vanderbilt University Medical Center with infection; 11,612 had HDL-C levels, and 12,377 had genotype information from which we constructed polygenic risk scores (PRS) for HDL-C and the effect of CETP on HDL-C. We tested the associations between predictors (measured HDL-C, HDL-C PRS, CETP PRS, and rs1800777) and outcomes: sepsis, septic shock, respiratory failure, and in-hospital death. In unadjusted analyses, lower measured HDL-C concentrations were significantly associated with increased risk of sepsis (p = 2.4 × 10-23 ), septic shock (p = 4.1 × 10-12 ), respiratory failure (p = 2.8 × 10-8 ), and in-hospital death (p = 1.0 × 10-8 ). After adjustment (age, sex, electronic health record length, comorbidity score, LDL-C, triglycerides, and body mass index), these associations were markedly attenuated: sepsis (p = 2.6 × 10-3 ), septic shock (p = 8.1 × 10-3 ), respiratory failure (p = 0.11), and in-hospital death (p = 4.5 × 10-3 ). HDL-C PRS, CETP PRS, and rs1800777 significantly predicted HDL-C (p < 2 × 10-16 ), but none were associated with sepsis outcomes. Concordant findings were observed in 13,254 Black patients hospitalized with infections. Lower measured HDL-C levels were significantly associated with increased risk of sepsis and related outcomes in patients with infection, but a causal relationship is unlikely because no association was found between the HDL-C PRS or the CETP PRS and the risk of adverse sepsis outcomes.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study.

Background: Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. Methods: A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis. Results: Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70-1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21-2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74-1.81; p=0.52]). Conclusions: APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. Funding: This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

When the body is fighting off an infection, the processes it uses to protect itself can sometimes overreact. This results in a condition known as sepsis which can cause life-threatening damage to multiple organs. In the United States, Black patients are 60-80% more likely to develop sepsis compared to individuals who identify as White; differences remain even after accounting for socio-economic status and presence of other illnesses. Recent work has suggested that two variants of the APOL1 gene which are almost exclusively found in people with African ancestry may be a contributing factor to this disparity. These 'high-risk' genetic variants have also been shown to increase the likelihood of kidney diseases. It is therefore possible that the elevated chance of sepsis is not directly linked to these variations of APOL1, but rather is the result of patients already having reduced kidney function. To understand the relationship between APOL1 and sepsis, Jiang et al. analyzed data from patients admitted to Vanderbilt University Medical Centre in the United States between 2000 and 2020. This included 2,242 patients who identified as Black and had been hospitalized with an infection. The analyses showed that 16% of these individuals were carriers of the APOL1 high-risk variants. The high-risk patients were more likely to experience sepsis and demonstrate kidney damage. But other organs commonly damaged by sepsis were not affected more in these individuals compared to the other 84% of patients who did not have these variants. Furthermore, when individuals with pre-existing kidney diseases were removed from this high-risk group, the increased likelihood of sepsis was no longer prominent. These findings suggest that the APOL1 variants do not directly increase the risk of sepsis, and this association is primarily due to patients with these genetic variations being more susceptible to kidney diseases. There are new drugs under development targeting the APOL1 variants. While these may provide protection against kidney diseases, they are unlikely to be successful at preventing or treating sepsis once a patient has been hospitalized with an infection.

Intermuscular adipose tissue in patients with systemic lupus erythematosus.

OBJECTIVE: Patients with SLE frequently have debilitating fatigue and reduced physical activity. Intermuscular adipose tissue (IMAT) accumulation is associated with reduced physical exercise capacity. We hypothesised that IMAT is increased in patients with SLE and associated with increased fatigue, reduced physical activity and increased inflammation. METHODS: In a cross-sectional study, 23 patients with SLE and 28 control participants were evaluated. IMAT was measured in the calf muscles using sequential T 1-weighted MRI. Patient-reported physical activity and fatigue were measured and a multiplex proteomic assay was used to measure markers and mediators of inflammation. RESULTS: IMAT accumulation (percentage of IMAT area to muscle area) was significantly higher in SLE versus control participants (7.92%, 4.51%-13.39% vs 2.65%, 1.15%-4.61%, median, IQR, p<0.001) and remained significant after adjustment for age, sex, race and body mass index (p<0.001). In patients with SLE, IMAT accumulation did not differ significantly among corticosteroid users and non-users (p=0.48). In the study cohort (patients and controls), IMAT was positively correlated with self-reported fatigue score (rho=0.52, p<0.001) and inversely correlated with self-reported walking distance (rho=-0.60, p<0.001). Several markers of inflammation were associated with IMAT accumulation in patients with SLE, and gene ontology analysis showed significant enrichment for pathways associated with macrophage migration and activation in relation to IMAT. CONCLUSION: Patients with SLE have greater IMAT accumulation than controls in the calf muscles. Increased IMAT is associated with greater fatigue and lower physical activity. Future studies should evaluate the effectiveness of interventions that improve muscle quality to alleviate fatigue in patients with SLE.

Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis.

OBJECTIVE: The prevalence of subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA), and the increased risk is associated with insulin resistance. Adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease in the general population. This study was undertaken to examine the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA. METHODS: The coronary calcium score, homeostatic model assessment for insulin resistance (HOMA-IR) index, and serum adipocytokine (leptin, adiponectin, resistin, and visfatin) concentrations were determined in 169 patients with RA. The independent effect of each adipocytokine on insulin resistance according to the HOMA-IR index and on coronary artery calcification determined by electron beam computed tomography was assessed in models adjusted for age, race, sex, body mass index (BMI), traditional cardiovascular risk factors, and inflammation mediators. In addition, an interaction analysis was performed to evaluate whether the effect of the HOMA-IR index on the coronary calcium score is moderated by adipocytokines. RESULTS: Increased concentrations of leptin were associated with a higher HOMA-IR index, even after adjustment for age, race, sex, BMI, traditional cardiovascular risk factors, and inflammation mediators (P < 0.001), but concentrations of visfatin (P = 0.06), adiponectin (P = 0.55), and resistin (P = 0.98) showed no association with the HOMA-IR index. None of the adipocytokines was independently associated with the coronary calcium score (all P > 0.05). Serum leptin concentrations showed a significant interaction with the HOMA-IR index (P for multivariate interaction = 0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to insulin resistance. Serum concentrations of the other adipocytokines showed no significant interactions with the HOMA-IR index (each P > 0.05). CONCLUSION: Leptin is associated with insulin resistance in patients with RA but, paradoxically, attenuates the effects of insulin resistance on coronary calcification.

Plasma miRNAs improve the prediction of coronary atherosclerosis in patients with rheumatoid arthritis.

OBJECTIVE: MicroRNAs (miRNAs) regulate gene expression and are disease biomarkers. Rheumatoid arthritis (RA) patients have accelerated atherosclerosis leading to excess cardiovascular morbidity and mortality, but traditional risk factors for cardiovascular risk stratification are inadequate. In the general population, miRNAs improve cardiovascular risk estimation beyond traditional risk factors. Our objective was to develop a miRNA panel that predicts coronary atherosclerosis in RA patients. METHODS: Plasma small RNA next-generation sequencing (NGS) was performed on 161 RA patients whose Agatston scores for coronary artery calcium were previously measured. Random forest analysis of plasma NGS miRNA expression was used to determine which miRNAs best differentiated between those patients with and without coronary artery calcium. Top predictive miRNAs were assayed by quantitative PCR (qPCR). Elastic net regression was used to develop the most parsimonious models with qPCR-measured miRNA concentrations and clinical variables (age, sex, ACC/AHA 10-year risk score, DAS28 score, and diabetes) separately to predict the presence of coronary artery calcium and high coronary artery calcium. C-statistics were used to assess performance model performance. RESULTS: The top miRNAs which differentiated those with and without coronary atherosclerosis based on random forest analysis included let-7c-5p, miR-30e-5p, miR-30c-5p, miR-4446-3p, miR-126-5p, miR-3168, miR-425-5p, miR-126-3p, miR-30a-5p, and miR-125a-5p. For coronary artery calcium prediction, addition of all miRNAs except miR-126-3p to clinical factors improved the c-statistic modestly from 0.86 to 0.87. For high coronary artery calcium prediction, addition of all miRNAs except miR-30c-5p to clinical factors improved the c-statistic from 0.75 to 0.80. CONCLUSION: A plasma miRNA panel improved the prediction of high coronary artery calcium beyond traditional risk factors and RA disease activity. Further evaluation of the miRNA panel for prediction of coronary events in RA is necessary. Key Point • A plasma microRNA panel including let-7c-5p, miR-30a-5p, miR-30e-5p, miR-125a-5p, miR-126-3p, miR-126-5p, miR-425-5p, miR-3168, and miR-4446-3p improved the prediction of high coronary artery calcium beyond clinical factors in patients with rheumatoid arthritis.

