Comprehensive arginine metabolomics and peripheral vasodilatory capacity in rheumatoid arthritis: A monocentric cross-sectional study.

BACKGROUND: The relationship between plasma arginine metabolites influencing vascular homeostasis and peripheral vasodilatory capacity in rheumatoid arthritis (RA) patients is not known. METHODS: l-arginine (Arg), monomethyl-l-arginine (MMA), l-homoarginine (hArg), asymmetric dimethyl-l-arginine (ADMA), symmetric dimethyl-l-arginine, and l-citrulline (Cit) were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 164 RA patients and 100 age- and sex-matched healthy controls without previous cardiovascular events. Log-transformed reactive hyperemia index (Ln-RHI) evaluated by flow-mediated pulse amplitude tonometry (PAT, EndoPAT2000 device) was assessed as surrogate measure of peripheral vasodilatory capacity in RA patients. Ln-RHI values <0.51 indicated peripheral endothelial dysfunction (ED). The relationship between plasma arginine metabolite concentrations, RA descriptors and peripheral vasodilatory capacity was evaluated by bivariate correlation and regression analyses. RESULTS: Plasma ADMA concentrations were significantly higher, and plasma hArg concentrations significantly lower, in RA patients than in controls (0.53 ± 0.09 vs 0.465 ± 0.07 µmol/L and 1.50 ± 0.60 vs 1.924 ± 0.78 µmol/L, respectively; p < 0.001 for both comparisons). Bivariate correlation analysis demonstrated no significant correlation between arginine metabolites and disease descriptors. In regression analysis in RA patients, higher plasma ADMA concentrations were independently associated with presence of ED [OR(95% CI) = 77.3(1.478-4050.005), p = 0.031] and lower Ln-RHI [B coefficient(95% CI) = -0.57(-1.09 to -0.05), p = 0.032]. CONCLUSIONS: ADMA was significantly, albeit weakly, associated with impaired microcirculatory vasodilatory capacity and peripheral endothelial dysfunction in RA. This suggests an important pathophysiological role of this metabolite in the vascular alterations observed in this patient group.

Meta-analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in rheumatoid arthritis.

BACKGROUND: We conducted a meta-analysis to review the available evidence regarding the associations between peripheral blood neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the presence of rheumatoid arthritis (RA). METHODS: PubMed, Web of Science and Scopus, from inception to January 2018, were searched for studies reporting on NLR and PLR in RA in comparison with healthy subjects. Standardized mean difference (SMD) was calculated with a confidence interval (CI) of 95%. RESULTS: Thirteen NLR studies (1550 RA patients and 1128 healthy controls) and 8 PLR studies (380 RA patients and 305 healthy controls) were included in the meta-analysis. NLR and PLR were significantly higher in patients with RA when compared to controls (SMD = 0.79, 95% CI 0.55-1.03; P < 0.001 and SMD = 0.66, 95% CI 0.43-0.88; P < 0.001, respectively). CONCLUSIONS: The NLR and PLR are significantly associated with the presence of RA. Further studies are required to ascertain the potential clinical use of these simple and relatively inexpensive markers in RA diagnosis.

Crosstalk between Inflammation and Atherosclerosis in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Is There a Common Basis?

Cardiovascular disease is the leading cause of morbidity and mortality in patients with rheumatoid arthritis and systemic lupus erythematosus. Traditional cardiovascular risk factors, although present in lupus and rheumatoid arthritis, do not explain such a high burden of early cardiovascular disease in the context of these systemic connective tissue diseases. Over the past few years, our understanding of the pathophysiology of atherosclerosis has changed from it being a lipid-centric to an inflammation-centric process. In this review, we examine the pathogenesis of atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis, the two most common systemic connective tissue diseases, and consider them as emblematic models of the effect of chronic inflammation on the human body. We explore the roles of the inflammasome, cells of the innate and acquired immune system, neutrophils, macrophages, lymphocytes, chemokines and soluble pro-inflammatory cytokines in rheumatoid arthritis and systemic lupus erythematosus, and the roles of certain autoantigens and autoantibodies, such as oxidized low-density lipoprotein and beta2-glycoprotein, which may play a pathogenetic role in atherosclerosis progression.

Estimated 10-year cardiovascular risk in a large Italian cohort of rheumatoid arthritis patients: Data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group.

BACKGROUND: Several cardiovascular (CV) risk algorithms are available to predict CV events in the general population. However, their performance in patients with rheumatoid arthritis (RA) might differ from the general population. This cross-sectional multicentre study aimed to estimate the 10-year CV risk using two different algorithms in a large RA cohort and in patients with osteoarthritis (OA). METHODS: In a consecutive series of RA patients and matched OA controls without prior CV events, clinical and serologic data and traditional CV risk factors were recorded. The 10-year CV risk was assessed with the Systematic COronary Risk Evaluation (SCORE) and the "Progetto Cuore" algorithms. RESULTS: 1,467 RA patients and 342 OA subjects were included. RA patients were more frequently diabetic (9.9% vs 6.4%; p=0.04) and smokers (20.4% vs 12.5%; p=0.002) but had lower prevalence of obesity (15% vs 21%; p=0.003). Dyslipidaemia was more prevalent in OA (32.5% vs 21.7%; p<0.0001). The 10-year estimated CV risk was 1.6% (95%CI 1.3-1.9) in RA and 1.4% (95%CI 1.3-1.6) in OA (p=0.002) according to SCORE and 6.5% (95%CI 6.1-6.9) in RA and 4.4% (95%CI 3.9-5.1) in OA (p<0.001) according to "Progetto Cuore". Regardless of the score used, RA patients had a 3- to-4-fold increased 10-year risk of CV events compared to OA subjects. CONCLUSION: RA patients have a significantly higher 10-year risk of CV events than OA subjects. In addition to effective disease control and joint damage prevention, specific protective measures targeting modifiable traditional CV risk factors should be implemented in RA.

Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case-control study.

BACKGROUND: The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined. METHODS: The presence of moderate to severe steatosis was assessed, using liver ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup. RESULTS: The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p < 0.0001). After adjustment for sex, age, cholesterol, triglycerides, body mass index, waist, hypertension and smoke, rheumatoid arthritis remained significantly associated with moderate to severe steatosis [odds ratio (95% confidence interval) = 2.24 (1.31, 3.84); p = 0.003]. In the rheumatoid arthritis group, male sex, higher body mass index, higher triglycerides concentrations and higher cumulative dosage of methotrexate [odds ratio (95% confidence interval) = 1.11 (1.01, 1.23); p = 0.026] were significantly associated with moderate to severe steatosis, while systemic inflammation, disease activity, use of steroids and biologics were not. CONCLUSION: Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.

Diagnostic accuracy of different blood cells-derived indexes in rheumatoid arthritis: A cross-sectional study.

To evaluate the performance of different blood cells-derived indexes in the diagnosis of rheumatoid arthritis (RA).Neutrophil-to-lymphocyte ratio (NLR), lymphocyte to monocyte ratio, platelet to lymphocyte ratio (PLR), systemic inflammation response index (SIRI), and aggregate inflammation systemic index were calculated in 199 consecutive RA patients and 283 sex and age-matched controls (147 healthy donors and 136 patients with other rheumatic diseases). Area under the curve (AUCs), sensitivity and specificity were calculated to evaluate the accuracy of indexes in discriminating between RA and controls. Association between indexes and RA variables was explored by multiple linear regression analyses.Blood cells-derived indexes did not demonstrate good accuracy in differentiating RA from controls with lymphocyte to monocyte ratio, the index with the best diagnostic performance, having 63.6% of sensitivity and 65.3% specificity [AUC (95%CI) = 0.67 (0.62-0.72]. The accuracy of the indexes in differentiating RA from healthy donors was significantly higher than that (AUCs < 0.6 for all comparisons) differentiating RA from rheumatic diseases. In RA, SIRI and aggregate inflammation systemic index showed significant association with C-reactive protein and erythrocyte sedimentation rate.Our results do not support the use of blood cells-derived indexes for the diagnosis of RA, suggesting that they might reflect chronic inflammatory burden in rheumatic diseases rather than, specifically, in RA.

Meta-Analysis of Asymmetric Dimethylarginine Concentrations in Rheumatic Diseases.

Raised circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), have been reported in several rheumatic diseases (RDs). However, the strength of this relationship is unclear. Therefore, the aim of this systematic review and meta-analysis was to evaluate the magnitude and the robustness of the association between ADMA concentrations and RDs. We calculated standardized mean differences (SMD, with 95% confidence intervals, CI). Study heterogeneity was evaluated by meta-regressions and sensitivity analyses according to type of RDs, conventional cardiovascular risk factors, inflammatory markers, and type of ADMA assessment methodology. Thirty-seven studies with a total of 2,982 subjects (1,860 RDs patients and 1,122 healthy controls) were included in our meta-analysis. Pooled results showed that ADMA concentrations were significantly higher in patients with RDs than in healthy controls (SMD = 1.27 µmol/L, 95% CI 0.94-1.60 µmol/L; p < 0.001). However, the between-studies heterogeneity was high. Differences in ADMA concentrations between controls and RDs patients were not significantly associated with inflammatory markers, increasing age, lipid concentrations, body mass index, blood pressure, or methodology used to assess ADMA. Furthermore, subgroup analysis showed no difference across RDs. This meta-analysis showed that, in the context of significant between-study heterogeneity, circulating concentrations of ADMA are positively related to RDs.

Methotrexate therapy is not associated with increased liver stiffness and significant liver fibrosis in rheumatoid arthritis patients: A cross-sectional controlled study with real-time two-dimensional shear wave elastography.

OBJECTIVE: To explore the significance of the association between treatment with methotrexate (MTX) and liver stiffness in rheumatoid arthritis (RA) patients. METHODS: We enrolled 140 consecutive RA patients under MTX treatment (MTX-treated RA; mean treatment duration: 6.2 years; mean MTX cumulative dose: 4.67 g), 33 RA patients naive to MTX (MTX-naive RA) and 100 age and sex-matched healthy blood donors (HD). Liver stiffness was assessed by real time two-dimensional shear wave elastography, with values ≥7.1 Kilopascals (kPa) defining significant liver fibrosis. RESULTS: kPa values in HD (4.32 ±â€¯0.7) were lower than that in MTX-naive RA (4.92 ±â€¯0.8) and MTX-treated RA (4.85 ±â€¯0.9, p < .0005 for trend). On the contrary, the difference in kPa between MTX-naive and MTX-treated RA was not significant (p = .89). Similarly, liver stiffness was not significantly different across strata of cumulative MTX dose (4.95 ±â€¯0.7 kPa in MTX <1 g, 4.90 ±â€¯1.1 kPa in MTX 1-3 g and 4.80 ±â€¯0.9 in MTX >3 g, p = .610). Significant liver fibrosis was diagnosed in 4 patients in the MTX-treated RA (highest kPa value = 7.6; no liver function test abnormalities or clinical signs of hepatic failure) and in none in both the MTX-naive RA and HD groups (p = .145). CONCLUSION: Liver stiffness values, although within the normal range, are significantly higher in RA patients vs. controls, irrespective of MTX treatment. RA patients taking MTX do not have a higher prevalence of significant liver fibrosis when compared to MTX naive RA patients and the general population.