Development and Validation of a MicroRNA Panel to Differentiate Between Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus and Controls.

OBJECTIVE: MicroRNA (miRNA) are short noncoding RNA that regulate genes and are both biomarkers and mediators of disease. We used small RNA (sRNA) sequencing and machine learning methodology to develop an miRNA panel to reliably differentiate between rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and control subjects. METHODS: Plasma samples from 167 RA and 91 control subjects who frequency-matched for age, race, and sex were used for sRNA sequencing. TIGER was used to analyze miRNA. DESeq2 and random forest analyses were used to identify a prioritized list of miRNA differentially expressed in patients with RA. Prioritized miRNA were validated by quantitative PCR, and lasso and logistic regression were used to select the final panel of 6 miRNA that best differentiated RA from controls. The panel was validated in a separate cohort of 12 SLE, 32 RA, and 32 control subjects. Panel efficacy was assessed by area under the receiver operative characteristic curve (AUC) analyses. RESULTS: The final panel included miR-22-3p, miR-24-3p, miR-96-5p, miR-134-5p, miR-140-3p, and miR-627-5p. The panel differentiated RA from control subjects in discovery (AUC = 0.81) and validation cohorts (AUC = 0.71), seronegative RA (AUC = 0.84), RA remission (AUC = 0.85), and patients with SLE (AUC = 0.80) versus controls. Pathway analysis showed upstream regulators and targets of panel miRNA are associated with pathways implicated in RA pathogenesis. CONCLUSION: An miRNA panel identified by a bioinformatic approach differentiated between RA or SLE patients and control subjects. The panel may represent an autoimmunity signature, perhaps related to inflammatory arthritis, which is not dependent on active disease or seropositivity.

The Endogenous Plasma Small RNAome of Rheumatoid Arthritis.

OBJECTIVE: Small RNA (sRNA) sequencing has revealed new sRNA classes beyond microRNAs (miRNAs). These sRNAs can regulate genes and act as biomarkers. The aim of this study was to determine if the endogenous plasma sRNA landscape is altered in patients with rheumatoid arthritis (RA) compared with control subjects and to determine its association with disease-related parameters in RA. METHODS: sRNA sequencing was performed on plasma from 165 RA and 90 control subjects who were frequency-matched for age, race, and sex. Endogenous sRNAs, such as miRNAs, isomiRs, sRNAs derived from small nuclear RNAs (snDRs), small nucleolar RNAs (snoDRs), Y RNAs (yDRs), transfer-derived RNAs (tDRs), long noncoding RNAs (lncDRs) as well as miscellaneous sRNAs (miscRNAs), were quantified using Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER). Individual and categories of sRNAs were compared between RA and controls, and significantly altered sRNAs and sRNA categories were correlated with disease activity and general laboratory measures in RA. RESULTS: Patients with RA had more miRNAs (1.42-fold, P = 0.01), more tDRs (1.14-fold, P = 0.04), and fewer yDRs (-1.41-fold, P = 0.009) compared with control subjects. Disease duration was inversely associated with yDRs. Disease-related parameters, such as Disease Activity Score-28 (DAS28), swollen joint count, and inflammatory markers were significantly positively associated with tDRs and miscRNAs, and miR-22-3p and related sequences and isomiRs were most significantly associated with DAS28. CONCLUSION: Endogenous plasma sRNAs are altered in RA compared with control subjects. Although individual miRNAs have been well studied and many are excellent biomarkers in RA, several non-miRNA sRNAs were significantly associated with disease-related parameters as classes and may represent novel biomarkers for RA.

Amino-terminal fragment of the prohormone brain-type natriuretic peptide in rheumatoid arthritis.

OBJECTIVE: Increased concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with cardiovascular morbidity and mortality, but little is known about their relationship to chronic inflammation. Patients with rheumatoid arthritis (RA) have chronic inflammation, increased arterial stiffness, and accelerated coronary atherosclerosis. This study was undertaken to test the hypothesis that NT-proBNP concentrations are elevated in patients with RA and are associated with coronary artery calcification and markers of inflammation. METHODS: In 159 patients with RA (90 with early RA and 69 with longstanding RA) without heart failure and 88 control subjects, serum concentrations of NT-proBNP, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFalpha) were measured and coronary calcification was assessed. Associations between NT-proBNP levels and the other parameters were investigated. RESULTS: NT-proBNP concentrations were elevated in patients with longstanding RA (median 142.8 pg/ml [interquartile range 54.8-270.5]) and those with early RA (median 58.1 pg/ml [interquartile range 19.4-157.6]) compared with controls (18.1 [3.2-46.0]) (P < 0.001). In patients with RA, NT-proBNP concentrations were associated with age (rho = 0.35, P < 0.001), levels of IL-6 (rho = 0.33, P < 0.001), TNFalpha (rho = 0.23, P = 0.003), and C-reactive protein (CRP) (rho = 0.21, P = 0.01), coronary calcium score (rho = 0.30, P < 0.001), systolic blood pressure (rho = 0.30, P < 0.001), and disease activity (rho = 0.29, P < 0.001). After adjustment for age, race, and sex, the associations between NT-proBNP concentrations and disease activity, TNFalpha, IL-6, and CRP remained significant, but those with systolic blood pressure and coronary calcium score were attenuated. CONCLUSION: NT-proBNP concentrations are increased in patients with RA without clinical heart failure and may indicate subclinical cardiovascular disease and a chronic inflammatory state.

Lipoprotein subclasses and particle size determined by nuclear magnetic resonance spectroscopy in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis, but the underlying mechanisms are unclear. The size and number of lipoprotein particles may be better predictors of atherosclerosis than conventional cholesterol measurements. We measured lipoprotein subclasses by nuclear magnetic resonance spectroscopy (NMR), coronary artery calcification by electron beam computed tomography, and insulin resistance by homeostasis model assessment in 105 patients with SLE and 77 control subjects. VLDL particles were larger (50.0+/-8.5 versus 47.7+/-8.5 nm, P=0.01) and concentrations of large high-density lipoprotein (HDL) particles lower (10.1+/-5.3 versus 11.3+/-5.1 nmol/L, P=0.03) in patients with SLE than controls. In patients with SLE, small LDL concentration was associated with body mass index (rho=0.27), insulin resistance (rho=0.34), C-reactive protein (CRP; rho=0.30), and erythrocyte sedimentation rate (ESR; rho=0.20); all P<0.05. Large HDL concentration was inversely associated with insulin resistance (rho=-0.29), disease activity (rho=-0.23), and ESR (rho=-0.39); all P<0.05. VLDL concentrations correlated with CRP (rho=0.22), ESR (rho=0.24), disease damage (rho=0.20), and corticosteroid exposure (rho=0.29); all P<0.05. Neither the concentration of lipoprotein subclasses nor particle size was associated with coronary artery atherosclerosis. There were only minor differences in the NMR lipid profiles of patients with SLE and controls. Lipoprotein subclasses were associated with metabolic variables, inflammatory markers, and corticosteroid use but not with coronary artery atherosclerosis in SLE.

Association between urinary sodium and potassium excretion and blood pressure and inflammation in patients with rheumatoid arthritis.

Hypertension is highly prevalent in patients with rheumatoid arthritis (RA). In other populations, high sodium (Na+) and low potassium (K+) intake are associated with an increased risk of hypertension, and in animal models, a high salt intake exacerbated arthritis. Patients with RA have many comorbidities associated with salt sensitivity, but their salt intake and its relationship to blood pressure and inflammation is unknown. Using the Kawasaki formula, Na+ and K+ urinary excretion (reflecting intake) was estimated in 166 patients with RA and 92 controls, frequency matched for age, sex, and race. Inflammatory markers and disease activity were measured in RA patients. We tested the associations between blood pressure and Na+ and K+ excretion. Estimated 24-h Na+ excretion was similarly high in both RA (median [IQR] 5.1 g, [3.9-6.6 g]) and controls (4.9 g, [4.0-6.5 g]), p = 0.9, despite higher rates of hypertension in RA (54 vs. 39%, p = 0.03). The Na+:K+ excretion ratio was significantly higher in RA (2.0 [1.6-2.4]) vs. 1.7 [1.5-2.1]), p = 0.02] compared to controls. In RA, a lower K+ excretion was inversely correlated with diastolic blood pressure (adjusted ß = - 1.79, p = 0.04). There was no significant association between Na+ or K+ excretion and inflammatory markers. Despite a similar Na+ excretion, patients with RA had higher rates of hypertension than controls, a finding compatible with increased salt sensitivity. Patients with RA had a lower Na+:K+ excretion ratio than controls, and lower K+ excretion was associated with higher diastolic blood pressure in RA.

Premature coronary-artery atherosclerosis in systemic lupus erythematosus.

BACKGROUND: Premature coronary artery disease is a major cause of illness and death in patients with systemic lupus erythematosus, but little is known about the prevalence, extent, and causes of coronary-artery atherosclerosis. METHODS: We used electron-beam computed tomography to screen for the presence of coronary-artery calcification in 65 patients with systemic lupus erythematosus (mean [+/-SD] age, 40.3+/-11.6 years) and 69 control subjects (mean age, 42.7+/-12.6 years) with no history of coronary artery disease. When calcification was detected, the extent was measured by means of the Agatston score. The frequency of risk factors for coronary artery disease was compared in patients and controls, and the relation between the patients' clinical characteristics and the presence or absence of coronary-artery calcification was examined. RESULTS: The two groups were similar with respect to age, race, and sex. Coronary-artery calcification was more frequent in patients with lupus (20 of 65 patients) than in control subjects (6 of 69 subjects) (P=0.002). The mean calcification score was 68.9+/-244.2 in the patients and 8.8+/-41.8 (P<0.001) in controls. Levels of total, high-density lipoprotein, and low-density lipoprotein cholesterol were not elevated in patients with lupus, but levels of triglycerides (P=0.02) and homocysteine (P<0.001) were. Among patients with lupus, measures of disease activity were similar in those with and those without coronary-artery calcification, but those with calcification were more likely to be older (P<0.001) and male (P=0.008). CONCLUSIONS: In patients with systemic lupus erythematosus, the prevalence of coronary-artery atherosclerosis is elevated and the age at onset is reduced. Early detection of atherosclerosis may provide an opportunity for therapeutic intervention.

Telomere Length and Coronary Atherosclerosis in Rheumatoid Arthritis.

OBJECTIVE: Telomeres protect against chromosomal end damage and shorten with each cell division; their length may be a marker of cardiovascular and overall biological aging. We examined the hypothesis that reduced telomere length is associated with increased coronary atherosclerosis in rheumatoid arthritis (RA). METHODS: We performed a cross-sectional study in 145 patients with RA and 87 control subjects frequency-matched for age, race, and sex. Coronary artery calcium score was determined by noncontrast cardiac computed tomography. Telomere length was measured from whole blood DNA, using real-time quantitative polymerase chain reaction and expressed as telomeric product to a single-copy gene product ratio (T/S ratio). Associations between telomere length, coronary artery calcium score, and 28-joint Disease Activity Score (DAS28) were assessed with Spearman correlation, proportional odds logistic regression, and linear regression, adjusting for age, race, and sex. RESULTS: Telomere length was significantly inversely correlated with age in patients with RA (ρ = -0.37, p < 0.001) and control subjects (ρ = -0.39, p = 0.001). Among patients with RA, for every interquartile range (IQR) decrease in telomere length (T/S ratio), the odds of higher coronary artery calcium score increased by 38% (95% CI: 4-60) after adjusting for age, race, and sex (p adjusted = 0.03). Telomere length was not associated with DAS28 (p adjusted = 0.17). Telomere length was not significantly different in patients with RA [median (IQR): 1.02 units (0.9-1.11)] compared to control subjects [1.05 units (0.95-1.17); p = 0.10]. CONCLUSION: Telomere length is inversely associated with coronary artery calcium score, independent of age, race, and sex in patients with RA.

Net cholesterol efflux capacity of HDL enriched serum and coronary atherosclerosis in rheumatoid arthritis.

BACKGROUND/OBJECTIVES: Cardiovascular (CV) risk is increased in patients with rheumatoid arthritis (RA), but not fully explained by traditional risk factors such as LDL and HDL cholesterol concentrations. The cholesterol efflux capacity of HDL may be a better CV risk predictor than HDL concentrations. We hypothesized that HDL's cholesterol efflux capacity is impaired and inversely associated with coronary atherosclerosis in patients with RA. METHODS: We measured the net cholesterol efflux capacity of apolipoprotein B depleted serum and coronary artery calcium score in 134 patients with RA and 76 control subjects, frequency-matched for age, race and sex. The relationship between net cholesterol efflux capacity and coronary artery calcium score and other clinical variables of interest was assessed in patients with RA. RESULTS: Net cholesterol efflux capacity was similar among RA (median [IQR]: 34% removal [28, 41%]) and control subjects (35% removal [27%, 39%]) (P=0.73). In RA, increasing net cholesterol efflux capacity was not significantly associated with decreased coronary calcium score (OR=0.78 (95% CI 0.51-1.19), P=0.24, adjusted for age, race and sex, Framingham risk score and presence of diabetes). Net cholesterol efflux capacity was not significantly associated with RA disease activity score, C-reactive protein, urinary F2-isoprostanes, or degree of insulin resistance in RA. CONCLUSIONS: Net cholesterol efflux capacity is not significantly altered in patients with relatively well-controlled RA nor is it significantly associated with coronary artery calcium score.

Endothelial function in systemic lupus erythematosus: relationship to disease activity, cardiovascular risk factors, corticosteroid therapy, and coronary calcification.

OBJECTIVES: Endothelial dysfunction is frequently present in patients with systemic lupus erythematosus and may increase their risk of premature coronary artery disease. In this pilot study we have characterized the relationship between endothelial function, measures of disease activity, and cardiovascular risk factors in patients with lupus. METHODS: Clinical characteristics and cardiovascular risk factors were evaluated in 20 patients with lupus. Flow-mediated dilation of the brachial artery was measured using high resolution ultrasound and the presence or absence of coronary calcification determined by electron-beam computed tomography. The relationship between these variables and flow-mediated dilation was determined using Spearman correlation coefficients (RHO) and Mann Whitney-Wilcoxon tests. RESULTS: Twenty patients (17 female) median age (interquartile range) 42.5 (32.0-47.5) years were studied. The median flow-mediated vasodilation was 3.6% (1.7%-7.7%). In patients with coronary calcification (n = 6), flow-mediated dilation was 2.1% (-0.42%-3.6%) compared with 4.0% (3.5%-8.3%) in those without (p = 0.12). There was no significant relationship between flow-mediated dilation and markers of disease activity, duration of disease, and cardiovascular risk factors. Lower flow-mediated dilation was associated with duration of corticosteroid therapy (RHO = -0.44, p = 0.05). CONCLUSIONS: In these preliminary results, endothelial dysfunction is associated with long-term exposure to corticosteroids.

The ability of the 2013 American College of Cardiology/American Heart Association cardiovascular risk score to identify rheumatoid arthritis patients with high coronary artery calcification scores.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have increased risk of atherosclerotic cardiovascular disease that is underestimated by the Framingham Risk Score (FRS). We undertook this study to test the hypothesis that the 2013 American College of Cardiology/American Heart Association (ACC/AHA) 10-year risk score would perform better than the FRS and the Reynolds Risk Score (RRS) in identifying RA patients known to have elevated cardiovascular risk based on high coronary artery calcification (CAC) scores. METHODS: Among 98 RA patients eligible for risk stratification using the ACC/AHA risk score, we identified 34 patients with high CAC (defined as ≥300 Agatston units or ≥75th percentile of expected coronary artery calcium for age, sex, and ethnicity) and compared the ability of the 10-year FRS, RRS, and ACC/AHA risk scores to correctly assign these patients to an elevated risk category. RESULTS: All 3 risk scores were higher in patients with high CAC (P < 0.05). The percentage of patients with high CAC correctly assigned to the elevated risk category was similar among the 3 scores (FRS 32%, RRS 32%, ACC/AHA risk score 41%) (P = 0.223). The C statistics for the FRS, RRS, and ACC/AHA risk score predicting the presence of high CAC were 0.65, 0.66, and 0.65, respectively. CONCLUSION: The ACC/AHA 10-year risk score does not offer any advantage compared to the traditional FRS and RRS in the identification of RA patients with elevated risk as determined by high CAC. The ACC/AHA risk score assigned almost 60% of patients with high CAC to a low risk category. Risk scores and standard risk prediction models used in the general population do not adequately identify many RA patients with elevated cardiovascular risk.